Pediatric Obesity Current Concepts 2018

Disease-a-Month ] (2018) ]]]–]]]
Contents lists available at ScienceDirect
Disease-a-Month
journal homepage: www.elsevier.com/locate/disamonth
Pediatric obesity: Current concepts

Donald E. Greydanus a,*, Marisha Agana a,
Manmohan K. Kamboj b, Saad Shebrain c,
Neelkamal Soares a, Ransome Eke d, Dilip R. Patel a
a
Department of Pediatric and Adolescent Medicine, Western Michigan University Homer Stryker M.D.
School of Medicine, Kalamazoo, MI 49008, USA
b
Section of Endocrinology, Metabolism and Diabetes, Nationwide Children’s Hospital, Columbus, OH,
USA
c
Department of Surgery, Western Michigan University, Homer Stryker M.D. School of Medicine,
Kalamazoo, MI, USA
d
Division of Epidemiology and Biostatistics, Department of Biomedical Sciences, Western Michigan
University Homer Stryker M.D. School of Medicine, Kalamazoo, MI, USA
a r t i c l e i n f o a bs t r a c t
This discussion reflects on concepts of obesity in children

Keywords: and adolescents in the early 21st century. It includes
Obesity reflections on its history, definition, epidemiology, diagnostic
Overweight perspectives, psychosocial considerations, musculoskeletal
Children complications, endocrine complications and principles of
Adolescents
management. In addition to emphasis on diet and exercise,
Pharmacology
research and clinical applications in the second decade of the
Bariatric Surgery
21st century emphasize the increasing use of pharmacother-
apy and bariatric surgery for adolescent and adult popula-
tions with critical problems of overweight and obesity. We
conclude with a discussion of future directions in pediatric
obesity management.
& 2018 Elsevier Inc. All rights reserved.
Introduction: Historical perspectives
The phenomenon of obesity is not a condition affecting just twenty-first century Homo sapiens
population. Obesity has been the object of public curiosity and concern since ancient times. Much of
*
Corresponding author.
E-mail address: Donald.greydanus@med.wmich.edu (D.E. Greydanus).
https://doi.org/10.1016/j.disamonth.2017.12.001
0011-5029/& 2018 Elsevier Inc. All rights reserved.
2 D.E. Greydanus et al. / Disease-a-Month ] (2018) ]]]–]]]
what is known about historical perspectives of obesity is interpreted from sculptures, drawings,
writings and discussions through the ages. This monograph begins with a brief historical perspective
on obesity in humans.
Ancient times
One of the earliest historical representations of obesity may be a large ivory figurine that was
unearthed from the basal Aurignacian deposits in the Swabian Jura of southwestern Germany that is
estimated at being 35,000 years old.1 The Venus of Willendorf is an ancient human figurine dated to
20-30 thousand years BC that depicts an overweight pregnant woman without an identifiable face
but representative of that time for beauty, fertility, health and high socioeconomic status.2
Other ancient artifacts depicting obesity have been discovered in various archeological
excavations around the world including the Venus of Berekhat Ram in the Golan Heights of Israel
and the Venus of Tan-Tan in Morocco; these works have been attributed to the Homo erectus
species.1 While fossilized remains of human predecessors do not seem to provide evidence of obese
beings in existence at that time period, the artifacts that show obese women in stone-age sculptures
possibly convey obesity as a fact of life for them.
In a recent anthropological review of cardiovascular disease among ancient Egyptian women
from 1570 BC, the investigators utilized computerized tomography scanning to visualize evidence of
vascular calcification as a manifestation of atherosclerosis.3 One of the Egyptian royalties, the
mummified body of Queen Hatshepsut (1507-1458 BC), has been found to have had pendulous
breasts that is postulated to be a marker for obesity and modern studies suggests she had diabetes
mellitus as well as bone cancer.1
The Greek mythological figure Pluto (Hades), the god of wealth, was often depicted as obese in
many great works of art. Writings of the French Rabbi Levi ben Gershon (1288-1344 AD) point to
infertility as a complication of obesity in Biblical stories of Sarah and Rachel (approximately 2000
BC) and one can infer a possible diagnosis of obesity-related polycystic ovarian syndrome as well.4 In
Christian Biblical religious works of art, a special group of angels known as cherubs were shown as
overtly obese young children. Even the rendition of the infant Jesus in the famous work of Lorenzo di
Credi (1459-1537), the Madonna and Child (1510), presents a cherubic” baby in the arms of the
mother Mary.4
Early physicians considered issues of obesity in relation to health risks as reflected in the writings
of Western medicine’s icons Hippocrates of Kos (460 BC-370 BC) and Galen of Pergamum (129 AD-
216 AD)5,6 These founders of Western medicine described complications or adverse effects of obesity
that included sexual dysfunction and infertility.1 Following this, various Western physicians from
circa 25 BC to the 9th century AD (Table 1) continued the discussion on obesity with reference to its
etiology, risks and potential treatment.7 These ancient physicians postulated that obesity resulted
from an imbalance in one of the four basic substances or humors of the body (black bile, yellow bile,
phlegm and blood).
Table 1
Key first century Western physicians with obesity reflections.
Aulus Cornelius Celsus (25 BC-50 AD

Dioscorides Pedanius (40-90 AD)
Rufus of Ephesus (80-150 AD)
Aretaeus of Cappadocia (81-138 AD)
Soranus of Ephesus (98 AD-138 AD
Galen of Pergamon (Aelius Galenus or Claudius Galenus–AD 129 – 216 AD)
Caelius Aurelianus (circa 400 AD)
Oribasius (325-403 AD)
Alexander Traillianus (Alexander of Tralles; 525-605 AD)
Aetius Amidenus (Aëtius of Amida—5th century AD)
Paulus of Aegina: 625-690 AD)
Theophilus Protospatharius (7th century AD)
Stephanus of Athens (7th Century AD)
D.E. Greydanus et al. / Disease-a-Month ] (2018) ]]]–]]] 3
These early clinicians considered obesity to be a pathological condition in need of urgent

remediation through fat reduction centered on purging, bleeding and blistering methods in the hope
of rebalancing these humors.6,7 Other treatment modalities that were introduced during the Greco-
Roman and early Byzantine periods represented the earliest form of a slimming diet collectively
known as the Mediterranean diet.8 This diet involves consumption of whole grains, fish, wine,
pomegranates, figs, walnuts and olive oil. They also espoused the idea of smaller portions of food
intake in proportion to physical activity or “exercise” taken validating the importance of frequent
smaller increments of food coupled with an active lifestyle as major factors in fat management.7
The Roman author Claudius Aelianus (170-235 AD) extensively described a person Dionysius of
Herclea of the 4th century BC as a lonely individual who resided in seclusion because of shame for his
large body.7 He developed significant breathing difficulty for which the physicians of his time
attempted to resolve by performing the first ever known form of liposuction: sticking long needles
into his redundant skin folds in the peri-abdominal region.7
Ancient Persian/Arabic clinicians
Perhaps the most extensive discussion of obesity before the advent of modern day medicine
comes from the Persian doctor, Muhammad ibn Zakariya al-Razi’s (854-925 AD) celebrated book, Al-
Hawi Fit-Tibb (An Encyclopaedia of Medicine), in which he critically evaluated all available
knowledge on obesity at that time.9 Al-Razi dismissed Galen’s idea that prolonged thinking and
mental activity would slim the obese while providing detailed documentation of his recommen-
dations for obesity management that included diet, drugs, exercise, massage, hydrotherapy and
lifestyle changes.9
Other well-known Persian/Arabic doctors who followed after Al-Razi and discussed obesity were
the Persian clinician Ibn Sina (Avicenna, 980-1037) and the Arabic clinician Ibn al Nafis (1210-1288).9
In Avicenna’s Canon in Medicine and Ibn al Nafis’ Al-Mujaz Fit-Tibb (The Concise Book of Medicine),
complications of obesity were noted including cardiovascular conditions as well as cerebrovascular
accidents along with respiratory and endocrine disorders.9
Obesity and the Renaissance
The French physician Jean Fernel (1497-1555) reported on the dangers of overeating in his
treatise, Universa Medicina, in which he noted that overeating led to an illness called morbum facit
with accumulation of material; he noted this would overwhelm blood vessels with resultant vessel
compression as well as rupture and subsequently lead to sudden death.10 Nicolaus Falcuccio
(Nicolaus Florentinus; died 1410) reminded his readers to abhor fat, “abhorreas pinguedinem”
because obesity he concluded would lead to epilepsy, paralysis, difficulty breathing, diarrhea,
fainting and hot fevers.10
Other Renaissance medical scholars such as Giovanni Argenterio (1513-1572) had predicted that
people who ate too much would have shorter lives and be more prone to infertility.10 The Italian
physician and philosopher, Girolamo Mercuriale (1530-1606), detailed in his 1585 book, De
decoratione liber, that obesity led to various problems including reduced mental capacity, apoplexy,
paralysis, asthma, syncope and infections.10
Seventeenth to nineteenth centuries
From the seventeenth century onwards, a great deal of medical literature was dedicated to
writing about the physiology, pathology and management of excessive fat metabolism in the human
body. In 1620 English physician Tobias Venner (1577-1660) was the first author to use obesity in a
medical context in his treatise, Via Recta ad Vitam Longam.11 Venner introduced three types of diet
that he noted could lead to attaining longevity and healthy life; these were the “accurate or precise”
diet, the “vulgar” diet and the “subvulgar” or in-between diet.11
In 1667 German physician and chemist, Johann Joachim Becher (1635-1682), influenced
clinicians of his era to utilize anti-phlogistic regimens of obesity based on Becher’s phlogiston
theory of combustion.11 The noted English physician often called the “English Hippocrates,” Thomas
Sydenham (1624-1689), wrote extensively on obesity, gout, exercise and nutrition for prevention as
well as cure of illnesses including obesity; he was a proponent of lifestyle change for better health.11
The prominent Scottish physician, George Cheyne (1671-1743), advocated for moderation in the
diet (advocate of vegetarianism) and physical activity as key factors for obesity management;
dealing with obesity himself, he championed the art of self-help by empowering his patients to take
control of their bodies.11 Cheyne was in agreement with Sydenham and other clinicians of this era
that the pathology of obesity required the use of laxatives and anti-emetics.10
The concept of abdominal obesity-associated premature death was championed by two noted
scholars, Giovanni Battista Morgagni (1682-1771) and William Wadd (1776-1829). Morgagni was
an Italian anatomist called the father of modern anatomical pathology who provided lengthy case
studies of obesity and emphasized the importance of abdominal adiposity.2,11 Wadd was a British
surgeon and medical writer who detailed graphic observations of post-mortem examination of an
obese patient.2,11
The concept of obesity as a medical disorder with negative consequences for vital organs was not
accepted by the general public until perhaps the 18th century partially due to the prominence of obesity
in wealthy persons including royalty.10 In his book, A Treatise on Man and the Development of His
Aptitudes, the Belgian astronomer and mathematician (statistician), Adolphe Quetelet (1796-1874),
introduced the Quetelet Index which is now known as the body mass index (BMI).12 Quetelet also
developed the table of average weight across specific ages based on a sample of Belgian men and women.
In 1846 British physician John Hutchinson (1811-1861), inventor of the spirometer, published his
reference table for the English population that was utilized by actuarial scientists of his times to
evaluate applicants for life insurance.12 Henry Clay Fish (1820-1877) was an American working for
the Mutual Life Insurance Company (MLIC) of New York City who published the 1867 book, The
Agent’s Manual of Life Assurance, for the American population that was adopted from the John
Hutchinson reference table for the English population.12
Twentieth century developments
American statistician Alfred James Lotka (1880-1949; born in the Ukraine) and Jewish American
statistician Louis Israel Dublin (1882-1969; born in Lithuania) devised the “ideal” weight concept to
reflect longevity using the three types of body frames (i.e., small, medium and large) which became
the national standards for “ideal” body weights.12 As the 20th century continued, The Society of
Actuaries collaborated with 26 insurance companies to publish the 1959 The Build and Blood Pressure
Study that revealed an association between body weight and cardiovascular disease; weight tables
from this 1959 publication replaced ideal weight with the term desirable weight.12
In 1973 the Fogarty International Center Conference on Obesity updated the MLIC 1959 “desirable
weight” tables with the term “acceptable range” of weights and a 1979 revision replaced tables of
height and weight with the term desirable weight.12 Through the years the World Health Organization
(WHO) has established the guidelines for defining overweight and obesity using the concept of body
mass index (BMI) which has been adapted by the Centers for Disease Control and Prevention (CDC)
in the United States.
Aside from the development of the BMI as an approximate measure to define overweight and
obesity, the twentieth century saw the urbanization of the world and the rise of global
industrialization.13 Standards of food consumption in the 20th century included highly processed
foods which are energy-dense and high in refined sugar, salt and saturated fat. Such foods reduced
cost, increased food safety and enhanced food texture, color as well as flavor. Unfortunately, such a
change also led to an increase in the global prevalence of obesity, diabetes and heart disease.14
Complicating this situation is that industry-funded food advertisements and marketing strategies
have impacted people’s choices for food that is especially impactful in children.13 As changes in
technology and lifestyle occurred, more children and youth are spending time in front of television
and computer screens. Hence, the vicious cycle continues with children and adolescents wanting
more processed food items they witness via television and computer advertising.
The obesity phenomenon of modern times has also brought about the demand for additional
treatment measures such as anti-obesity medications in addition to surgical procedures of last resort
for morbidly obese individuals.15 As previously noted ancient remedies for weight loss included
emetics and cathartics utilized during the ancient Greek and Roman times. The 20th century
introduced dinitrophenol as the first modern day anti-obesity drug that was used in 1933 to increase
fat metabolism through uncoupling oxidative phosphorylation. However, it was discontinued in
1938 due to its toxic hyperthermic effects.15
This anti-obesity drug was followed by use of amphetamine and its derivatives (i.e., sibutramine)
from the 1940s through the 1990s. Amphetamine is a neuroactive agent that acts on hypothalamic
receptors to release norepinephrine, dopamine and serotonin with resultant increase in central
nervous system (CNS) activity along with rise in resting energy expenditure; thus, there is a
resultant decrease in appetite and food intake leading to weight loss.15 Other anti-obesity
medications then followed and are considered later in this discussion followed by concepts of
bariatric surgery.15
Denouement: historical issues in obesity
The obesity phenomenon can be traced from ancient times to the present. Paleolithic Homo
erectus species depicted obesity as a component of their life with drawings and artifacts showing
obese figurines unearthed from ancient diggings all over the world.
Hippocrates (460 BC-370 BC) theorized that obesity was an excess of one of 4 humors in the body and
Galen (129 AD-216 AD) later advised on obesity treatment utilizing the earliest forms of lifestyle change
through diet moderation in conjunction with a physically active lifestyle. Medieval physicians sought
bodily evacuation to expunge excess fat through utilization of emetics and cathartics.
Modern developments in obesity research include the body mass index as a measure for obesity
that has been combined with the knowledge that obesity increases risks for cardiovascular disease
and other co-morbidities. Adding on to Hippocratic and Galenic doctrines of lifestyle change, 21st
century research is looking at anti-obesity medication and bariatric surgery. This document now
proceeds with consideration of modern views of obesity dealing with its definition, epidemiology,
diagnostic perspectives, complications and principles of management.
Definitions
The description of obesity and overweight has been limited through the centuries by the concept
that utilized terminology focused on weight and not fat.16 Synonyms in the medical literature for
this condition include fatness, corpulence, stoutness, portliness, plumpness, chubbiness, rotundity,
flabbiness and grossness. The actual definition of obesity by the Merriam-Webster dictionary is it is
“a condition characterized by the excessive accumulation and storage of fat in the body; obesity
affects not just the appearance, but the disease processes as well.”17
A current "proxy" for body composition estimate, the body mass index (BMI), is a measurement
of weight in relation to height.16,18 BMI is calculated by dividing an individual's weight in kilogram
by their height in meter squared. Overweight and obesity can be defined based on weight (Table 2)
Table 2
Obesity classified based on body mass index in adults.
Category BMI
Underweight Less than 18.5

Normal weight Between 18.5 and 24.9
Overweight or pre-obese Between 25 and 29.9
Obese in adults More than 30
Table 3
Obesity classified based on body mass index criteria in children and adolescent.
Category BMI percentile
Overweight BMI greater than or equal to 85th percentile for age and sex specific BMI
Class 1 obesity BMI greater than or equal to 95th percentile for age and sex
Class 2 obesity BMI greater than or equal to 120% of the 95th percentile or BMI greater than or equal to 35
Class 3 obesity BMI greater than or equal to 140% of the 95th percentile or BMI greater than or equal to 40
or more preferentially BMI (Table 3).16,18 The World Health Organization (WHO) has established
standards to be used in defining the condition of obesity and overweight for the past decade using
BMI as the basic index of measurement.
Serious limitations exist when estimating body composition, as BMI underestimates the body fat
percentage or adiposity levels in the population as a whole.16,18 Athletes with higher levels of muscle
(which is lean body mass) can have high BMI but do not necessarily meet official obesity standards.
The World Health Organization (WHO) classifies overweight and obesity as abnormal and refers to
them as having excessive fat accumulation in both adults and children but fails to directly measure
body fat.18
Body fat itself is difficult to calculate and track. Useful scientific tools for direct fat content
measurement include skinfold calipers, body fat scales measuring biometrical impedance analysis,
BOD POD (air displacement plethysmography), water displacements (very accurate method) and the
most accurate tool, DEXA (dual energy X-ray absorptiometry) scanning; however, they are far less
utilized in clinical practice.18,19
BMI is highly unreliable in children in lieu of body composition changes that occur in different
stages of growth and development. Healthy children demonstrate significant fluctuations in the
relationship between weight and height as they proceed from infancy through childhood and
adolescence.20 These gross differences are further compounded by the diversity encountered in
various ethnic and racial body compositions. In the United States the standards of weights, heights
and BMI as recommended by the WHO have been adapted by the National Institutes of Health (NIH)
and the CDC. These will remain the standard that are used as a valid “indirect” measure of excess fat
in children.
There are two current approaches for categorizing BMI that provide different BMI cut-off
thresholds; such modi operandi are taken from the World Health Organization and the International
Obesity Task Force (IOTF).18 Researchers have compared the results of the sensitivity (correctly
including children with cardiovascular risk factors) and specificity (correctly excluding children
without cardiovascular risk factors) of both paradigms. Evaluation of these comparisons reveals that
the IOTF criteria showed higher specificity, while the WHO criteria demonstrated higher
sensitivity.18 Thus, clinicians must weigh the benefits and consequences of over-treating patients
or missing true cases of obesity to determine which is more beneficial in the long-term. As the WHO
approach provides the highest estimates for potential disease, this is the more preferred method for
screening children but unfortunately will include more false positive cases.18
Epidemiology of obesity
Prevalence of obesity - Global perspective
Obesity is among the leading public health concerns affecting populations of all ages around the
world. In the past, obesity and overweight were described mostly as a problem with developed and
industrialized countries.21–23 Conversely, several recent epidemiological studies have reported a
substantial upsurge in the prevalence of obesity and overweight in both low- and middle-income
countries in the past two decades.22–25 Obesity is more prevalent among urban middle-aged adults
in low and middle-income countries; also, it is rapidly spreading to the younger age groups in
suburban and rural regions of these countries. Furthermore, data show that overweight and obesity
are progressively becoming a serious health problem across the globe that also affects low and
middle-income countries.22–25
Over the past three decades the world had seen a transition from a high prevalence of
underweight to a high prevalence of overweight and obesity in low- and middle-income countries;
this is also seen to a smaller extent in high-income countries. Evidence from data reveals a
remarkable increase in the prevalence of obesity in every country from 1975 to 2016, although this is
not statistically significant in high-income countries.26–29
It was not until recently that the global focus on obesity and the overweight epidemic has led to
the inclusion of adiposity as part of the global non-communicable disease (NCD) targets.
Importantly, there is a 2011 Global Action Plan developed by the World Health Organization to
target the prevention and control of non-communicable diseases; a major component of this plan is
to halt the rising prevalence of obesity by 2025.22,30,31
According to a 2016 World Health Organization (WHO) report, the estimated worldwide
prevalence of obesity (defined as BMI of greater than or equal to 30 kg/m2) among adults 18 years
and older was about 13% (650 million adults); this prevalence is approximately three-fold higher
than the prevalence noted in 1975 (105 million adults).32 This report reveals that over 1.9 billion
(39%) adults worldwide are overweight, with male and female distribution estimated at 39% and 40%
respectively. Several data have shown a high correlation between the dramatic rise in the rate of
obesity and the global increase in the prevalence of chronic health conditions including
cardiovascular diseases, type II diabetes and cancers in adults.33–39
It is estimated that more than 340 million children and adolescents between 5 and 19 years of
age are either obese (weight-for-height greater than 2 standard deviations above the WHO Child
Growth Standards median) or overweight (weight-for-height greater than 1 standard deviations
above WHO Child Growth Standards median).32 This indicates an alarming global increase in the
prevalence of obesity to 18% in 2016 from 4% in 1975 where an estimated 124 million children and
adolescents were affected. The report from the 2016 non-communicable disease (NCD) Risk Factor
collaboration study (relating pooled analysis of study data published from 1975 to 2016) reveal an
increase in the global age-standardized prevalence of obesity among children and adolescents aged
5–19 years of age.26,27
Among boys the rate increased from 0.9% (6 million) in 1975 to 7.8% (74 million) in 2016; whereas
among girls, the prevalence increased from 0.7% (5 million) in 1975 to 5·6% (50 million).26,27
Evidence from this study also suggests that these rates are expected to significantly exceed moderate
and severe underweight by 2022 if the post year 2000 obesity trend continues. This finding further
buttresses current growing attention on global childhood obesity, especially among children and
adolescents in low- and middle-income countries.
The number of children under 5 years of age with obesity (weight-for-height greater than
3 standard deviations above the WHO Child Growth Standards median) has increased by nearly 50%.
Compared to underweight, more deaths and morbidities have been reported among children and
adolescents with overweight and obesity. Unlike adult population with obesity, there is no
significant gender difference in the distribution of obesity or overweight among children and
adolescents.
Obesity in the United States
Compared to the rest of the world obesity remains highest in the United States.40,41 Reduction of
obesity and overweight has been the focus of most population health initiatives in the United States.
Between 2011 and 2014 obesity affected about 37% of adults as well as 17% of children and
adolescents within the age range of 2 to 19 years.42 Estimates from the 2007-2008 National Health
and Nutrition Examination Survey (NHANES) data indicate that obesity prevalence increased by over
100% and about 50% when compared to the 1976-1980 and 1988-1994 NHANES data, respectively.43
Obesity has also been shown to vary by gender, race/ethnicity and age group. It more common
among women (38%) than men (34%) and is higher among non-Hispanic Blacks (38%) and Hispanics
(39%) compared to non-Hispanic Whites (34%) and the non-Hispanic Asians (11%).40,42,44 Compared
to other age groups, there is a higher prevalence of obesity in age groups 20 to 39 years and 40 to 59
years and the increase in obesity is higher among adults than in children.45 Among children no
significant change in the prevalence of obesity has been reported in the latest publications and this
could imply that the obesity trend is stabilizing among children in the United States.27,31,32 Yet, it has
been projected that there would be a continued rise of obesity among adults by about 51% in 2030 if
this trend in the rise of obesity continues in the United States.45
Also notable in recent reports is the rapid rise of severe obesity which was rare in the 1970s. This rise
in severe obesity has been remarkably higher than the rate of obesity among the US population.43,46–51
Finkelstein and colleagues conducted a study between 2009 to 2010 using Behavioral Risk Factor
Surveillance System (BRFSS) data from 1990 through 2008; as a result they forecasted a 130% increase in
the prevalence of severe morbid obesity compared to 33% in the prevalence of obesity by the year 2030.43
Comparison of data from the USA and Canada, a neighboring high-income country, reveals that the United
States has a significantly higher prevalence of obesity than Canada among adults as well as in children and
adolescents across all genders.52,53
Social determinants of obesity
Social determinants of health are “the conditions in the environments in which people are born,
live, learn, work, play, worship and age that affect a wide range of health, functioning and quality-of-
life outcomes and risks”.54 The escalating toll of worldwide obesity in the low and middle-income
countries over the years is to a large degree influenced by epidemiologic transition such as the
demographic and socioeconomic transition in developing nations. With the growing urbanization
and industrialization in most low- and middle-income countries, there is a consequent change in
lifestyles predisposing this population to the high risk of obesity and other health effects associated
with obesity.
Another significant effect of globalization and economic growth in these regions is the blurring of
the socioeconomic divide between the rural and urban regions. There has been an enormous
transition from residential rural to urban patterns.55,56 The changing paradigm in socioeconomic and
nutritional motifs in the developing countries also influences health-related behaviors such as
unhealthy eating habit resulting in obesity.
Major risk factors associated with obesity in Western and high-income countries (such as the
United States and the United Kingdom) include consumption of energy-dense foods, the
preponderance of food desserts with limited healthy choices located in areas with lower
socioeconomic status and the significant reduction in physical activities (vida supra).57–64 Overall
the interaction of environmental and social factors plays a pivotal role in the global prevalence of
obesity. Creating social and physical environments that promote good health is one of the major
highlights of the U.S. CDC’s Healthy People 2020 stratagem in gearing towards addressing the social
determinants of health conditions including obesity.40,65
Obesity: diagnostic perspectives
It is important to keep in mind that obesity is a multifactorial entity that involves an interplay of
diverse conditions.66 Tables 2 and 3 provide BMI-based diagnostic criteria for using the terms
overweight and obesity in clinical practice.16,18 The anthropometric measurements of BMI cut-offs are
considered the prevailing diagnostic standards in clinical settings. Current research is showing that
the waist circumference to height ratio is a more accurate tool for obesity diagnosis and a better
prognosticator of associated health risks.67
The Task Force for Pediatric Obesity of the Endocrine Society has described obesity-associated
endocrine causes or syndromic conditions.68 Thus, it is also clinically critical to identify endocrine
and syndromic conditions that present with obesity in its differential diagnoses in order to manage
these specific conditions. Most of these endocrine etiologies for obesity are rare and are
accompanied by attenuated growth patterns as well as co-morbid conditions. The distinguishing
feature of endocrine-induced obesity is that stature and height velocities are decreased— as for
example, noted with growth hormone deficiency, hypothyroidism or Cushing syndrome.68 There is a
close association with earlier breast development, pubarche and menarche in girls; also, more
apparent in males with obesity is advanced skeletal development leading to increased growth rate
and delayed testicular development.
Physicians should test for endocrine causes of obesity when there is evidence of stunted growth
relative to the individual’s genetic potential and there is decreased growth velocity against the
backdrop of continued weight gain.68–77 Endocrine complications of obesity (i.e., polycystic ovary
syndrome, diabetes mellitus, other) are reviewed later in this discussion and genetic syndromes
associated with obesity are noted in Table 4.68–77
Obesity: medical history perspectives
Along with BMI criteria, a careful and detailed evaluation of obesity should include certain
specific aspects of the medical history (Table 5). The clinician should remember that an extensive
dietary intake history and level of physical activity are two of the most important determinants of
pediatric obesity development.78 Since the use of BMI as an approximate measure of body fat
content, clinicians typically do not anecdotally diagnose obesity in one who appears heavier than
other children in his or her age level but may be taller and have advanced bone age. Table 6 provides
features that may be found in obese children as well.
Laboratory perspectives in obesity
There are laboratory and radiographic tests that can confirm the presence or absence of co-
morbid conditions associated with obesity. The standard laboratory studies for evaluation of obesity
Table 4
Genetic syndromes associated with obesity.
Syndrome Key features Genetics
Bardet-Biedl Vison loss, obesity, intellectual disability, learning problems, AR

syndrome genitourinary abnormalities
Prader-Willi Hypotonia, hyperphagia, mild to moderate intellectual disability, AD
syndrome behavioral problems, narrow forehead, almond shaped eyes,
downward mouth, short stature, small hands and feet, fair skin and
light colored hair, delayed puberty
Alström syndrome Cone rod dystrophy resulting in blindness, progressive hearing AR
impairment, cardiomyopathy, metabolic defects, progressive
pulmonary, hepatic and renal dysfunction
Albright syndrome Short stature, obesity, round face, subcutaneous ossifications, AD
brachydactyly, impaired olfaction, resistance to parathyroid hormone
and thyroid stimulating hormone
Carpenter Craniosynostosis, abnormalities of fingers and toes, congenital heart RAB23 gene
syndrome defects, cryptorchidism in males MEFGF8 gene
Rubinstein-Taybi Broad thumbs and toes, short stature, convex nasal ridge, down AD
syndrome slanting palpebral fissures, hypertelorism, high arched palate, varying CREBBP gene
degrees of intellectual disability EP300 gene
Fragile X syndrome Usually males with range of developmental and intellectual learning FMR1
problems, long and narrow face, large ears, prominent jaws and
forehead, enlarged testicles
Börjeson- Intellectual disability, epilepsy, microcephaly, short stature, X linked
Forssmann- gynecomastia, hypogonadism, obesity, tapering fingers and short
Lehman toes, impaired vision, nystagmus, cataracts, hyperopia, coarse facial
syndrome features, ptosis, large and long ears, supraorbital ridge
MOMO syndrome Macrosomia, obesity, macrocrania, ocular abnormalities,
cryptorchidism, hepatosplenomegaly, hypertelorism, down slanting
palpebral fissures, prominent forehead, broad nasal root
Table 5
History of specific relevance in pediatric obesity evaluation.
1. Patient’s family history especially of obesity and weight-related health problems such as diabetes, hypertension and
hyperlipidemia;
2. The child’s dietary habits from infancy to current, and in context of family cultural dietary practices;
3. The child’s activity level;
4. Other concurrent health conditions of the child;
5. Psychosocial history including events surrounding depression, sleep disturbances, presence or absence of friends
and school situations involving bullying;
6. Social and physical environmental issues such as exposure to chemicals and toxins
include those listed in Table 7.19,78 These preliminary tests are also good screening tools to aid in
finding children and adolescents with a pre-diabetes mellitus condition or the metabolic syndrome.
The Task Force for Pediatric Obesity of the Endocrine Society also suggests testing for polycystic
ovarian syndrome with free and total testosterone levels (vida infra), obstructive sleep apnea (in the
presence of a positive family history) with nocturnal polysomnography or overnight oximetry and
psychiatric conditions (if there is a positive family history).68
There are biological markers of altered fat metabolism and inflammation that are being utilized
in obesity research studies and these include C-reactive protein (CRP), adiponectin (an
adipocytokine which is produced primarily in adipose tissue), and leptin (the “satiety”
hormone).79–82 There are other less known biological markers that include gut intestinal peptides
(i.e, GLP-1 and GLP-2) which promote satiety, inhibit gastric emptying and regulate lipid
metabolism.79 However, little relevant clinical data is available on these tests in pediatric
populations at this time.
Finally, there are various epigenetic gene markers that are on the horizon of obesity research and
include the obesity-related gene (FTOrs9939609), melanocortin-4 receptor (MC4R) and FLJ35779
(rs2112347).79 As genetic engineering becomes successful in identifying the particular locus in the
chromosome that is turned on or off in the expression of excessive amount of fat accumulation in
humans, genetic testing may be the future method of paramount importance in obesity diagnosis.
Radiographic perspectives
Radiographic imaging for obesity in children is exclusively utilized for an accurate assessment of
fatty deposition through the dual energy x-ray absorptiometry (DEXA) scan. It is a type of
radiographic study that primarily measures bone mineral density. Also, DEXA scanning can be used
to measure total body composition and fat content with a high degree of accuracy because it can
differentiate between fat mass (FM) and lean tissue mass (LTM); such diagnostic demarcation is
particularly important since visceral FM has been discovered as a strong predictor of adverse
obesity-related health events.83
Computed tomography (CT) has recently emerged as an option for bariatric imaging because of
the modifications made by manufacturers to accommodate bigger and heavier patients weighing
more than 205 kg (450 lb).84 Not only are these CT table loads bigger and wider, the apertures of
Table 6
Features that may be found in obesity.
Disproportionately fine facial features

Adiposity of mammary glands in males
Pendulous striated abdomen
External genitalia of boys appearing disproportionately small in size because of excessive fat accumulation in the
pubic area
Shorter stature than average
Excessive fat accumulation around the extremities especially in the arms and thighs
Small hands and fingers
Genu valgum
Table 7
Laboratory testing in obesity evaluation.
Fasting glucose
Hemoglobin A1c
Liver function studies (AST [aspartate transaminase], albumin, others)
Thyroid function tests (TSH, free T4, others)
Fasting lipid panel (fasting cholesterol, triglycerides and high density lipoprotein cholesterol)
Others
newer models have become larger (4 85 cm). Nevertheless, CT bariatric imaging is currently
relegated to tertiary centers. In order to identify a more cost-effective measure to evaluate obesity in
children, a recent study concluded that the medial longitudinal arch height (MLA), which serves as a
main reference for diagnosis of flat feet in children, also correlated well with obesity by measuring
the footprint angle (FA) as well as the Chippaux-Smirak index (CSI) and comparing their mean
values between the normal-weight group and obese group.85
Psychosocial perspectives
Childhood obesity has been known to have wide-ranging health consequences, including both
physical and psychological effects.86 The psychological effects of being obese or overweight on the
child as well as the adolescent is now considered as well as the impact of psychosocial and
psychological factors on obesity; in this regard, it is important to understand that some effects may
be bidirectional. There also can be biological or genetic influences that result in the co-occurrence of
obesity and psychological conditions. As seen with physical health outcomes, many of the
psychological outcomes of childhood obesity last for years and often into adulthood.87,88
Obese individuals often struggle in their transition from adolescence to young adulthood with
factors such as interpersonal relationships, friendships, social support, other relationships and
physical as well as verbal victimization.89 Childhood obesity has been associated with increased risk
for adult depression and lasting effects can be seen decades later, especially in women with higher
rates of depression and lower psychological well-being.90,91
Impact of psychological and psychosocial factors on obesity
Factors that impact obesity throughout childhood include family characteristics (i.e., stress,
parenting styles) and child characteristics (i.e., temperament, stress). Maternal stress can have an
impact on childhood obesity starting during the prenatal stage.92 In addition, infant feeding styles
are also impacted by maternal stress, anxiety and depression.93 A cascading sequence of events is
hypothesized to explain prenatal maternal depression impact on child obesity starting with less
positive parenting behaviors during infancy, leading to lower levels of child regulation during
toddlerhood, rather than having a direct impact.94
Parenting styles such as authoritarian and indulgent rearing techniques have been linked to
increased risk of obesity among children and adolescents.95 Child feeding practices can also affect
child food preferences and intake; these include modeling eating behaviors as well as using
coercion, punishment, rewards and/or restriction for foods or meals. Maternal stress as children get
older has been associated with controlling feeding practices, which have a negative impact on and
contribute to childhood overweight and obesity.95,96 Parental stress has also been linked with
obesity-risk behaviors in children such as fast food consumption and television viewing.97
Family stress also impacts cognitive stimulation and emotional support in younger children and
is associated with increased weight; also, parental mental health problems and financial strain are
predictive of overweight conditions for older children.98 These are likely mediated behaviorally
through unhealthy eating patterns and/or a lack of physical activity in youth; also, biological
influence is noted through increase in cortisol levels in the child or adolescent, resulting in a
greater risk of weight gain.99 One particular form of family stress (i.e., marital conflict) is
significantly related to disordered eating with child emotional insecurity and anxiety mediating
the association.100
Individual temperament can play a role, as children with a difficult temperament may increase
the risk of emotional eating.101 Temperamental factors continue to play a role as children get older
especially when combined with maternal sensitivity (goodness-of-fit), in which child temperament
and parenting style jointly play a role in the development (or prevention) of becoming overweight or
obese.102
Similar to family stress, chronic stress in children and adolescents may lead to increased food
intake, greater emotional eating and decreased physical activity.97 Stress is hypothesized to be
mediated through the cortisol and catecholamine systems, though the exact direct mechanism is
unclear.103 Adverse childhood experiences (ACEs) such as neglect and poverty cumulatively can
increase the risk of obesity in children.104 Some stressors have long-lasting impacts, as in the case of
child abuse (physical, emotional, sexual) which has been significantly associated with adult
obesity.105
Depression has a persisting effect on obesity, with depression occurring by early adolescence
predicting the development of obesity in late adolescence among females more than males.106 The
pathway from depression to obesity could be through symptoms related to obesity-risk (i.e.,
increased appetite, unhealthy food choices, reduced sleep, reduced physical activity) and
antidepressant medication side-effects.106 There is also emerging evidence that the pathway is
not only behavioral but also biological—through increased insulin resistance.107 Impulsivity is
indirectly correlated with obesity through lower perceived self-regulatory success in dieting with
high motor impulsivity.108 Apart from poor inhibitory control, reward sensitivity seen in impulsive
behavior has also been linked to childhood obesity.109
Impact of obesity on psychological functioning
Obesity is known to have significant psychological impact in childhood; this impact is often not a
direct association but depends on other mediating factors such as age, gender, race and ethnicity.110
Obese children and adolescents are often targets of societal stigmatization (including verbal and
physical bullying) from peers, educators, other and even parents. Biased attitudes toward
overweight peers can begin as young as preschool, increase through grade school and plateau at
a high rate during adolescence and young adulthood.111,112 Obese children are at increased risk for
being targets of teasing and bullying which is mainly weight-related but also non weight-related
with victimization peaking in adolescence.113
A bidirectional effect is seen with weight-related teasing serving as a significant risk factor for the
development of psychosocial problems, peer rejection and later eating disorders, depression and
unhealthy weight-control behaviors.114 Stigmatization includes ostracism (neglect and rejection) by
peers, lower “liked” status and fewer friendships (particularly for obese adolescents) which increases
with higher weights. In response, obese children tend to experience greater levels of loneliness.115
Additionally, body dissatisfaction is higher in obese children (particularly girls) and this is found
to be associated with weight-based teasing.116 Obese children are more likely to have lower self-
esteem, self-worth and self-competence than non-obese peers; however, girls have more negative
perceptions of their physical appearance, self-worth and social acceptance than boys.117 Older
children report significant reduction in self-esteem related to physical appearance than younger
children.118
Obesity places children and adolescents at risk for various affective disorders with psychosocial
factors again playing a mediating role. Obesity can lead to depression due to impacts of weight
stigma, poor self-esteem and/or functional impairments; children are particularly vulnerable in this
regard since early onset may impact psychological and behavioral function over a longer term.106
Obese children are reported to have more behavioral issues than non-obese children and weight is
directly related to behavioral problems at younger ages as well as peer relationship problems in
older children.119
While the research has not found a definitive causal relationship, obesity is associated with
greater alcohol use, and obese adolescents are more likely to initiate smoking and become regular
smokers. This is thought to be mediated by the negative psychosocial contexts obese adolescents
may be experiencing and the peer group they keep, as well as a way to increase social acceptance
and self-medication to decrease negative emotions.120
Conclusion: psychosocial issues
Obesity in childhood and adolescence is associated with several negative psychological outcomes
which can persist over a long time and even into adulthood. Additionally, certain psychosocial
situations and psychological factors are associated with the development of obesity in children and
adolescents. This information is important to consider when developing obesity-related intervention
programs and for public health purposes. It additionally provides the clinician a framework to apply
biopsychosocial principles when managing children and adolescents with obesity.
Musculoskeletal considerations
Overweight and obesity in children and adolescents is associated with multiple musculoskeletal
concerns (Table 8).121 The developing musculoskeletal system in children and adolescent is
especially vulnerable to increased stress from such weight-related conditions. Excessive weight
imparts increased compressive forces on the growing bones and growth plates. Such compressive
forces that are sustained over time have been shown to cause multiple osteo-articular abnormalities
in 50% of obese children and adolescents. The excessive forces across joints, articular surfaces and
epiphyses have been shown to contribute to the increased incidence of certain conditions seen in
obese children and adolescents such as Blount disease, slipped capital femoral epiphysis and
increased kyphosis (Table 8).121
A higher prevalence of musculoskeletal pain is reported in obese children and adolescents. Also,
there is an increased incidence of lower back pain, shoulder pain, foot pain and knee pain in obese
children and adolescents.121 Implicated contributing factors for increased incidence of musculoske-
letal pain in obese children include altered musculoskeletal biomechanics, increased forces across
joints, poor coordination, altered gait pattern, lack of physical activity and poor conditioning. Obese
children are more likely to be obese adults and carry an increased risk for osteoarthritis as adults.
Fracture risks
An increased incidence of fractures, especially of the spine and upper extremity has been
reported in obese children.121,122 This is in contrast to adults, in whom obesity is not associated with
an increased incidence of fractures. Although there is a positive correlation with obesity and bone
mineral density, it is hypothesized that altered biomechanics in obese children may partly explain
increased risk for fractures. Treatment of fractures in obese children is also complicated. For
example, closed fracture reduction is difficult with excessive fat tissue around fracture sites.
Excessive fat impedes access to fracture sites and makes splinting or cast immobilization difficult.
Table 8
Musculoskeletal concerns in obese children and adolescents.
1. Increased incidence of specific conditions: Blount disease, kyphosis, slipped femoral capital epiphysis
2. Increased risks for fractures of extremities and spine
3. Difficulties with anesthesia and airway management
4. Difficulties with management of musculoskeletal trauma
5. Increased post-operative risks
6. Higher prevalence of musculoskeletal pain
Special surgical hardware and operative techniques may be required to treat major extremity
fractures in obese children, as for example treatment of femur fracture.
Post-operative risks
Risks and complications associated with surgical procedures are also higher in obese and
overweight children and adolescents.122 For anesthesia, special considerations are needed in terms
of induction, intubation, airway maintenance, choice of anesthetics and post-operative care. Airway
and neck anatomy in obese patient pose technical challenges in airway management. There is a
higher risk for hypoxemic episodes in obese patients post-operatively. Obese patients with multiple
trauma are also at higher risks for infections and multi-organ failure.
Endocrine conditions associated with obesity
There are multiple health conditions that may be associated with obesity. Many of these are
results and complications of obesity, while other conditions are found as an association with an
elevated body mass index. In addition, there are other clinical scenarios where obesity may result
from another underlying condition and still others where it may be difficult to discern the cause and
effect relationship. In the context of this section we will focus on a few of these important endocrine
conditions (Tables 4 and 9).
Polycystic ovarian syndrome (PCOS)
Polycystic ovarian syndrome (PCOS) is the most common endocrine condition noted in women
with a variable prevalence of about 4-12 %.123 It is a heterogeneous, multi-systemic condition that is
associated with significant morbidity and is a common cause of impaired reproductive health in
these persons. Other important associations in PCOS include obesity (although PCOS is seen in non-
obese women as well), metabolic syndrome, cardiovascular heart disease, increased oncologic risk
and psychosocial dysfunction.124,125 The need for more research is well recognized in almost all
aspects of PCOS including underlying etiopathogenesis, diagnostic criteria and recommendations for
therapy—especially in adolescents. Over the last few years more evidence- based expert
recommendations have become available for PCOS diagnosis and management.126–128
Table 9
Endocrine conditions associated with overweight and obesity.
Polycystic Ovarian Syndrome/Ovarian hyperandrogenism
Dysregulation of glucose and insulin metabolism:

• Hyperinsulinemia and insulin resistance
• Impaired glucose tolerance or prediabetes
• Metabolic syndrome
• Type 2 diabetes mellitus:
Endocrine conditions associated with Obesity:
o Hypothyroidism
o Hypercortisolemia
o Growth hormone deficiency
o Pseudohypoparathyroidism
Genetic syndromes associated with obesity (Table 4)
o Turner syndrome
o Prader-Willi syndrome
o Beckwith-Wiedemann syndrome
o Bardet-Biedl syndrome
Down syndrome
PCOS is believed to result from an underlying genetic predisposition with an additional effect of
environmental factors. A number of pathophysiologic changes are noted including dysregulation of
gonadotropin secretion and hyperandrogenism as well as hyperinsulinemia and insulin resistance;
also, there is a very common association with obesity.129 A spectrum of dysfunction in various
multiple hormone axes results in the heterogenous presentation of PCOS and consequently, the
diagnosis of PCOS becomes challenging for clinicians.
In adults with PCOS there are a number of well-established sets of diagnostic criteria that are
available. These are the National Institute of Health (NIH) criteria, the Rotterdam criteria, the
Androgen Excess and PCOS Society criteria and additional guidelines from The NIH Evidence –based
Methodology workshop on PCOS.124 Although there is lack of consensus among these various
criteria, the clinical/biochemical evidence of androgen excess and manifestations of ovulatory
dysfunction are essential in all sets of criteria.130–133
There are no specific criteria available for use in adolescents and typically these same set of
criteria have been variably used in adolescents. However, there are some basic challenges in doing
such a combination that includes physiologic anovulatory periods in the first 2 years after menarche,
the overlap of normal adolescent ovarian morphology with that of PCOS ovarian morphology and
the presence of acne in normal pubertal age group. In addition, the normal ranges for free
testosterone are not well defined in this young age group.134–136
In order to address these well recognized concerns about the diagnostic quandary of PCOS in
adolescents, a recent consensus statement has been published by experts and include these
recommendations regarding PCOS in adolescent females131:
• Irregular menstrual periods: the consensus group concluded that the majority of these adolescents
establish a menstrual pattern with a 20 to 45-day interval by 2 years after menarche and failure to
do so is evidence of oligo-anovulation. However, menstrual patterns with intervals longer than 90
days consecutively are uncommon even during the 2 years after menarche and should be
investigated. Also, lack of menarche by 15 years of age or 2-3 years post-thelarche should also be
evaluated.126
• Evidence of hyperandrogenemia: Isolated mild hirsutism in early post-menarchal years may be
normal; however, moderate to severe hirsutism and persistent acne should be considered as
clinical evidence of hyperandrogenemia. Biochemical hyperandrogenemia is indicated by
persistent elevation of serum testosterone (free and total) as tested in a reliable reference
laboratory.126
• Polycystic ovarian morphology (PCOM): The data around a diagnosis of PCOM is unclear and the
criteria for this diagnosis are not well established. As per the consensus group, an ovarian volume
of more than 12 ml may be considered as evidence of ovarian enlargement; however, follicle
counts and a multi-follicular ovarian morphology should not be used for defining PCOM in
adolescents.126 There are challenges around adequate assessment with abdominal ultrasonog-
raphy in obese adolescents and this may be deferred in routine evaluation in these girls. In the
absence of menstrual period abnormalities and anti-Müllerian hormone levels, PCOM morphol-
ogy should not be used for the diagnosis of PCOM.126
• Other diagnostic issues: It is also extremely important to understand that all other causes of
androgen excess and amenorrhea be excluded with a detailed history, physical examination and
appropriate laboratory testing as needed. It is well recognized that hyperinsulinemia and insulin
resistance are prevalent in adolescents with PCOS but they should be used only for evaluation of
comorbidities and not as diagnostic measures for PCOS.126
• Other considerations: Since currently available research data is limited, it is recommended that,
though all efforts should be made to diagnose and treat PCOS in adolescent girls, it is also
important to avoid overtreatment of PCOS as well.
PCOS diagnostic considerations

In a diagnostic (clinical and biochemical) evaluation, a detailed history should be elicited to
evaluate for typical features of PCOS; these include menstrual pattern irregularity, hirsutism, acne,
history of pubertal development as well as progression and menarche. Symptomatology

suggestive of other causes for such PCOS features (i.e., irregular menstrual periods/amenorrhea,
hirsutism, virilization or acne) should be evaluated; this includes the potential history of any intake
of relevant medications such as androgenic steroids, anti-seizure medications and oral contraceptive
pills.
Clinicians should be cognizant of other disorders that can result in PCOS findings; these include
hyperprolactinemia, thyroid dysfunction, hypercortisolemia, congenital adrenal hyperplasia (CAH)
and androgen-producing neoplasms. The physical examination may supplement historical details,
evaluate for severity of hirsutism as well as acne and assess for evidence of hyperprolactinemia,
obesity, acanthosis nigricans, hyperinsulinemia and insulin resistance.137
A tiered approach may be used to corroborate the clinical findings with appropriate laboratory
testing. Initial laboratory testing should corroborate hyperandrogenemia and exclude other
important causes of the clinical presentation such as pregnancy, CAH, androgen-producing
neoplasms and hyperprolactinemia as well as evaluate the glycemic control. Total/ free testosterone
testing is recommended to evaluate for high androgen levels. Other first-tier tests include DHEAS
(dehydroepiandrosterone sulfate) for adrenal androgens, morning 17-hydroxy- progesterone as a
screening test for CAH (secondary to 21 hydroxylase deficiency), prolactin level to exclude
hyperprolactinemia, pregnancy testing and thyroid function testing to evaluate for thyroid function
status.137
Further testing may be needed to exclude other causes as needed; these include ACTH
stimulation testing for CAH; 12 MN (midnight) salivary cortisol, 24-hour urine free cortisol, and/or a
dexamethasone suppression test for hypercortisolemia. Others that may needed for evaluation of
glycemic status include blood glucose, hemoglobin A1c or a 2-hour glucose tolerance test. Pelvic
ultrasonography is not recommended for routine evaluation but may be undertaken depending on
specific presentation.138 However, some experts feel that it should be done in all girls presenting
with PCOS.139
PCOS Therapeutic management

The therapeutic options for girls with PCOS will need to be individualized to address the specific
needs of each patient. The overall goals of therapy are to address the multi-systemic needs of these
patients. The therapeutic options are listed as follows:
• Lifestyle modifications and weight control strategies: Implementation of a healthy lifestyle to

achieve weight stabilization and weight loss remain the treatment of choice for addressing
concerns with obesity in PCOS. Improvement has been demonstrated in menstrual period
regularity, hyperandrogenemia, hyperinsulinemia as well as insulin resistance and in the
cardiometabolic risks.140–142
• Treatment of hyperandrogenemia and menstrual irregularity: The medical treatment of first choice
for addressing many of the clinical and biochemical features of PCOS is the combined oral
contraceptive pill (OCP).128 There is a broad range of options available for OCPs and these
preparations consist of an estrogen combined with a progestin component. The estrogen
component reduces the androgen production from the ovary and also increases the production of
sex hormone binding globulin, thereby effectively lowering the free testosterone levels. The
progestin component prevents endometrial hyperplasia and thereby decreases future risks of
endometrial cancer.128,137
• Additionally, OCPs offer contraception as well for these adolescents. The high androgen levels are
noted to normalize in 1-3 months and may be re-measured to show effectiveness of treatment in
PCOS after that time. OCPs are effective in management of all patterns of menstrual irregularity
that may be seen in PCOS including amenorrhea, oligomenorrhea, menorrhagia and abnormal
uterine bleeding.128,143 The duration of therapy with OCPs is not well defined; some clinicians
suggest use of OCPs for about 2 years followed by a trial off period of 6 months and observing the
regulation of subsequent menstrual patterns. However, this will need to be balanced against risk
of pregnancy in individual cases. Other less common options that may be used in specific cases
include progestin-only preparations; gonadotropin releasing hormone (GnRH) agonists and

glucocorticoids.
• Treatment of hirsutism: OCPs are also the drug of choice for treatment of cutaneous manifestations
of PCOS including hirsutism and acne. Antiandrogens may be used as an adjuvant with OCPs if the
response is inadequate with OCPs alone.143 Antiandrogen agents that are used include
spironolactone, cyproterone acetate, flutamide and finasteride. Spironolactone is the most
commonly used medication and is a relatively safe as well as somewhat effective option. The other
agents are less commonly used and have side effects that will need to be closely monitored.
Metformin has been shown be effective in hirsutism as well.144 These young women may need
additional temporary cosmetic measures for hirsutism with use of laser hair removal, electrolysis,
threading plus waxing and topical pharmacologic options such as eflornithine.
• Treatment of acne: OCPs are also quite effective for acne treatment. Additional measures in
consultation with dermatologists include adequate cleansing agents, topical agents with salicylic
acid, antibiotics, benzoyl peroxide, retinoids, chemical peels and/or laser therapy.
• Therapeutic options for hyperinsulinemia, insulin resistance, prediabetes: These include lifestyle
modifications as discussed in this publication in order to achieve weight control and weight loss
leading to improvement of hyperinsulinemia and insulin resistance.
Diabetes mellitus
Associated with obesity is dysregulation of glucose and insulin with a spectrum of

hyperinsulinemia, insulin resistance, prediabetes and type 2 diabetes mellitus (T2DM). Diabetes
mellitus (DM) is a multi-systemic, chronic, metabolic condition characterized primarily by
hyperglycemia secondary to insulin deficiency, insulin resistance or both. Type 1 diabetes mellitus
(T1DM) is the most common type of diabetes seen in children as well as adolescents and is caused by
autoimmune or non-autoimmune destruction of the pancreatic beta cells resulting in insulin
deficiency.
Type 2 diabetes mellitus (T2DM) is typically non-autoimmune and initially results from insulin
resistance followed by progressive impaired insulin secretion as well. Patients with T1DM may not
be obese but an increased prevalence of overweight and obesity is being noted in these patients as
well that is consistent with the overall increase in prevalence of obesity identified in the general
population (vide supra).21–32
On the other hand, patients with T2DM generally have elevated BMIs and acanthosis nigricans as
a reflection of insulin resistance. It is now well recognized that there may be an overlap of clinical
and biochemical characteristics between these two entities; indeed, it may be challenging at times
to differentiate between particular types of diabetes mellitus. T2DM is believed to be caused by a
complex interplay of genetic influences (polygenic) and environmental factors.
T2DM is more common in certain ethnic groups. In the United States, in contrast to the general
population, a higher prevalence is noted in Native Americans, African-Americans, Hispanics, Asian-
Americans and Pacific Islanders. It is also noted that during adolescence, girls have a 1.3-1.7 times
the risk of developing T2DM than boys145,146 Research data (2015) from U.S. Centers for Disease
Control and Prevention (CDC) indicated that 23.1 million people or 7.2% of the population in the
United States (USA) had a diagnosis of diabetes mellitus.147 Of this number, 132,000 were in the age
group below 18 years and about 5% of the total number of people with DM were estimated to have
T1DM.147
DM may develop quite insidiously and patients may be asymptomatic. There are various typical
clinical presenting features that many times are noted retrospectively; these include polyuria,
nocturnal enuresis, polydipsia and weight loss—generally along with elevated BMI and acanthosis
nigricans. Glycosuria or hyperglycemia may be inadvertently found on laboratory testing done for
other reasons. Less commonly, patients with T2DM may also present in diabetic ketoacidosis (DKA)
or with a hyperglycemic hyperosmolar state (HHS). The diagnostic criteria for diagnosis of DM
include blood glucose measurements as noted in Table 10 in the presence of symptoms suggesting
diabetes mellitus.148
Table 10
Diagnostic blood glucose measurements (see text)148.
1. Fasting blood glucose of ≥ 126 mg/dL;

2. Random or 2-hour postprandial (after 75 grams glucose/adjusted for body weight or a heavy mixed meal) blood
glucose of ≥ 200 mg/dL as tested on two separate occasions;
3. Glycated hemoglobin (HbA1c) ≥ 6.4%
Patients with obesity more commonly may have prediabetes that is diagnosed with impaired
fasting glucose ≥ 100 mg/dl, impaired glucose tolerance with a 2-hour post prandial glucose ≥ 140
mg/dl, and/or HbA1c ≥ 5.7 - 6.4%. If these test levels are found along with the presence of
prediabetes, there is a higher risk for developing T2DM. If an adolescent has evidence of prediabetes,
annual screening is recommended unless other symptoms suspicious of DM are noted before that
time. The American Diabetes Association recommends screening of asymptomatic children/
adolescents at age 10 years or at onset of puberty (whichever comes first) if they meet any of the
criteria noted in Table 11.148
The treatment modalities for T2DM include healthy life-style modifications for weight control
and loss; insulin may be used if needed. Oral medications include metformin (only medication
approved for T2DM in younger than 16 years of age) and other oral hypoglycemic agents such as
thiazolidinedione and sulfonylureas (not approved in children less than 16 years of age). A tiered
approach is generally used based on initial presentation, response to dietary changes, exercise, oral
medications and level of glycemic control. There is a high prevalence of long term microvascular and
macrovascular complications in T2DM. It is important to maintain adequate glycemic control to
mitigate long-term complications of DM.
Endocrine conditions associated with obesity
A number of hormone disturbances may result in overweight and obesity. These include
hypothyroidism, hypercortisolemia, pseudohypoparathyroidism and growth hormone deficiency.
Exogenous or excess caloric-caused obesity is associated with linear growth acceleration and taller
stature, along with advanced skeletal maturation as evidenced by bone age measurements.
However, endocrine related causes of obesity mentioned above are all associated with linear growth
deceleration and delayed bone age.
Detailed history, physical examination and appropriate laboratory work up should be undertaken to
identify the specific hormone abnormality that is present such as thyroid hormone deficiency, high
cortisol levels, low levels of growth hormone or clinical phenotype of Albright’s hereditary osteodystrophy
in pseudohypoparathyroidism. Once the underlying hormone abnormality is identified, appropriate
therapeutic interventions will result in normalization of clinical presentation including growth.
General Principles of Obesity Management
Treatment of obesity involves primary prevention of obesity and management of obesity

complications as well as co-morbid conditions. Since childhood obesity prevalence has more than
doubled over the past 3 decades, research efforts have increased to find effective interventions.
A number of treatment strategies are available that range from lifestyle changes to pharmacotherapy
and bariatric surgery for the most severe cases of obesity. A comprehensive review of multiple
Table 11
Indications for DM screening at age 10 or puberty onset (see text)148.
1. First or second degree relative with T2DM;

2. Belong to high risk T2DM ethnicity;
3. Have evidence of insulin resistance;
4. Have maternal history of T2DM
5. Or gestational DM in mother
Table 12
Recommendations for pediatric obesity prevention (see text)144,149.
1. Avoidance of calorie-dense, nutrient poor foods (i.e., sugar-sweetened beverages, sports drinks, fruit drinks, most
fast foods).
2. Engagement in physical activities for at least 20 minutes to 60 minutes 5 times daily per week.
3. Foster healthy sleep patterns.
4. Establish a balance between unavoidable technology-related screen time with increased opportunities for physical
activity.
5. Enlist the participation of the entire family not just the child or teenager.
6. Provide assessment of family function and appropriate referral to address family stressors.
7. Utilization of school-based programs and community engagement in pediatric obesity preventive programs.
8. The use of comprehensive behavior-changing interventions.
9. The promotion of breast-feeding in infants.
obesity interventions over the past decade was conducted by a panel of experts commissioned by
the Endocrine Society in 2016 to appraise and summarize the evidence behind various interventions
employed to treat pediatric obesity.149
Utilizing a meta-analysis methodology the panel found that the comprehensive non-surgical
interventions that yielded the most clinically relevant improvements in weight reduction and
metabolic outcomes were those that combine diet, physical activity, education and behavior
therapy.149 These findings led to recommendations for the assessment, treatment and prevention of
pediatric obesity utilizing current clinical practice guidelines established by this Endocrine Society
Task Force in collaboration with the European Society of Endocrinology and the Pediatric Endocrine
Society.144 Based on such findings prevention of obesity was the primary goal with recommenda-
tions outlined in Table 12.144,149 These recommendations provide guidance for clinicians who
participate in the care of obese or overweight children and promote ongoing healthy dietary as well
as appropriate activity education for all children, adolescents and their parents.
Some researchers have expressed concern over the unique and daunting challenges facing
pediatric obesity interventional research at this time; such issues include the recruitment of study
patients and the ability to have sustained study participation that has impacted a significant amount
of research work in this field.150 Some researchers undertook an experimentation initiative to study
the barriers to recruitment of pediatric patients utilizing a grounded theory approach; comparing
the personal perspectives of eleven childhood obesity researchers currently involved in this type of
investigation, a number of barriers to recruitment of patients for study were found as outlined in
Table 13.150 Suggestions for obesity research are offered as well while data-based reasons for
childhood obesity prevention are outlined in Table 14.150,151
Perspectives on pediatric obesity programs

The best long-term data on childhood obesity treatment is noted with the research results of LH
Epstein and associates in their classic paper on diet and exercise published in 1985.152 Leading
experts (i.e., The World Obesity Federation (previously called the International Obesity Task Force
[IOTF]) have called for longitudinal clinical trials to test the validity of Epstein’s work and alert the
world to the growing health crisis caused by soaring levels of obesity.151–153 Research seeks to utilize
Table 13
Barriers in recruiting patients for obesity research (see text)150.
1. Family and study logistics

2. Family economics
3. Lack of provider interest
4. Use of invasive protocols
5. Stigma to obesity label
6. Time restraints of clinicians
7. Lack of patient motivation/interest
8. Participants or others who did not accept his or her own weight status (i.e., overweight or obese)
Table 14
Data-based reasons for prevention of pediatric obesity151.
1. An overweight child or adolescent is likely to become an obese adult unless active intervention is implemented.
2. Weight management decreases likelihood of cardiovascular risk factors in obese children and adolescents which
leads to decreased morbidity and mortality.
3. Obese children and adolescents have established physical and psychosocial morbidities as result of their obesity.
4. There is growing evidence that obese children are able to maintain their relative weight loss over time as compared
with obese adults.
controlled trials of dietary measures and physical exercise with strong parental involvement to
reduce the percentage of overweight children by at least 20%.151
Experts stress that the best evidence for improved weight loss among adolescents is seen with
dietary intervention in the form of low fat foods and low glycemic index snacks along with slow
reduction in portion size as well as elimination of sugar-based drinks; complementary parental
modeling activity (including positive parenting as well as salubrious parental weight status) is
important as well.151,154 Numerous cross-sectional studies have shown a positive correlation between
overweight and sedentary activity (i.e., television or other small-screen watching).151 Also important is
the application of beneficial behavioral modification for promotion of needed lifestyle changes.
However, there remains great diversity of pediatric obesity management programs as a
result of variations in assessment tools, protocols and techniques; thus, there are no
standardized methodologies across clinic settings or established national registries because of the
inability of researchers to select a valid instrument to obtain good data. Researchers are seeking to
improve this situation as seen, for example, in studies in Australia, United Kingdom, Spain, and
others.
For example, two research groups in Australia have looked at the impact of an existing obesity
program called “Go4Fun” and a web-based software called HopSCOTCH.155–157 While the Go4Fun
study was formally launched in July 2015, no results have been published. On the other hand, the
HopSCOTCH test, conducted between 2008-2011 across Australia involving 22 family practices and
1 tertiary referral center, showed disappointing results.157 No significant change in body mass index
and other outcomes were demonstrated between intervention and control groups.157
In the United Kingdom, the Healthy Eating and Lifestyle Program (HELP) initiative was created to
evaluate the management of adolescent obesity within the primary care setting.158 It was a
community-delivered, multi-component intervention designed specifically for adolescents (12 –
18-year-old). Again, the results were disconcerting in that the HELP intervention was not shown to
be effective in improving BMI of the study participants158,159 The THAO-Child health program in
Spain was a rare country study to date that showed a stabilization of the obesity prevalence for the
interventional group of municipalities involved.160,161
From such a sampling of country studies and our review of current literature, the intervention
that consists of lifestyle change is the prevailing key to success in slowing down the surge in obesity
prevalence in the future. This lifestyle change includes a societal shift to lower consumption of
processed food and less reliance on high technology for entertainment—this translates to increased
physical activity in outdoor settings with intensive, healthy parental modeling and support. This
successful lifestyle change must come from prevailing society’s moral compass to curb and hopefully
eradicate the obesity epidemic of the 21st century. This monograph now turns to perspectives in
pharmacology of obesity and bariatric surgery.
Pharmacotherapy for Pediatric Obesity
Introduction
As noted body weight is an important component of overall health and involves a complex
balance between intake of food and expenditure of energy.162 Many neural circuits are involved with
complex communication between the brain, gastrointestinal tract, adipose cells as well as other
body parts in response to many inputs including the availability of food and energy expenditure
necessary to acquire food for life and for the survival of the person.163
Clinicians should understand that the use of pharmacology for obesity in pediatric and adult
obese patients should only be done as part of an overall plan that includes behavioral modification
(with diet instruction) and exercise.164–171 It is normally considered when achievement of
recommended weight guidelines in pediatric and adult patients is not met with diet and
exercise.167,168,172–174
It is important for clinicians dealing with overweight patients to understand what anti-obesity
medications are available even though relatively few are Food and Drug Administration (FDA)-
approved. However, more are being approved for adults and this trend can be expected to continue
over the near and far future. Also, various countries have their own approval agency such as the
European Medicines Agency in Europe.175,176
In order to deal with this chronic disorder involving 2.8 to 3.5 billion human beings, clinicians are
using various prescription and over-the-counter drugs in both FDA-approved and off-label manners
to seek to help their obese or overweight patients.177 Thus, it is vital that clinicians dealing with
these patients remain up-to-date on these medications and such knowledge includes appreciation of
potential adverse effects—both common and unusual side effects that are possibe.178
Guidelines to consider obesity pharmacology generally note obesity as body mass index (BMI)
≥ 30 kg/m2 and overweight as BMI ≥ 27 kg/m2 with comorbid conditions.170 Also, clinicians should
carefully prescribe all medications for all health disorders and keep in mind the potential effect on
weight that these various medications may induce.179 For example, weight gain may be seen in
those with diabetes mellitus who are managed with insulin, sulfonylureas, and/or thiazolidine-
diones.180 Another classic example is weight gain noted with various antipsychotic medications.181
Anti-obesity medications approved for adults (including those over age 16) can be classified in
various groups as outlined in Table 15.182,183 None are approved for pregnancy or lactating females
and the high cost of many of these medications prevents their use by some adults. Careful
monitoring of the potential effects and side effects of these various medications in patients of all
ages is an important part of clinical practice.
The actual weight loss is dependent on various factors and is typically modest (i.e., 2 to 10
kilograms or 3% to 10% of the starting weight) and usually seen during the first 6 months or less of
pharmacologic therapy; also, ongoing use of these drugs are typically needed for avoidance of
weight loss reversal.167,168,184
It must be stressed that adverse effects of these medications can be considerable and serious—
leading to the withdrawal of some medications from time to time over the past several decades. Side
effects for children and adolescents are often unknown or poorly understood and support for use in
pediatric patients is compromised by limited and/or poorly conducted research trials.185,186
It is easy for patients, clinicians and pharmaceutical companies to be lulled into a false sense of
security with some anorexigenic agents first felt to be safe and later identified as containing serious
risks.187 Medication side effects are an important cause of medication discontinuation in all patients
including adolescents.188
The only currently approved medication for pediatric patients with obesity is orlistat for those ≥ 12
years of age.189 Pharmacologic drugs with current FDA-approval for obese adults are listed in
Table 16. The sympathomimetics (i.e, phentermine, others) are approved for short-term use (i.e.,
≤ 12 weeks) while the others listed in Table 2 are FDA-approved for long-term use.184,190,191
Table 15
Classification of anti-obesity medications.
Sympathomimetics (with or without topiramate)

Serotonin agonists
Fat blockers (gastrointestinal lipase inhibitors)
Glucagon-like peptide 1 agonists (GLP 1)
Antidepressant/opioid antagonist combination Others: See text
Combination drug therapy for obesity management has become more common in the 21st
century and often contain established medications that were initially used for conditions other than
obesity.170,184,192 Also, there are a number of over-the-counter herbal products that have been
utilized in efforts seeking weight loss and these will be briefly considered as well.167,168
Commentary is also provided for some medications that have lost approval and others now in
research for potential use with or without FDA approval in the near future.
Sympathomimetics (noradrenergics)
Phentermine
A number of sympathomimetic drugs (Table 16: phentermine, diethylpropion, benzphetamine and
phendimetrazine) are available that can reduce intake of food via mimicking norepinephrine effects193,194
Phentermine is a sympathomimetic amine known for its weight-inducing properties for many
decades and FDA-approved for short-term weight loss (i.e., under 12 weeks) since 1959.195 It is a
central adrenergic-mediator that suppresses serotonin clearance with increased effect on serotonin-
releasing drugs that has been approved for weight-loss enhancement in various countries.178,196,197
Phentermine is taken at 37.5 mg once per day and though not recommended, it has been taken in
combination with other sympathomimetic appetite suppressants (Table 16).198
Some clinicians have been reluctant to use phentermine because of its resemblance to
amphetamine even though it is FDA-approved for short-term use and is relatively inexpensive as
a generic medication.177 Phentermine is classified as a schedule IV controlled substance while
amphetamine products are classified as schedule II controlled substances.
It can increase blood pressure, is contraindicated in pregnancy (category X) as well as those with
a history of cardiovascular disease and in some countries, it is classified as a narcotic.196,199
Phentermine is being combined with other medications and researched as 21st century anti-obesity
drugs such as seen with its addition to the anticonvulsant topiramate; this combination is approved
for adults and is reviewed later (Table 16).
Diethylpropion
Diethylpropion (amfepramone) is a noradrenergic agent that has been identified for many
decades as an appetite suppressant.200,201 It is FDA-approved for short-term weight loss in those
over 16 years of age; it is classified as a schedule IV controlled substance.178,197,202 As noted with
phentermine, the structure of diethylpropion has been linked by some clinicians with an
amphetamine structure and essentially unproved yet ongoing worries about its side effects.177,203,204
As seen with various medications, its therapeutic effect is based on understanding how to use it
in combination with a high fat dietary restriction program and activity.205 Though not approved for
long-term use studies have noted its benefit in the long-term (i.e., one year or more).206 As noted
with other sympathomimetics research has noted essentially mild adverse side effects with dry
mouth being the most common in addition to insomnia, constipation, anxiety and irritability.206–209
Table 16
Anti-obesity medications with FDA approval for long-term use in adults (2017).
A. Sympathomimetics
1. phentermine,
2. benzphetamine,
3. diethylproprion
4. phendimetrazine
B. Gastrointestinal lipase inhibitor: orlistat (Starting at age 12 years)
C. Glucagon-like peptide 1 (GLP 1) analog: liraglutide (diabetes mellitus drug)
D. New monoamine modulators:
1. lorcaserin
2. phentermine/topiramate ER
3. naltrexone/bupropion ER
Diethylpropion should not be used in those with a history of pulmonary arterial hypertension or
psychosis.210–212
Benzphetamine
Benzphetamine is a central adrenergic-mediator that is a schedule III drug and is FDA-approved
in those ≥ 12 years of age for short-term use (under 12 weeks). Its weight-inducing properties, like
other sympathomimietic amines, have been known for decades.213 Potential side effects have
limited their use that include insomnia and/or restlessness, gastrointestinal problems (i.e., nausea,
constipation, diarrhea) and cardiovascular (valve disease, hypertension).167,168
Clinicians traditionally avoided these agents in those with hypertension (moderate to severe),
pulmonary hypertension, hyperthyroidism, and history of substance use disorders. A large number
of illicit chemicals are available that are related such as illicit phenethylamines and result in keeping
many clinicians from using benzphetamine and other Schedule III or IV drugs.214
Phendimetrazine
Phendimetrazine is a stimulant chemical known to have appetite suppressant properties for
many decades.215–217 It is from the morpholine chemical class and classified as a Schedule III
controlled substance since 1970. It is a stimulant used for short-term management of obesity in
adults with no advantage over the others used for weight loss purposes and with side effect issues as
seen with these others as well.182,218–220 Its group of appetite suppressants link the past with the
future of pharmacologic management of obesity.182
Phentermine/topiramate ER
The combination of the known sympathomimetic agent, phentermine, with the known
anticonvulsant, topiramate, is part of the current trend in using combination medications as anti-
obesity drugs. Weight loss was noted in persons with epilepsy taking topiramate and combining it
with the already approved anti-obesity drug, phentermine, resulted in more weight loss than using
this anticonvulsant alone.221–223 The combination of topiramate with phentermine, phentermine/
topiramate ER (extended release) was FDA approved for long-term treatment of obesity in adults in
2012.191,224 Another combination using an anticonvulsant medication under study is combining
zonisamide with bupropion; zonisamide has been studied as an anorexigenic agent197,199
Topiramate is a sulfamate-substituted monosaccharide developed from monosaccharide
D-fructose that has been approved for management of epilepsy and migraine headaches.225 This
anti-obesity combination medication allows rapid (immediate) release of phentermine as well as ER
(extended-release) (15 mg/92 mg) of an approved anticonvulsant, topiramate (66). Other doses are
11.25 mg/69 mg, 7.5 mg/46 mg and 3.75 mg/23 mg.
In contrast to lorcaserin (another novel anti-obesity agent–see below), phentermine/topiramate
ER had a greater weight loss profile but more side effects.226,227 One review of miscellaneous studies
notes the highest chances of reaching 5% or more weight loss at 52 weeks with phentermine/
topiramate ER versus orlistat, lorcaserin, liraglutide and naltrexone-burpropion.228 Other work notes
that phentermine/topiramate ER has the highest overall weight loss profile in obese adults (meeting
≥ 5% and ≥10% weight loss benchmarks) when compared to liraglutide, lorcaserin and naltrexone/
bupropion.229 Table 17 notes potential benefits of using this anti-obesity agent though side effects
must be carefully considered as well.202
Adverse side effects

Table 18 lists some potential side effects of phentermine/topiramate
ER.178,199,226,234–238 A key issue that will require prolonged study is whether or not all adverse
effects of each drug in combination products will occur or if combining these drugs will ameliorate
some individual effects.178 Some effects may not be seen in early trails of combination drugs and
research on anti-obesity drugs has been critiqued by some for not having extensive, well-devised
research trials showing safety before releasing a product.186
Table 17
Potential benefits of phentermine/topiramate ER in adults178,202,223,230–233.
Average weight loss of 5%-10%

Improved glucose tolerance
Improved fibrinogen and lipid levels
Improved liver testing profiles
Reduced C-reactive protein levels
Less type 2 diabetes mellitus
Improvement in sleep apnea evaluations
Decrease in blood pressure in obese adults with hypertension
Naltrexone/bupropion
Another combination anti-obesity drug now available is the pairing of a known mu-opioid
receptor antagonist (naltrexone-32 mg) with a known catecholamine reuptake inhibitor anti-
depressant (bupropion-360 mg) that was FDA-approved for adult obesity treatment in
2014.191,224,239–241 Bupropion shares similar structural design and central nervous system actions
as the sympathomimetic diethylpropion.208
Beneficial effects have been noted on the mesolimbic system and the melanocortin pathway of
the hypothalamus with this combination that research suggests allows adults improved food craving
control and reduced over eating episodes.178,242 Some research has noted that such effects results in
weight loss in adults that is less than noted with phentermine/topiramate ER but more than seen
with lorcaserin, orlistat and liraglutide.229,237
Naltrexone/bupropion completion rates in some research was similar to lorcaserin but below that of
phentermine/topiramate ER, placebo and liraglutide.229 As weight loss occurred with naltrexone/
bupropion, glucose tolerance and lipid profiles improved.231 Abuse potential has not been reported.237

Potential adverse effects are listed in Table 19.199,233,243–246 Bupropion is not given to those with a
history of eating disorders (anorexia nervosa or bulimia nervosa) or seizure disorders.246 Bupropion
is also avoided for those taking opioids and sudden withdrawal from such drugs as alcohol, anti-
epileptics, barbiturates, and benzodiazepines.246
Lorcaserin
Lorcaserin is a selective serotonin 2C receptor agonist that reduces food intake (appetite
suppressant) resulting in a mean weight loss of 5% after one year of use.178,202,247–250 It was FDA
Table 18
Potential adverse effects of phentermine/topiramate ER in adults (partial list)178,199,226,234–238.
Abuse
anxiety
cognitive dysfunction
dry mouth
constipation
dizziness
dysgeusia
insomnia
metabolic acidosis (typically mild)
paresthesias
psychiatric complications
resting heart rate increase
teratogenicity
topiramate level instability
Others
Table 19
Potential adverse effects of Naltrexone/bupropion in adults (partial list)199,233,243–246.
Black box warning for suicidality

blood pressure increase
constipation
dizziness
headache
insomnia
nausea
neuropsychiatric dysfunction (seen in monotherapy with bupropion taking for smoking cessation)246
seizures (rare)
vomiting
Others (see text)
approved for long-term treatment of obesity in adults in 2012.191 Its dose is 10 mg twice daily as
lorcaserin immediate release (IR) versus 20 mg daily of lorcaserin ER 20 mg daily. Use of lorcaserin
also improved glucose tolerance, lipid profiles, and blood pressure; C-reactive protein levels were
reduced.178,230,231
In contrast to another novel anti-obesity agent, phentermine/topiramate ER, lorcaserin had a
decreased weight loss profile but also a decreased side effect profile.226,250 In some research this
medication has the lowest weight loss benchmarks compared to phentermine/topiramate ER,
liraglutide and naltrexone/bupropion.229 In this same research lorcaserin has the same completion
rates as compared to naltrexone/bupropion but below phentermine/topiramate ER, placebo
medications; also, lorcaserin had the lowest side effects profile in adults.229
Adverse effects
Table 20 lists side effects identified with use of lorcaserin in those taking this product for weight
loss and not for management of diabetes mellitus per se.199,250–255 In a study in which lorcaserin was
added to phentermine short-term weight loss was increased and serotonergic adverse effects were
not increased.255 Abuse potential has been reported and lorcaserin should not be added to agents
with serotonergic effects.199,237
Liraglutide
Another approach for weight loss pharmacotherapy is utilization of incretin mimetics such as
liraglutide, exenatide and lixisenatide; these agents are glucagon-like peptide-1 (GLP-1) analogs of
gastrointestinal hormones.199 Glucagon-like peptide-1 (GLP-1) agents are polypeptide incretin
hormones that produce various effects including insulin secretion (via gastrointestinal L-cells) and
Table 20
Potential adverse effects of lorcaserin in adults (partial list)199,226,233,235,236,250–255.
blood pressure increase

cognitive impairment
constipation*
dizziness*
dry mouth*
fatigue*
headache*
hypoglycemia
nasopharyngitis*
nausea*
psychiatric events
upper respiratory tract infection*
valvulopathy
Others (see text)
*(≥ 5%)
suppression of appetite.256–258 Liraglutide is a glucagon-like peptide-1 (GLP-1) analog that has been
approved for management of type 1 diabetes mellitus.178,180,259,260
Natural GLP-1 would have to be given intravenously because of its rapid removal by the enzyme
DPP-IV (dipeptidyl-peptidase IV); thus, it is not used as an appetite control agent as such. GLP-1
agonists (incretin mimetics) are used in this capacity as they are structurally altered from natural
GLP-1, are not affected by this enzyme (DDP-IV) and do not need intravenous administration.
The dose of liraglutide is three mg per day given via subcutaneous injection. As noted some
research has indicated that its use in adults results in more weight loss compared to lorcaserin but
less than seen with phentermine/ topiramate ER and naltrexone/bupropion.229 In this same research
liraglutide was in second place with regard to completion rates but was number one in terms of side
effects with gastrointestinal adverse effects the most common.229 Adults with obesity-induced
hypertension may have a reduction of their blood pressure when taking liraglutide.233
The action of these agonists is centrally to increase a sense of fullness and/or reduce gastric
emptying.259 Limits to use of liraglutide in a pediatric population include non-FDA approval for this
group, high cost and its injection administration.256 A number of GLP-1 receptor agonists are
available to treat type 2 diabetes mellitus in adults.258 Potential adverse side effects of liraglutide are
noted in Table 21.
Orlistat
Orlistat is a gastric and pancreatic lipase inhibitor and leads to weight reduction with a dose-
dependent fat malabsorption.164,189,261–268 It was approved as an anti-obesity drug for adults in 1998
and for management of obesity in pediatric patients ≥12 years of age.189 Cetilistat is a medication
with similar activity to orlistat that was approved in 2013 in Japan for treatment of adults with
obesity, type 2 diabetes mellitus and dyslipidemia.178
Orlistat is generally given at an oral dose of 120 mg three times a day with meals for adults and it
decreases fat absorption by 30% with the 120 mg prescription versus 25% with the 60 mg
dose.164,263,266,268 Orlistat has also been approved by the FDA as an over-the-counter medication for
weight loss at half its prescription dose.268,269
Mild to modest weight loss effects (less than 5 kilograms) have been seen for up to 4 years with
the prescription dose.169,186 In one study involving adults in a 16 week study the group taking
orlistat (with a low fat, lowered calorie diet) had a loss of 1.15 kilograms versus the placebo group.270
A study of this medication for obese adolescents noted no observable benefit.271
Table 21
Potential adverse effects of liraglutide in adults (partial list)199,229,256–260.
*abdominal pain
category X drug (contraindicated in pregnancy)
*constipation
*decreased appetite
*diarrhea
*dizziness
*dyspepsia
*emesis
fatigue
gallbladder disease (acute)
*headaches
*hypoglycemia
*increased lipase
Increased pulse (over time)
*nausea
pancreatitis
thyroid tumors (warning given)
OTHERS
*≥5%
Other research has recorded a lowering of body mass index up to 4.09 kg/m2.267 Use of this
medication can also lead to improved blood pressure, insulin sensitivity, serum glucose and lipid
levels.164,261,263 Also, adults with nonalcoholic fatty liver disease (NAFLD) who are placed on orlistat
have been found to have reduced hepatic infiltration with increased serum adiponectin and
decreased serum periostin.272

Though approved as an anti-obesity agent in the United States and Europe, it has a high
discontinuation rate due to its side effects, particularly gastrointestinal (Table 22).186,221,273–280
Clinicians should be aware of the high discontinuation rate seen with obese youth.167,168 Because
orlistat leads to decreased fat-soluble vitamins, a multivitamin containing fat soluble vitamins
should be taken on a daily basis at least 2 hours before or after taking this anti-obesity agent.
Liver function should be carefully monitored as acute liver failure has been reported in rare
instances.274,275 Renal function should also be monitored for persons taking orlistat and it should not
be provided to those with renal insufficiency.276–278 Its effect on growth of youth is not known.167,168
Other proposed anti-obesity agents
In addition to the medications that have been reviewed as noted in Table 16, other drugs have
been proposed and have been used to reduce body weight, though they are not FDA-approved.
Table 23 provides a list of these drugs and some are considered in this section of this monograph.
Researchers seek medications that induce weight loss while being used to treat other disorders.
A classic method in this manner is use of anti-hyperglycemic agents used to treat type 2 diabetes
mellitus in adults that include insulin secretagogues (GLP-1 receptor agonists, DPP-IV inhibitors),
alpha-glucosidase inhibitors (acarbose, miglitol), amylin receptor agonists (pramlintide), and
blockers of renal glucose reabsorption (SGTL2 [sodium glucose cotransporter-2] inhibitors.281
Acarbose
Prescribed for type 2 diabetes mellitus, acarbose is an inhibitor of intestinal alpha-glucoside

hydrolase and pancreatic alpha-amylase. It can be beneficial for those with obesity (including those
with polycystic ovary syndrome) by its lowering of blood glucose after meals from delay of
consumed carbohydrates.282–289 Another alpha-glucosidase inhibitor under study as a potential anti-
obesity drug is miglitol.290
Table 22
Potential adverse effects of orlistat (partial list)167,168,186,189,221,268,269,273–280.
abdominal pain
contraindicated with renal failure and renal insufficiency
contraindicated in pregnancy (category X).
contraindicated in chronic malabsorption syndrome and cholestasis
contraindicated with liver failure
dyspepsia
gastric upset
fecal incontinence
fecal urgency
flatulence
increase warfarin’s anticoagulant effect (due to decreased vitamin K absorption)
Interference with various medication absorption
liver failure (acute; rare)
malabsorption
reduced absorption of fat-soluble vitamins (A, D, E, and K)
steatorrhea
Others
An initial dose of acarbose is 25 mg orally, three times a day, that is increased as tolerated;
maintenance doses in adults is 50 to 100 mg three times a day given orally. Potential adverse effects
from acarbose includes flatulence, diarrhea, and other gastrointestinal upset; blood glucose can be
lowered with resultant symptoms if this medication is added to usage of insulin or a sulfonylurea.289
Metformin
Metformin is in the biguanide class of drugs; discovered in 1922; it received FDA approval in
1995 for management of type 2 diabetes mellitus. It reduces liver gluconeogenesis and improves
glucose transport in cell membranes (i.e., adipose tissue, skeletal muscles); other metformin action
includes heightening insulin uptake and effects of insulin in muscle, liver, and adipose tissue.168,261
Its potential to cause weight loss in those obese persons without diabetes mellitus has been
recognized for many decades.188,285–287,291–294 Mild weight loss may occur in obese pediatric
patients though more studies of high scientific quality are needed.186 Metformin can be useful for
mild weight loss in adolescents and adults with obesity, insulin resistance and metabolic
syndrome.261,295,296 A study of Australian males (9 to 18 years of age) with 1 gram of metformin
twice a day induced an average of 4.35 kg weight loss over 6 months.297
A typical dose in adolescents (10-16 years of age) is 500 mg twice daily; if the patient has type
2 diabetes mellitus, this dose can be increased 500 mg weekly up to a maximum of 2 daily grams. In
a recent study comparing metformin with orlistat, more weight loss was seen with orlistat in adult
females though metformin use resulted in less android adipose tissue.295 Metformin has been
utilized for management of adults with polycystic ovary syndrome (with hyperinsulinemia and
hyperandrogenism); it may lead to more regular menstruation, decreased androgens and ovulation
enhancement in PCOS.298–301

Table 24 lists metformin side effects that are typically dose-related and improve over time. Lactic
acidosis is found in one in 30,000 and is more common in those with renal insufficiency; the
mortality rate is 50%.174,267,298 Gastrointestinal adverse effects tend to be mild and treated with
dosage changes.221
DPP-IV Inhibitors
Drugs that inhibit dipeptidyl peptidase-IV (DPP-IV) are classified as insulin secretagogues and
include sitagliptin, vildagliptin and saxagliptin. They are prescribed as oral medications and used to
treat type 1 diabetes mellitus as well as dyslipidemias; they are under study for potential use in
adults with obesity with and without type 2 diabetes.302,303
SGLT2 inhibitors
Another group of medications used to manage type 2 diabetes mellitus are the blockers of renal
glucose reabsorption (SGLT2 [sodium glucose cotransporter-2] inhibitors.304–306 They are also called
gliflozins and include canagliflozin, empagliflozin and dapagliflozin. SGLT-2 inhibitors act on the
renal proximal tubule brush border and lead to leakage of urinary glucose and subsequent weight
Table 23
Non-FDA-approved anti-obesity medications utilized by clinicians.
Alpha-glucosidase inhibitors: acarbose, miglitol

Metformin
DPP-IV Inhibitors
Blockers of renal glucose reabsorption (SGLT2 [sodium glucose cotransporter-2] inhibitors
Amylin receptor agonists: pramlintide
Table 24
Side effects and contraindications for metformin174,267,298.
A. Adverse Effects
1. Abdominal discomfort
2. Diarrhea
3. Emesis
4. Flatulence
5. Indigestion
6. Lactic acidosis
7. Nausea
8. Vitamin B12 malabsorption
B. Contraindications
1. Congestive heart failure
2. Critically ill persons (including hypoxia)
3. Liver disease
4. Renal insufficiency
loss.259 These agents have a low risk for hypoglycemia in addition to an increased risk for fractures as
well as leg and foot amputations (2017 FDA Black Box Warning).307,308
The role of gliflozins as anti-obesity drugs is under study for adults. For example, research is
evaluating the safety and efficacy of combining phentermine with canagliflozin for obese or
overweight persons without type 2 diabetes mellitus.309 More combinations of medications can be
expected based on the studies of previous discussed combinations naltrexone/ bupropion and
phentermine-topiramate extended release.224
Medications that lower blood sugar and also reduce weight are being studied to manage those
with diabetes mellitus and also those with obesity with or without diabetes mellitus. These include
sodium-glucose cotransporter 2 inhibitors (SGLT-2i) but also glucagon-like-peptide-1 receptor
agonists (GLP-1RAs; GLP-1 agonists)—as noted previously.
Amylin receptor agonists: pramlintide
Pancreatic islet cells secrete amylin which is a 27-amino acid peptide that is released with insulin
and is called an insulin physiologic modulator. This pancreatic β-cell hormone acts centrally to lower
or restrict postprandial hyperglycemia (as well as postprandial release of glucagon); it influences
appetite and can slow gastric emptying.310
Pramlintide is an injectable analog of amylin under study for treatment of diabetes as well as
obesity.168,305 It is FDA-approved for management of type 1 as well as 2 diabetes mellitus and is used
with insulin.311 It can cause nausea that usually improves over time. A combination of pramlintide
with a leptin analog (metreleptin) is being research for obesity management.310
Brown fat activators
Brown adipose tissue is identified as energy-expending cells that if activated could be utilized in
a pharmacotherapeutic approach to obesity management.183,312,313 A drug that activates brown fat
with resultant increased metabolism is mirabegron, a beta 3-adrenoreceptor (ADRB3) agonist used
for management of an overactive bladder but is under study as a potential anti-obesity agent.314,315
Another brown fat activator and potential agent in obesity management is orexin-A (hypocretin-1)
which is a natural neuropeptide in association with the orexinergic nucleus in the lateral
hypothalamus.316
Also under review as brown adipose tissue activators and potential anti-obesity agents are drugs
of the (poly)phenol groups——flavan-3-ols and resveratrol.317,318 Resveratrol is a polyphenol (non-
flavonoid) in the stilbenes subgroup of polyphenols that are natural chemicals found in various
natural plants.319
Antidepressants
A number of antidepressant medications are known to have variable weight loss effects. For
example, use of fluoxetine (a selective serotonin reuptake inhibitor [SSRI]) can provide small
reductions in body mass index but is not approved for treatment of obesity.186,320 Also complicating
this picture of using such a drug as fluoxetine is its potential for a variety of adverse effects as noted
in Table 25.
Another SSRI that has been used in the past for mild weight loss is sertraline though it is not
approved as an anti-obesity medication.181–186,323 Though the search for use of an antidepressant
with significant appetite suppressant effects goes on, bupropion remains the only antidepressant
currently approved as an anti-obesity drug when combined with naltrexone—as reviewed earlier.224
Gastrointestinal Hormones
Amylin
A number of gastrointestinal hormones are under active study for potential use in various forms
for pharmacological management of obesity (Table 26). For example, research is seeking various co-
agonists for gut hormones such as glucagon, GLP-1 and gastric inhibitory peptide.324 The peptide
amylin has been previously discussed as well as the injectable amylin analog, pramlintide, now
under study for management of diabetes mellitus as well as obesity.168,305 Another amylin analogue
is davalintide.
Ghrelin
Called the “hunger hormone” ghrelin is an appetite stimulator that is produced mainly in gastric
tissue but also in the small intestine, pancreas and the brain.325–327 Ghrelin opposes action of leptin
and acts on receptors in the hypothalamic arcuate nucleus. Ghrelin is an acylated gastrointestinal
peptide that alerts the brain to the presence of hunger; it increases prior to meals and its levels fall
after meals. It also has anti-inflammatory effects and is involved with growth hormone.328,329
The roles of ghrelin in normal and obese states is under review as is the potential use of ghrelin
receptor inverse agonists as anti-obesity medications.330–332 For example, obestatin is a peptide
hormone which can inhibit ghrelin and its potential role in managing digestive disorders and obesity
remains to be clarified.333
Leptin
Leptin was the first of hundreds of adipokines identified and characterized as cytokines secreted
by adipose cells. Leptin is taken from the Greek work, leptos, and means “thin.” It is an anorexigenic
Table 25
Potential side effects of fluoxetine181,321,322.
1. abdominal discomfort
2. agitation
3. black box warning for suicidality (through age 24 years)
4. diarrhea
5. dry mouth
6. emesis
7. headache
8. increased sweating
9. nausea
10. nervousness
11. rash
12. pulmonary artery hypertension
13. serotonin syndrome
14. sexual dysfunction
15. Others
Table 26
Gastrointestinal (GI) hormones, related chemicals and obesity management (see text).
amylin (amylin analogues: pramlintide; davalintide)

ghrelin (ghrelin inhibitor: obestatin)
leptin
(leptin analogue: metreleptin)
(leptin sensitizer: celastrol)
cholecystokinin (CCK)
(research looking for stimulators of type 1 cholecystokinin receptors)
octreotide (somatostatin receptor analog)
ciliary neurotrophic factor (CNTF)
(polypeptide used to overcome leptin resistance)
neuropeptide Y
(neuropeptide Y antagonist: velneperit)
Peptide YY (PYY) (PYY with oxyntomodulin)
Bombesin (selective BRS-3 agonists)
Others (incretin mimetics, gliptins—see text)
hormone (adipokine) produced or released by adipose cells, stimulates receptors in the

hypothalamic arcuate nucleus, aids in hunger control, influences energy balance and is
influenced by obesity as well as weight loss.334 It is a 167 amino acid polypeptide and neuropeptide
that has significant importance in signaling central nervous system centers regarding nutrient
status.
Obese persons typically have increased leptin levels that reflects hypothalamic resistance to
leptin that worsens with increased obesity (7). Low levels of leptin not only affect neurons on the
arcuate nucleus but other areas of the brain involved in tasting, smelling and food acquisition in a
modern world with food challenges different than the ancient world.335
States of hyperleptinemia can increase adipose tissue and stimulate appetite while those with
this condition are resistant to leptin treatment.336,337 Aging can lead to increased leptin resistance
and hyperleptinemia while physical training can lower leptin levels as well.338
Deregulation of neuropeptides in obese youth with hyperleptinemia can be seen during weight
loss periods that can lead to a number of consequences including improvement of depression in
obese adolescent females.339,340 Leptin was approved in 2014 for management of congenital leptin
deficiency and generalized lipodystrophy. Research is currently occurring seeking use of leptin or its
analogs to ameliorate obesity via complex actions on the brain (i.e., hypothalamus) and other body
tissues (i.e., adipose tissue, gastrointestinal tract, pancreas, others).341–343 Studies on leptin
analogues (i.e, metreleptin) are underway.344
Another approach to obesity management is utilization of chemicals that increase energy
expenditure. An example is celastrol that increases sensitivity to leptin and can influence appetite
and energy balance. Celastrol is a triterpenoid (i.e., consists of three terpene units) found in plant
resins and gums such as that of the herb, Tripterygium wilfordii, that is found in traditional Chinese
medicine. Celastrol has a number of beneficial effects that include anti-inflammatory and anti-
oxidant; research is seeking potential benefits in chronic conditions including obesity and
inflammatory bowel disease.345,346
Cholecystokinin (CCK)
Cholecystokinin (previously called pancreozymin) is a peptide hormone discovered in 1928 that
is involved in the complex process of satiety. It is a peripheral neuropeptide produced in the
duodenum that stimulates release of gallbladder bile and pancreatic enzymes leading to fat as well
as protein digestion.347
Cholecystokinin (CCK) and other gastrointestinal hormones (i.e., ghrelin, glucagon-like peptide 1,
others) are involved in appetite control and are altered during states of obesity.325,327,328 As the roles
of these hormones are unraveled they are being studied as anti-obesity drugs such as use of agents
that stimulate type 1 cholecystokinin receptors.348,349
Octreotide
Octreotide is a somatostatin receptor analog that is an inhibitor of insulin, glucagon and growth
hormone. It is available to treat various conditions such as acromegaly and gigantism.350 Octreotide
has been prescribed for management of obesity due to hypothalamic lesions that distort feelings of
hunger and satiety.351,352 Research into this chemical is also looking at its ability to lower intestinal
glucose absorption, inhibit low-grade inflammation and induce weight loss.353
Ciliary neurotrophic factor

Ciliary neurotrophic factor (CNTF) is a neuroprotective polypeptide hormone part of the
interleukin (IL)-6 family cytokines with myriad actions involving energy balance and being a
neuropeptide of the hypothalamus, CNTF is important for neuron growth.354 It can reduce the intake
of food and may be beneficial in obese persons who are resistant to leptin—though early use of CNTF
for obesity has failed due to development of neutralizing antibodies.355 CNTF remains under study as
a potential anti-obesity medication to overcome leptin resistance and decrease body weight.356
Neuropeptide Y
This is an orexigenic hypothalamic neuropeptide with many complex functions including
influences on food intake, growth of adipose tissue, stress and pain perception.357,358 Ghrelin can
have orexigenic effects moderated by neuropeptide Y neurons in the arcuate nucleus; dysfunction of
these neurons has been noted in laboratory research to induce hyperphagia and obesity in Rattus
norvegicus.326 The potential of neuropeptide Y as an anti-obesity drug is under current research on
such agents as velneperit, a neuropeptide Y antagonist.343
Also under study is the role of Tenebrio molitor larvae extract, a popular food in many countries;
its inclusion in food may influence the appetite stimulant effects of neuropeptide Y and help with
obesity control.359 This is an example of diet control of excessive weight gain versus overt use of
pharmacotherapy. Discussion of over-the-counter agents and medicinal herbs will be provided later
in this review.
Peptide YY (PYY)
The role of gut hormones in the management of obesity remains under study as this section
discusses.360 Another example is peptide YY (PYY; pancreatic peptide YY3-36) that is a 36-amino
acid gut peptide hormone structurally similar to neuropeptide Y as well another gut peptide
hormone, pancreatic polypeptide. Peptide YY is released by gastrointestinal L cells that aid in food
intake regulation by interaction with the Y2R receptor in the hypothalamic arcuate nucleus.360,361
Oxyntomodulin is a peptide produced in colonic mucosa and structurally related to glucagon as
well as glucagon-like peptide (GLP-1) and PYY. Anti-obesity research is looking at oxyntomodulin
analogues as well as combining PYY with oxyntomodulin.343,362
Bombesin
Bombesin is a peptide (14-amino-acid) found on the skin of a toad (Bombina bombina); it has two
homologs: gastrin-releasing peptide and neuromedin B.363 Bombesin is a stimulator of gastrin
release from G cells that involve stimulation of G-protein-coupled receptors: BBR (BRS) 1,2 and
3.363,364 The gastrointestinal G-cell secretes gastrin and is found in gastric and duodenal tissue.
Research notes that bombesin receptor subtype 3 (BRS-3) has an important function in energy
and glucose metabolism and thus, research seeks selective BRS-3 agonists for potential agents in
management of diabetes mellitus and obesity.363–367
Miscellaneous
In the exciting and persistent search for improved anti-obesity drugs a wide variety of agents are
and will be under scrutiny as noted in Table 27. The search targets neuroendocrine peptide
hormones (vida supra), sirtuins, vaccines, over-the-counter agents, traditional herbal plants and
others.178,305,368 Some of these potential chemicals are considered now.
Sirtuins
Sirtuins are antioxidant enzymes first found in yeast and to have various functions in metabolism
and overall lifespan.369,370 They are a group of chemicals called conserved histone deacetylases and
are divided into seven groups called Sir T 1-7. There is potential for this class of chemicals to help
with 2 diabetes mellitus, obesity, and cancer.369–371
Genistein
Genistein (identical to prunetol) is an isoflavone that was originally found in Genista tinctoria
(flower plant from Fabaceae family) and is found in various plants from the bean family (Fabaceae: i.
e., fava beans, soybeans, others), coffee, as well as various identified medicinal plants (Flemingia
vestita, Flemingia macrophylla).372,373
Genistein has anti-oxidant, anti-inflammatory, anti-cancer and phytoestrogen activities.374 Its
potential benefit in type 2 diabetes mellitus and obesity is under study and improvement may occur
by its ability to allay underlying pathophysiologic etiologies of type 1 diabetes mellitus—as
increased cytokines and leptin released from adipose tissue and increased levels of free fatty
acids.374–376 Another isoflavone under study is daidzein which is the second most abundant
isoflavone in soy after genistein.377,378
MetAP2 inhibitors (i.e., beloranib)
Methionine amino peptidase 2 (MetAP2) is an important enzyme involved in growth of new

blood vessels, protein breakdown, repair of tissues and other critical physiologic functions. Research
has looked at the use of MetAP2 inhibitors as a possible pharmacologic approach to obesity
management. In 1949 an antimicrobial chemical, fumagillin, was found in a fungus (Aspergillus
fumigatus) and identified as having the ability to inhibit angiogenesis with an adverse profile that
included reduction in weight and adipose cells.379
Beloranib was identified as a fumagillin analog and has been under study as a potential anti-
obesity agent that acts peripherally and perhaps avoids some problems seen with central acting
agents.199,343,379–382 Beloranib has been beneficial in those with hypothalamic injury-associated
obesity and Prader-Willi syndrome.383,384 As with all these promising and new (as well as old) drugs,
safety is important and clinicians must carefully evaluate for the presence of adverse effects in their
patients taking such medications—whether they are or are not FDA-approved as anti-obesity drugs.
Side effects often identified with beloranib, for example, include nausea and infusion site injury
while others include headache as well as diarrhea; the most common cause of medication
discontinuation was inability to access a vein site.385 However, in a study of patients with Prader-
Table 27
Additional New/Old agents in the anti-obesity drug pipeline.
1. Sirtuins (Sir T 1-7)

2. Isoflavones: genistein; daidzein
3. MetAP2 inhibitors (i.e., beloranib)
4. Triple monoamine reuptake inhibitor (i.e., tesofensine)
5. MC4R agonists (RM-493)
6. Vaccines
7. Over-the-Counter agents (21st century look)
8. Herbal Plants (21st century look)
9. Additional Combination products
10. Others
Willi syndrome, use of beloranib was stopped because of two deaths from pulmonary embolism and
two situations of deep vein thrombosis compared to placebo.384 As always, benefit of a drug must be
balanced with potential for unacceptable adverse effects in a primum non nocere approach that is
thousands of years old for caring clinicians.386
Triple monoamine re-uptake inhibitors
Tesofensine is a triple monoamine reuptake inhibitor that was studied as a potential medication for
neurodegenerative disorders; though it did not significantly help these conditions, a weight loss effect was
seen sparking further research into using this drug as an anti-obesity drug even though increase in heart
rate and blood pressure was also seen.343,381,387–389 The term “triple” refers to effects on the monoamine
neurotransmitters dopamine (DA), norepinephrine (NE) and serotonin (5-HT).
Research that includes animal as well as human studies notes its appetite suppression (enhanced satiety)
is partly due to effects on the dopamine D1 receptor and alpha1 adrenoceptor pathways.390–392 A number of
issues regarding tesofensine as an anti-obesity agent remains under study including its precise action on
dopaminergic pathways, it acute versus long-term use, and its detailed adverse side effect profile.393,394
MC4R agonists (RM-493)
Genetic defects in the melanocortin MC4 receptor (MC4R) can be associated with obesity and
research seeks agents such as MC4R agonists (RM-493) to centrally control appetite and potentially
serve as anti-obesity drugs.343,395–397 The central melanocortin system (including the lateral
hypothalamus and brainstem) is under laboratory (animal) as well as human study for feeding and
energy expenditure regulation to help with management of hyperphagia and human obesity.395–403
An oral MC4R agonist, RM-493, is a peptide under study for obesity management though
cardiovascular and behavioral side effects of such agonists remain concerning from a primum non
nocere perspective.343,386,404
Vaccines
The pioneering work of English physician Dr. Edward Jenner (1749-1823) with 8-year old James
Phipps in 1796 lead to the eventual elimination of smallpox from the world and stimulated a
movement over three centuries that has led to untold millions of lives being saved and human
disease morbidity being immensely improved.405–409
The science of vaccinology is applied in the 21st century to various non-communicable diseases
that include hypertension, cancer, obesity, diabetes mellitus and others.410 In addition, as research
identifies the importance of infection and inflammation in the pathogenesis in obesity, the potential
of vaccinology to benefit the global epidemic of obesity in the 21st century is considerable.411
Approaches include targeting various antigens directed against
ghrelin, somatostatin, glucacon-like peptide (GIP) and other obesity-associated chemicals.412–416
One of various complications in this arena is the decreased or impaired immune response to
vaccination noted in those with obesity by some studies.417–419
Over-the-counter (OTC) and Herbal Agents

Issues of Safety and Efficacy Caveat emptor
Human beings have sought chemicals for improved health and well-being probably since the
dawn of human existence. Extensive pharmacopoeias have been found in ancient China and India
thousands of years ago based on ancient knowledge of herbs and plants.420–423 In 1550 BC ancient
Egyptian clinicians had their Ebers Papyrus which was a 110-page scroll listing 700 formulas and
remedies based on agents from vegetable, mineral and animal sources.424–426
Clinicians and patients in this early part of the 21st century have a long list of agents that have
been identified from a variety of sources as being “health-promoting” that are not included in the
more than 1450 products that are U.S. FDA-approved nor in the official pharmaceutical pipeline for
new drugs.427 It is important for clinicians to seek application of scientific principles to all chemicals
taken by their patients including those in the over-the-counter and herbal market.428
Many chemicals including those identified as herbal supplements that are found around the world
with unproven health-promoting benefits including claimed weight loss properties. Considerable
controversy occurred in the United States in the 20th century that has continued into the 21st century.
The United States Congress passed the United States Pure Food and Drug Act of 1906 that stopped
misbranded or adulterated food and drugs from being produced, sold or taken across state lines.429
In 1938 another U.S. law was passed—the Federal Food, Drug, and Cosmetic Act (FFDCA). FFDCA
made it law that medication must be tested for safety.430 In 1962 the Harris-Kefauver Amendment of
the FFDCA was made law that such drugs must be proven effective for their intended use before
being marketed.431
In 1994 dietary supplements were placed in a separate category in the Dietary Supplement
Health and Education Act (DSHEA).428,432 In DSHEA dietary supplements were defined as products
with vitamin, herb, mineral, botanical substance, amino acid or components of these chemicals—
including metabolites, extractions, concentrations or combinations of these chemicals.428,432 In this
law producers of these supplements did not need to get FDA approval before marketing these
products if they were marketed in the United States before October 15, 1994. If such a product did
not meet this 1994 requirement (called New Dietary Ingredient) the manufacturer must provide
“reasonable evidence” of safety that would be reviewed but not approved by the FDA.
This has opened up the market with a large number of products that the public thinks will help
them in various ways including weight management. Clinicians and the general public are inundated
in the 21st century with a wide variety of over-the-counter products and herbal products with
various claims but proof of efficacy or safety can be elusive. Unfortunately, the US FDA has identified
various products with ingredients (such as phenethylamines) that can be harmful to the public and
the federal law does require that serious dietary-supplement-related adverse effects be reported to
the FDA.433 Caveat emptor!
The issue of protecting the public from potential harm of prescription and non-prescription drugs has
continued in the 21st century and the FDA has received increased post-market legal authority to review
and make public potential health risks seen in various foods, nonprescription drugs, dietary supplements,
and miscellaneous public health products marketed in the United States.434,435 The US Congress gave
additional legal authority to the FDA in 2007 to have the pharmaceutical industry perform post-
marketing studies on their products with regard to safety of these drugs.436 Thus, the battle continues
with claims of drug benefit and safety that must be monitored by the FDA but also by clinicians caring for
patients seeking health benefits of various products including potential anti-obesity agents.
Over-the-counter and herbal drugs (medicinal plants)
A wide variety of over-the-counter chemicals are available around the world with variable links
to “medicinal” plants—some of which have a long anecdotal history. Though not approved by a
country’s official agencies (i.e., FDA in the United States), they may be taken by the public with or
without a clinician’s recommendation. Many have limited research if any behind them and a lack of
standardization for these studies may be an issue.
Some, as noted with ephedra or herbal ephedra have been found to be harmful.167,168 Time may
tell if these agents and phytochemicals from medicinal plants (i.e., Nigella sativa, Camellia sinensis,
green tea, black Chinese tea) are effective and safe for children, adolescents and adults who have
overweight or obese conditions requiring anti-obesity agents.269,389,437,438 Table 28 lists some over-
the-counter agents, so called dietary supplements that have been proposed and/or marketed as
weight loss chemicals.
Caffeine
Some weight loss (“modest” in some studies) may occur in caffeine consumers due to
hypothalamic effects of oxytocin neurons with lowered energy intake and augmented energy
expenditure.280,439,440 Caffeine release via a dissolving microneedle is under study.441 Adverse

effects of the xanthine derivative caffeine include increased sympathomimetic stimulation, physical
dependence with chronic use, diuresis and even death with excessive consumption.442,443
A 2012 Cochrane Database analysis concluded that consumption of green tea (with caffeine and
catechins) led to a small but not significant weight loss in adults that was not maintained.444 The
overall potential health benefits of teas (green and white) remain controversial and under
study.445,446 Some studies note health benefit such as weight loss with green tea and black Chinese
tea.447 Weight loss may occur with green tea but does not increase with added caffeine and high-
protein diet.448
Some researchers link a reduced risk of type 2 diabetes mellitus in those drinking 3 to 4 cups of
coffee each day and suggest this health benefit is due to presence of caffeine and chlorogenic acids in
coffee.449 Potential health benefits from drinking tea or coffee may also be due to the presence of
catechins that are antioxidants from the flavonoid chemical family.450 Isoflavones such as genistein
and daidzein can be found in coffee beans (as well as soybeans and fava beans) that has been
reviewed earlier in this monograph.374–378,451
Chitosan
Chitosan is a deacetylated chitin that is globally found in various OTC products and advocated as
a diet supplement with various health benefits.452,453 Research has thus far not shown statistically
significant weight loss development or maintenance.454,455 Chronic use may interfere with vitamin
B12 properties.456
Chromium picolinate
This is a chemical compound found in various supplements globally and, though claimed
to have benefit in helping with obesity, has not been proven as an effective anti-obesity agent.457
Chromium picolinate is needed by insulin for proper utilization of glucose but deficiencies
are rare.
Citrus aurantium
Citrus aurantium is a citrus tree and various health benefits are purported with its fruit; it can be
found in various diet supplements. Various names are given to this fruit and its components
including bitter orange and sour orange. Its primary main protoalkaloidal component is
p-synephrine and its potential action is via its properties as a potent, selective neuromedin U2
receptor agonist.458,459
Its potential anti-obesity effects are noted as “modest” by some but minimal if at all by many
researchers and its place as an anti-obesity agent remains unproven.460–462 As with all medication
including over-the-counter diet supplements, adulteration may occur as with phenethylamines
(PEAs).463
Table 28
Anecdotal, proposed and/or marketed (OTC) weight loss products.
1. Caffeine
2. Soybeans Isoflavones: genistein; daidzein (vida supra)
3. Chitosan
4. Chromium picolinate
5. Citrus aurantium (bitter orange)
6. I-carnitine
7. Garcinia cambogia
8. Hoodia
9. Yerba mate
10. Korean herbal formula
11. Others
L-carnitine
Carnitine is a quaternary ammonium compound found in D and L forms. It is involved in various
metabolism functions, is produced in the human body and rare cases are noted in males who cannot
make it. L-carnitine has been utilized as a performance enhancing agent as well as an anti-obesity
chemical. Its role in both remains understudy and a case of reversible cerebral vasoconstriction
syndrome has been reported in an adult on L-carnitine.442,464,465
Garcinia cambogia
There are studies noting that some weight loss may occur from consumption of Garcinia
cambogia (Garcina gummi-gutta) and its fruit rind that contains hydroxycitric acid is often used on
foods (as fish curries) for its sour taste.466 Endogenous lipid biosynthesis control is also seen with
use of Garcinia cambogia.467
Its actual ability to induce weight loss remains unproven despite its popularity as a diet
supplement and hydroxycitric acid is an active component of diet supplements banned by the FDA in
2009 for risk of hepatotoxicity.468 Cases have been reported of acute liver failure, acute necrotizing
eosinophilic myocarditis, and mania in patients using Garcinia cambogia.468–471
A number of “medicinal” plants are being studied which have shown anti-obesity effects in
addition to Garcinia cambogia. These plants include Camellia sinensis, Caralluma fimbriata, Cissus
quadrangularis, Curcuma longa, Emblica officinalis, Nigella sativa, Portulaca oleracea L, Salacia oblonga,
Panax ginseng (ginseng), Zingiber officinale (zingiber), Momordica charantia (bitter mellon) and
others.437,438,462,472,473
Hoodia
Hoodia is part of the family Apocynaceae, a southern African plant (stapeliads), and Hoodia
gordonii is the best known of a number of Hoodia species.474–476 Though Hoodia gordonii is often
called a natural appetite suppressant, scientific support for such a description is sparse and in need
of more sound literature support.477,478
Yerba mate
Yerba maté (Illex paraguariensis) is another popular herb used for weight loss effects as well as
enhancement of metabolic health effects.479,480 However, more research is needed to scientifically
verify these positive effects and allow it to find its place if any in the anti-obesity pharmacopoeia.481
Side effects must be identified as well including potential problems from metal content of various
herbal supplements (321).482
Korean herbal formula

A popular herbal product in Korea and other areas that is advocated as a weight loss product and
has some research support for children (average age of 11 years) and adults is the Korean herbal
formula (based on Taeumjowi-tang).483,484 This product contains a variety of agents including
berries, nuts, roots, stalks and seeds (Table 29).
This formula includes a species of ephedra (Ma Huang) called Ephedra sinica and contains
alkaloids of ephedrine and pseudoephedrine (7).168 Use of ephedrine and ephedrine alkaloids in
dietary supplements was banned in 2004 because of a large number of reports of adverse effects
including abuse potential and sudden death.485 After the ban on ephedra products, manufacturers
changed their supplements to be ephedra free and added such ingredients as Citrus aurantium and
caffeine (vida supra).168
Anti-obesity agents previously approved
A number of medications have been pulled from the market over the past decades that had
shown promise for safe weight loss but are no longer available due to concerns with their adverse
side effect profile (Table 30).168 It is vital that clinicians understand the current and proposed anti-
obesity drugs as well as follow their patients on these agents very closely to protect the human
Table 29
Constituents of the Korean Formula based on Taeumjowi-tang168,483,484.
1. Roots
a. Liriope platyphylla
b. Acorus calamus
2. Nuts (Castanea crenata) (Chinese or Japanese chestnut)
3. Stalks (Ephedra sinica) (see text)
4. Berries (Schisandra chinensis)
5. Seeds
a. Coix lacryma-jobi (Job’s tears)
b. Raphanus sativus (Japanese radish)
c. Pinus koraiensis (Korean pine)
6. Pelargonium grandiflorum (Andrews)
beings under their care. These now abandoned drugs should be remembered as new ones come
along with great hype and hope.
Some of these former drugs are now briefly considered. For example, FDA-withdrawn anti-
obesity drugs include aminorex (amphetamine-like agent) in 1968 (increased risk for pulmonary
hypertension), fenfluramine as well as dexfenfluramine in 1997 and phenylpropanolamine (PPA)
in 2000.185,187,261,486,487
Phenylpropanolamine (PPA)
PPA is produced from the phenethylamine drug family and utilized as a decongestant and
appetite suppressant. PPA was withdrawn as an appetite suppressant because of its association with
risk of hemorrhagic cardiovascular accidents in 18 to 49-year old females; though the risk was not
great, this adverse effect was too serious to ignore.487–490 Also, the possibility of birth defects has
been raised for pregnant females taking decongestants such as PPA.491
Fenfluramine
An increased risk for primary pulmonary hypertension and valvulopathy was identified with the
serotonergic agent fenfluramine as well as dexfenfluramine and they were withdrawn as anti-
obesity agents in 1997.168,487 The combination of fenfluramine and phentermine (Fen-Phen diet) was
also discontinued though approval of phentermine for short-term obesity management which was
approved in 1959 was not changed.
Various drugs have been associated with pulmonary artery hypertension including
selective serotonin reuptake inhibitors (SSRIs), fenfluramine products, aminorex, phenylpropanol-
amine, L-tryptophan and others.322,492 In 1997 the FDA also alerted the public to avoid the
combination of ephedra and Hypericum perforatum (herbal “Fen-Phen”) due to reported adverse
effects.168,485
Table 30
Withdrawn of proposed and/or formerly approved anti-obesity agents.
1. Aminorex (withdrawn in 1968)

2. Fenfluramine (withdrawn in 1997)
3. Dexfenfluramine (withdrawn in 1997)
4. Phenylpropanolamine (PPA) (withdrawn in 2000)
5. Sibutramine (withdrawn from USA market in 2010)
6. Rimonabant (never approved in United States)
7. Beloranib (research halted in 2015 due to adverse profile)
Sibutramine
Sibutramine is a norepinephrine-5-hydroxytryptamine reuptake inhibitor with a DEA Schedule

IV classification that was approved by the FDA for those ≥ 16 years of age as an anti-obesity
agent.168,493 A number of cardiovascular, neuropsychiatric and carcinogenic adverse effects were
linked with this drug.178,186,193,197,280,495–497 A number of contraindications were noted with
sibutramine as listed in Table 31.
The Sibutramine Cardiovascular Outcomes (SCOUT) Trial revealed an increase in serious
(typically non-fatal) cardiovascular complications from sibutramine and it was withdrawn from
the market in 2010.178,488,494,498 Though withdrawn from some markets (as the United States and
Europe), sibutramine is available in others and also found in so-called “herbal” products or dietary
supplements—whether adulterated or not.497,499–502
Rimonabant
Rimonabant (AM-6545) is a cannabinoid type-1 receptor blocker (CB1-selective cannabinoid

receptor antagonist/inverse agonist) that was used in Europe for management of adult obesity due to
its effect on appetite reduction.173,503,504 Rimonabant has also been utilized as a drug to treat
substance use disorders such as nicotine use disorder.505,506
Its approval in Europe in 2006 was withdrawn globally due to identified side effects that included
increased risk for neuro-psychiatric issues such as depression and suicide.197,280,494,498 The U.S. Food
and Drug Administration’s (FDA) Endocrinologic and Metabolic Drug Advisory Committee voted that
rimonabant should not be approved as a drug for adult obesity treatment.507
Beloranib
Beloranib is a selective methionine aminopeptidase 2 inhibitor that was proposed and studied as
an anti-obesity agent.199 During research using this drug two persons with Prader-Willi syndrome
died and the Phase III clinical trial of beloranib was stopped.382 The story of this drug and others
listed in Table 30 is that clinicians caring for pediatric and adult patients with overweight and
obesity should be careful with recommendations of anti-obesity agents and must follow their
patients very carefully with a wary eye for known and potentially yet-to-be identified adverse effects
that may profoundly and negatively affect these precious patients.
Summary: Pharmacology of Obesity
The use of medications to benefit overweight or obese pediatric patients remains limited and
challenging at this time. Only one drug, orlistat, is currently FDA-approved for those 12 years of age
and older, though adverse effects limit its use in many. Those 16 years of age and especially older
have more approved drugs as reviewed in Table 16.
Table 31
Contraindications for Sibutramine.
1. Avoid in those with bulimia or anorexia

2. Avoid with serotonergic agents (triptan drugs, tramadol, selective serotonin reuptake inhibitors, others)
3. Avoid during or within 2 weeks of monoamine oxidase inhibitors (MAOIs)
4. Do not use in those with narrow-angle glaucoma
5. Do not use in those with severe liver or kidney dysfunction
6. Do not use in those with substance abuse history
7. Do not use in those with poorly controlled hypertension
8. Do not use in those with various heart diseases
Research is recognizing the importance of the hypothalamus in regulating food intake with energy
expenditure and thus, more medications with central effects are emerging from the efforts of 21st century
researchers.508 Focus is also on various gastrointestinal hormones as well as their receptors, vaccines, and
other agents especially in poly- versus monotherapy (Tables 26 and 27).509,510
Complicating this quest for the nepenthe of anti-obesity medication are many factors including
these: 85% or more of early clinical trials of new drugs fail, the road from research to clinical practice
is complex as well as very costly, side effects may be unacceptable to patients (or clinicians), serious
adverse side effect profiles of these drugs may not be known until after approval is given (thus, the
need for post-marketing safety research), various drugs of promise have been withdrawn from
the market (Table 30) and the cost of approved anti-obesity agents may be prohibitive to many in
the highly political milieu of 21st century American insurance coverage.231,316,486,489,494,510–514 Thus,
primum non nocere remains important for all clinicians to remember when considering anti-obesity
medication for pediatric and adult patients with obesity. Clinicians must utilize modern principles of
pharmacology along with non-maleficence in caring for these precious pediatric patients.510–515
Bariatric surgery in adolescents
Childhood obesity is a progressive disease with 50-75% of these patients carrying their obesity
into adulthood. With few successful non-operative treatment options for some, bariatric surgery has
emerged as the primary treatment modality in recent years for these individuals. This discussion
now reflects on concepts of bariatric surgery including pre-operative evaluation, indications for
surgery and specific bariatric surgical procedures (vida infra).
Pre-operative evaluation
There has been a recent dramatic increase in adolescent bariatric surgical procedures as a
primary treatment modality for severe childhood obesity in pediatric tertiary care centers that offer
a comprehensive multidisciplinary care through childhood obesity programs. These programs are
offered jointly by the American College of Surgeons (ACS) and the American Society for Metabolic
and Bariatric Surgery (ASMBS). Approved sites, often in the same institution and incorborated within
an adult program, are required to have the participation of pediatric specialists within a
multidisciplinary team and participating surgeons must demonstrate adequate volume to ensure
current proficiency.516
Multiple recent reports showed that postoperative complication rates for adolescents appear to
be the same or better when compared to adult cohorts.516 Early intervention for treatment of
adolescent obesity is very effective as demonstrated by marked improvement, if not complete
resolution, of the major comorbid conditions associated with obesity, as well as quality of life
improvement.517 Compared to adults, comorbidities are less advanced and more likely to be
reversible in younger patients.518 Similar to adult obese patients, recent studies suggest the
existence of an inverse relationship between the severity of preoperative body mass and the
probability of achieving a non-obese state during the postoperative time period in adolescent
patients.516,518
For a successful treatment of obese adolescents, it is critical to have a multidisciplinary team
available that includes a primary care physician, cardiologist, pulmonologist, psychiatrist,
nutritionist and adolescent obesity specialist. Family participation and support during the treatment
process is of paramount importance for positive outcomes. It is critical for the adolescent patient to
understand that surgery is only the beginning of a permanent lifestyle change that requires hard
work and commitment. Therefore, psychological evaluation is particularly important and adequate
emotional maturity as well as stability is necessary to ensure competent decision-making and
vigilant follow-up after surgery. Complete nutritional and endocrine assessment is important to rule
out metabolic derangements or medically treatable causes of obesity.
When surgery is considered, usually six months or more after failure of non-surgical options, the
patient must undergo rigorous preoperative evaluation, testing and counseling. The optimal timing
of adolescent bariatric surgery has not been determined. However, adolescent bariatric surgery
should not occur until physiological maturation is generally complete and sexual maturation is at
Tanner stage III–IV. The guidelines for surgical weight loss therapies for severely obese adolescents
will most likely continue to evolve.516,517
Indications for surgery
The indications for bariatric surgery that were established at the 1991 National Institutes of
Health (NIH) consensus conference continue to be the standard for adult patient selection.519 These
criteria include persons with a BMI of 40 kg/m2 or greater or those with a BMI of 35 kg/m2 or greater
with obesity-related comorbidities and who strongly desire weight loss because obesity severely
impairs their quality of life. Although no final consensus exists for the pediatric patient, current
recommendations from the professional pediatric community call for a higher threshold from that
used in the adult population. Prevailing recommendations and guidelines for indications of
adolescent bariatric surgery include.519
1. Failure of ≥ 6months of organized weight loss attempts.

2. BMI ≥ 40 kg/m2 with serious obesity-related comorbidities.
3. BMI ≥ 50 kg/m2 with less serious obesity-related comorbidities.
Many clinicians advocate bariatric surgery for adolescents only when severe obesity with a BMI
440 is reached, and once they have achieved skeletal maturity (age 13 for girls and 15 for boys).519
Surgical Procedures
Introduction
The weight loss procedures that are currently utilized in the adolescent population include Roux-
en-Y gastric bypass (RYGBP), sleeve gastrectomy, biliopancreatic diversion and adjustable gastric
band. Additionally, a recently FDA-approved intragastric balloon (IGB) has been used selectively over
the last two years (Fig. 1). There is no clear consensus on which procedure(s) is the most effective or
appropriate in the adolescent population. As mentioned earlier, current reports examining the use of
various bariatric procedures in the adolescent population demonstrate safety and efficacy profiles
that are similar to those seen in the adult population.516,518
Three mechanisms by which bariatric surgery produces weight loss are malabsorptive (i.e.,
biliopancreatic bypass), restrictive (i.e., adjustable gastric band or sleeve gastrectomy) and combined
malabsorptive as well as restrictive mechanisms (i.e., Roux-en-Y gastric bypass). The two procedures
most commonly performed on adolescents are gastric bypass and sleeve gastrectomy. Roux-En-Y
gastric bypass (RYGBP) is currently the gold standard weight loss surgery in United States for both
adolescent and adult patients.519 The two procedures less commonly performed in this age group
include biliopancreatic bypass with duodenal switch and adjustable gastric band (AGB). The former
is associated with severe nutritional and protein deficiencies and the latter has fallen out of favor
after surgeons shifted to sleeve gastrectomy. Additionally, utilization of gastric bands for adolescents
has not yet received United States Food and Drug Administration (FDA) approval for patients under
age 18.
The National Institutes of Health (NIH) conducted a multicenter trial between 2007 and 2012 to
evaluate preoperative characteristics and outcomes in severely obese adolescents undergoing
weight loss surgery. In this study (Teen Longitudinal Assessment of Bariatric Surgery [Teen-LABS]),
242 patients were included in the final analysis.520 The mean age of participants was 17.1±1.6 years
and the median BMI was 50.5 kg/m2; fifty-one percent demonstrated four or more major co-morbid
conditions.
Bariatric procedures performed in the Teen-LABS study included laparoscopic Roux-en-Y gastric
bypass (66%), vertical sleeve gastrectomy (28%) and adjustable gastric banding (6%).520 There was no
mortality within 30 days of surgery; however, major complications (e.g., reoperation) were seen in
Fig. 1. Bariatric Surgery Procedures. (A) Normal Gastrointestinal Anatomy. (B) Sleeve Gastrectomy, and (C) Roux-en-Y
Gastric Bypass are the most commonly performed weight loss procedures in adolescents. (D) Biliopancreatic diversion
with duodenal switch; not performed in adolescents due to risk of complications in this age group. (E) Intragastric
Balloon (IGB); a newly introduced endoscopic weight loss procedure. (D) Adjustable Gastric Band (AGB).
19 patients (8%) and minor complications (e.g., readmission for dehydration) were noted in 36
patients (15%). All re-operations and 85% of re-admissions were related to weight loss surgery. The
results of this study demonstrated a favorable short-term complication profile, supporting the early
postoperative safety of weight loss surgery in select adolescents.520 Common complications of
bariatric procedures are listed in Table 32.521–536
Laparoscopic Sleeve Gastrectomy (LSG)

LSG has recently surged in popularity in adults and is being increasingly used in adolescents. LSG
is a purely restrictive weight loss procedure weight loss in which a 70-75% of the stomach is excised
along the greater gastric curvature creating a long gastric tube while leaving the bowel in normal
anatomical continuity. Initially, this procedure was used as step 1 of a 2-stage procedure in
management of super-obese patients (BMI 450) to allow some degree of weight loss and decrease
in liver size for few months. Then a formal gastric bypass is performed on the remaining stomach, as
described above.
The increasing popularity of sleeve gastrectomy is due to its technical simplicity with decreased
complication rate compared to RYGBP. When compared to laparoscopic adjustable gastric banding,
sleeve gastrectomy significantly reduces plasma ghrelin levels and subsequently suppresses
appetite.521
The outcomes of LSG are comparable to gastric bypass. A report522 at 12 months demonstrated
BMI reduction from 49.6 to 32.4 kg/m2 and a study reported at 12 and 24 months demonstrated a
reduction of BMI from 38.5 to 26.3 kg/m2.523 All studies also reported improvement in insulin
resistance, dyslipidemia and obstructive sleep apnea. A few retrospective studies noted that LSG had
a successful short-term weight loss in more than 90% of pediatric patients and 70% or more
comorbidity resolution during a 24-month follow-up period.524–526
Table 32
Complications of Bariatric Surgeries (%)521–536.
Complications of Sleeve Gastrectomy (LSG)

• Staple line disruption (0-20%)
• Bleeding (0-14.3%)
• Gastric stenosis (0-2%)
• Marginal ulcerations
• Gastroesophageal reflux
• Gastric dilatation and weight gain
Complications of Roux-en-Y Gastric By-Pass (RYGBP)
▪ Acute:
o Anastomotic leak (2- 5%)
o Pulmonary embolism ( o 1%)
o Internal hernia and bowel obstruction (1-2%)
o Gastrointestinal Bleeding (2%)
o Wound infection (0-8%)
o Acute gastric dilatation
o Death
▪ Chronic:
o Marginal ulceration (2-10%)
o Stomal stenosis (2-14%)
o Cholelithiasis (0-2%)
o Port-site hernia (0-3%)
o Nutritional deficiencies (iron, B12)
o Inadequate weight loss
Adjustable Gastric Band (AGB)
• Band slippage (14%)
• Band erosion (1-3%)
• Port site infection (0.4-4%)
• Band malfunction (0.5-2%)
• Esophageal dilatation
• Inadequate weight loss
Intragastric Balloon (IGB)
▪ Gastric ulcers
▪ Gastric erosion
▪ Esophagitis
▪ Spontaneous deflation of the balloon
▪ Gastroesophageal reflux.
▪ Death (rare)
Roux-en Y Gastric Bypass (RYGBP)

Roux-en Y gastric bypass (RYGBP), the most effective weight-reducing procedure, is a combined
restrictive and malabsorptive procedure. It is usually performed laparoscopically and some bariatric
surgeons perform this operation utilizing robotic-assisted technology as well. Additionally, a “single
incision” gastric bypass has been performed though less frequently.
In this procedure a small gastric pouch (about 30 ml) is created by dividing the proximal gastric
fundus from the rest of the stomach. The small bowel (jejunum) is then divided beyond the ligament
of Treitz. The distal end of the divided bowel is brought up as a roux limb (alimentary limb) and
anastomosed to the pouch. The proximal end of the small bowel (biliary limb) is then reconnected to
the small bowel distally creating a Roux limb of 100-150 cm.
Nutritional complications are common after gastric bypass and include deficiency of folate, vitamin
B12, iron and calcium. Dumping syndrome occurs in most patients; however, this complication can be
ameliorated by dietary behavior modification to avoid sweets and high-calorie foods. In a meta-analysis,
weight loss in adolescents after gastric bypass ranged from 17.8 to 22.3 kg/m2 in studies with one to six
years of follow-up.518 Several series have reported 56 to 62 percent excess weight loss after Roux-en-Y
gastric bypass in pediatric cohorts.527–529
Laparoscopic Adjustable Gastric Band (AGB)

AGB is rarely used now in United States, however, it was approved by the Food and Drug
Administration (FDA) in 2001 for treatment of morbid obesity in adults and then was utilized by a
few centers for treating obese adolescents. The procedure involves placing a specially designed
device around the proximal gastric fundus, thus creating a small gastric pouch. This is a purely
restrictive surgical procedure that works by limiting the amount of food intake. The pouch can be
adjusted by injecting saline into a port placed in the abdominal wall. This procedure is reversible and
carries lower risks of morbidity (complications) and mortality (0-0.1% compared to 1% for gastric
bypass). In spite of effective short-term outcomes, this procedure is performed less frequently
especially with the current feasibility of sleeve gastrectomy.530,531
Endoscopic procedures
Recently the FDA has approved an intragastric balloon(IGB) device for treatment of patients with
BMI 30-40 kg/m2 who have failed to lose weight through diet and exercise. This is a restrictive
procedure in which the balloon is inserted into the stomach through the mouth, using upper
gastrointestinal endoscopy while the patient is under mild sedation. Once in place, the balloon is
filled with saline from 400 to 700 mL and left in place for 6 months. Reports showed this technique
is safe and effective with short-term weight loss (weight loss between 20-50%).532 The IGB is a
reversible, minimally invasive and non-surgical procedure. It was initially used as an adjuvant before
bariatric surgery in morbidly obese patients to reduce life-threatening co-morbidities and surgical
risk.533
Conclusion: Bariatric surgery

Most of major obesity-related medical comorbidities show dramatic improvements after bariatric
surgery. Such improvements, for example, are noted in type II diabetes mellitus, (80-95%),
triglyceride levels (85-95%), obstructive sleep apnea (70-90%) and reduced depression as well as
improved quality of life.534–536 For the best outcomes, potential candidates should be referred to
nationally accredited adolescent bariatric programs that have multidisciplinary weight management
teams with expertise in meeting the unique needs of obese adolescents. The perioperative education
and follow-up of the adolescent patient and family is critical for better outcomes and the avoidance
of potential adverse events after bariatric surgery.
Conclusions and Future Directions
The obesity phenomenon has become a global concern that has sparked public health initiatives
from different countries to prevent it, in the hope of improving quality of life as well as curtailing the
astronomical costs involved in the management of the serious co-morbid conditions that accompany
obesity in adulthood; these include cardiovascular, respiratory, gastrointestinal, renal and
psychological diseases.
Reflection on historical perspectives regarding obesity has demonstrated the overwhelming
realization that ancient health scholars (from Hippocrates to Galen to Sydenham) to modern day
physicians already knew that obesity is dangerous for human beings. Clinicians from ancient to
modern times have recommended that management of obesity should be accomplished through a
balance between sound dietary habits coupled with physical activity that is promoted by the
individual’s own self-preservation values and beliefs.
Since children in particular have not acquired the maturity required to make their own self-
preservation goals, the role of the parent or guardian is critical to serve as a modeling perspective to
educate and implement the healthy lifestyle needed for overall health promotion and prevention of
obesity. Prevention and management programs should start in utero and extend throughout
childhood, adolescence and adulthood.537,538
Multiple interventional programs have been attempted that utilize varying degrees of patient-
centered care to family-focused participation and community based models; they have
demonstrated different effects from no success to very little success in changing attitudes and
behavior around childhood obesity. Barriers to participation from recruitment to sustained

involvement in these studies have been identified.
Newer anti-obesity drugs are being manufactured in the hope of alleviating or reducing obesity;
however, clinicians must remember that their risk-to-benefit ratio for use in pediatric populations is
still controversial and must be under the watchful eye of concerned, caring clinicians. The role of
such pharmacology and also bariatric surgery in pediatric obesity continues to evolve in this early
part of the 21st century.527,539,540
It is in the light of this emergent situation on global obesity that the World Health Organization
along with the Centers for Disease Control and Prevention provide the call for primary preventive
programs to become the focus of governments and public health agencies around the world. A
multi-faceted, family-focused, community-assisted primary prevention program can use intensive
educational support and actual demonstration involving meal planning, grocery shopping and meal
preparation for at-risk families.
These meals should start with a base ingredient that is mixed with different nutritional
components with fruits and vegetables that can be interchanged to create different acceptable
recipes. It is our premise that if we teach the world’s precious children how to participate in healthy
meal preparation with their parents, the family has a better chance of adapting these healthy meal
choices as part of their lifestyle.
References
1. Haslam D, Rigby N. A long look at obesity. Lancet. 2010;376(9735):85–86.

2. Ferrucci L, Studenski SA, Alley DE, et al. Obesity in aging and art. J Gerontol A Biol Sci Med Sci. 2010;65(1):53–56.
3. Abdelfattah A, Allam AH, Wann S, et al. Atherosclerotic cardiovascular disease in Egyptian women: 1570 BCE-2011 CE.
Int J Cardiol. 2013;167(2):570–574.
4. Ben-Shlomo I, Grinbaum E, Levinger U. Obesity-associated infertility - the earliest known description. Reprod Biomed
Online. 2008;17:5–6.
5. Christopoulou-Aletra H, Papavramidou N. Methods used by the Hippocratic physicians for weight reduction. World J
Surg. 2004;28(5):513–517.
6. Papavramidou NS, Papavramidis ST, Christopoulou-Aletra H. Galen on obesity: etiology, effects, and treatment. World J
Surg. 2004;28(6):631–635.
7. Papavramidou N, Christopoulou-Aletra H. Greco-Roman and Byzantine views on obesity. Obes Surg. 2007;17(1):
112–116.
8. Berry EM, Arnoni Y, Aviram M. The Middle Eastern and Biblical origins of the Mediterranean diet. Public Health Nutr.
2011;14(12A):2288–2295.
9. Abdel-Halim RE. Obesity: 1000 years ago. Lancet. 2005;366(9481):204. http://dx.doi.org/10.1016/SO140-6736
(05)66907-3.
10. Stolberg M. ‘Abhorreas pinguedinem’: Fat and obesity in early modern medicine (c. 1500-1750). Stud Hist Philos Biol
Biomed Sci. 2012;43(2):370–378.
11. Haslam D. The history of obesity. Clin Obes. 2011;1(4-6):189–197.
12. Komaroff M. For researchers on obesity: historical review of extra body weight definitions. J Obes. 2016;2016:
2460285. http://dx.doi.org/10.1155/2016/2460285.
13. Rush EC, Yan MR. Evolution not revolution: nutrition and obesity. pii: E519. Nutrients. 2017;9(5): http://dx.doi.org/
10.3390/nu9050519.
14. Popkin BM. Global changes in diet and activity patterns as drivers of the nutrition transition. discussion 10-4, 259-68.
Nestle Nutr Workshop Ser Pediatr Program. 2009;63:1–10. http://dx.doi.org/10.1159/000209967.
15. Haslam D. Weight management in obesity – past and present. Int J Clin Pract. 2016;70(3):206–217.
16. Maffetone PB, Rivera-Dominguez I, Laursen PB. Overfat and underfat: new terms and definitions long overdue. Front
Public Health. 2017;4:279. http://dx.doi.org/10.3389/fpubh.2016.00279.
17. Merriam-Webster. https://www.merriam-webster.com. [Assessed 3 December 2017].
18. {C}Skinner AC, Perrin EM{C}, Skelton JA. Prevalence of obesity and severe obesity in US children, 1999-2014. Obesity
(Silver Spring) 2016; 24(5):1116-1123.
19. Higgins V, Adeli K. Pediatric metabolic syndrome: pathophysiology and laboratory assessment. EJIFCC. 2017;28(1):
25–42.
20. Lobstein T. Commentary: which child obesity definitions predict health risk? Ital. J Pediatr. 2017;43(1):
20. http://dx.doi.org/10.1186/s13052-017-0337-0.
21. Sassi F, Devaux M, Cecchini M, et al. The obesity epidemic: analysis of past and projected future trends in selected OECD
countries. OECD Heal Work Pap 2009;45(45).
22. Swinburn BA, Sacks G, Hall KD, et al. The global obesity pandemic: shaped by global drivers and local environments.
Lancet. 2011;378(9793):804–814.
23. Poobalan A, Aucott L. Obesity among young adults in developing countries: A systematic overview. Curr Obes Rep.
2016;5(1):2–13.
24. Wang Y, Lobstein T. Worldwide trends in childhood overweight and obesity. Int J Pediatr Obes. 2006;1(1):11–25.
25. Hu F. Obesity Epidemiology. 512 pages. Oxford, England: Oxford Scholarship Online. 2009. http://dx.doi.org/10.1093/
acprof:oso/9780195312911.003.0021.
26. Abarca-Gómez L, Bentham J, Di Cesare M, et al. Worldwide trends in body-mass index, underweight, overweight, and
obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128·9 million children,
adolescents, and adults. Lancet. 2017. http://dx.doi.org/10.1016/S0140-6736(17)32129-3. published online Oct 10.
27. Di Cesare M, Bentham J, Stevens GA, et al. Trends in adult body-mass index in 200 countries from 1975 to 2014: a pooled
analysis of 1698 population-based measurement studies with 19.2 million participants. Lancet. 2016;387(10026):
1377–1396.
28. Braun N, Gomes F, Schülz P. “The obesity paradox” in disease—is the protective effect of obesity true? Swiss Med Wkly.
2015;145:w14265. http://dx.doi.org/10.4414/smw.2015.14265. eCollection 2015.
29. Musaad S, Haynes E. Obesity. IARC Sci Publ. 2011;163:441–452.
30. World Health Organization. 2008-2013 Action Plan for the Global Strategy for the Prevention and Control of
Noncommunicable Diseases. Geneva, Switzerland [electronic article]. 2008{C}; ISBN 9789241597418 (NLM Classification:
WT500).
31. WHO. Global action plan for the prevention and control of noncommunicable diseases 2013-2020. World Heal. Organ.
[electronic article]. 2013. 102. Resolution WHA66.10. http://www.who.int/nmh/events/ncd_action_plan/en/. [Accessed:
3 December 2017].
32. World Health Organization. WHO | Obesity and overweight. WHO [electronic article]. 2016{C}; http://www.who.int/
mediacentre/factsheets/fs311/en/. [Assessed 3 December 2017].
33. Sowers JR. Obesity as a cardiovascular risk factor. Am J Med. 2003;115(Suppl 8A):37S–41S.
34. Shiri R, Lallukka T, Karppinen J, et al. Obesity as a risk factor for sciatica: a meta-analysis. Am J Epidemiol. 2014;179(8):
929–937.
35. Stein PD, Beemath A, Olson RE. Obesity as a risk factor in venous thromboembolism. Am J Med. 2005;118(9):978–980.
36. De Pergola G, Silvestris F. Obesity as a major risk factor for cancer. J Obes. 2013;2013:291546.
http://dx.doi.org/10.1155/2013/291546. Epub 2013 Aug 29.
37. Jochem C, Leitzmann M. Obesity and colorectal cancer. Recent Results Cancer Res. 2016;208:17–41.
38. Mokdad AH, Ford ES, Bowman BA, et al. Prevalence of obesity, diabetes, and obesity-related health risk factors, 2001.
JAMA. 2003;289(1):76–79.
39. Després JP. Intra-abdominal obesity: an untreated risk factor for type 2 diabetes and cardiovascular disease. J Endocrinol
Investig. 2006;29(3 Suppl):77–82.
40. Arroyo-Johnson C, Mincey KD. Obesity epidemiology worldwide. Gastroenterol Clin North Am. 2016;45(4):571–579.
41. Woolf SH, Aron LY. The US health disadvantage relative to other high-income countries: findings from a national
research council/institute of medicine report. JAMA. 2013;309(8):771–772.
42. Ogden CL, Carroll MD, Fryar CD, et al. Prevalence of obesity among adults and youth: United States, 2011-2014. NCHS
Data Brief. 2015(219):1–8.
43. Finkelstein EA, Khavjou OA, Thompson H, et al. Obesity and severe obesity forecasts through 2030. Am J Prev Med.
2012;42(6):563–570.
44. Ogden CL, Carroll MD, Kit BK, et al. Prevalence of obesity and trends in body mass index among US children and
adolescents, 1999-2010. JAMA. 2012;307(5):483–490.
45. Wang Y, Beydoun MA, Liang L, et al. Will all Americans become overweight or obese? estimating the progression and
cost of the US obesity epidemic. Obesity (Silver Spring). 2008;16(10):2323–2330.
46. Pan L, Blanck HM, Sherry B, et al. Trends in the prevalence of extreme obesity among US preschool-aged children living
in low-income families, 1998-2010. JAMA. 2012;308(24):2563–2565.
47. Wen X, Gillman MW, Rifas-Shiman SL, et al. Decreasing prevalence of obesity among young children in Massachusetts
from 2004 to 2008. Pediatrics. 2012;129(5):823–831.
48. Robbins JM, Mallya G, Polansky M, et al. Prevalence, disparities, and trends in obesity and severe obesity among
students in the Philadelphia, Pennsylvania, school district, 2006–2010. Prev Chronic Dis. 2012;9:E145.
http://dx.doi.org/10.5888/pcd9.120118.
49. Skinner AC, Perrin EM, Skelton JA. Prevalence of obesity and severe obesity in US children, 1999-2014. Obesity. 2016;24
(5):1116–1123.
50. Steinbrook R. Surgery for severe obesity. N Engl J Med. 2004;350(11):1075–1079.
51. Claire Wang Y, Gortmaker SL, Taveras EM. Trends and racial/ethnic disparities in severe obesity among US children and
adolescents, 1976–2006. Int J Pediatr Obes. 2011;6(1):12–20.
52. Shields M, Carroll MD, Ogden CL. Adult obesity prevalence in Canada and the United States. NCHS Data Brief. 2011;56:
1–8.
53. Carroll MD, Navaneelan T, Bryan S, et al. Prevalence of obesity among children and adolescents in the United States and
Canada. NCHS Data Brief. 2015;211:2009–2013.
54. Braveman P, Gottlieb L. The social determinants of health: it’s time to consider the causes of the causes. Public Health
Rep. 2014;129(Suppl 2):19–31.
55. Monteiro CA, Conde WL, Lu B, et al. Obesity and inequities in health in the developing world. Int J Obes Relat Metab
Disord. 2004;28(9):1181–1186.
56. Popkin BM, Gordon-Larsen P. The nutrition transition: worldwide obesity dynamics and their determinants. Int J Obes
Relat Metab Disord. 2004;28(Suppl. 3):S2–S9.
57. Hill J. Physical activity and obesity. Lancet. 2004;363(9404):182.
58. Fox KR, Hillsdon M. Physical activity and obesity. Obes Rev. 2007;8(Suppl. 1):S115–S121.
59. {C}Health and Social Care Information Centre. Statistics on obesity, physical activity and diet. 39 pages, 2016. http://
www.digital.nhs.uk/catalogue/PUB20562. [Assessed 23 November 2017].
60. Weiler R, Stamatakis E. Physical activity in the UK: a unique crossroad? Br J Sports Med. 2010;44(13):912–914.
61. Henderson VR, Kelly B. Food advertising in the age of obesity: Content analysis of food advertising on general market
and African American television. J Nutr Educ Behav. 2005;37(4):191–196.
62. Anderson SE, Martins PA, Gittelsohn J. Changing the food environment for obesity prevention: key gaps and future
directions. Curr Obes Rep. 2014;3(4):451–458.
63. Jeffery RW, Baxter J, McGuire M, et al. Are fast food restaurants an environmental risk factor for obesity? Int J Behav Nutr
Phys Act. 2006;3:2.
64. Wang Y, Lim H. The global childhood obesity epidemic and the association between socio-economic status and
childhood obesity. Int Rev Psychiatry. 2012;24(3):176–188.
65. Koh HK, Piotrowski JJ, Kumanyika S, et al. Healthy people: a 2020 vision for the social determinants approach. Health
Educ Behav. 2011;38(6):551–557.
66. No authors listed. American Academy of Pediatrics. Committee on Nutrition. Nutritional aspects of obesity in infancy
and childhood. Pediatrics. 1981;68(6):880–883.
67. Bravo J, Raimundo AM. SDTR. Abdominal obesity in adolescents: development of age-specific waist circumference cut-
offs linked to adult IDF criteria. Am J Hum Biol. 2017. http://dx.doi.org/10.1002/ajhb.23036.
68. Styne DM, Arslanian SA, Connor EL, et al. Pediatric obesity–assessment, treatment, and prevention: An endrocrine
society clinical practice guideline. J Clin Endocrinol Metabol. 2017;102(3):709–757.
69. Hsieh J, Hayashi AA, Webb J, et al. Postprandial dyslipidemia in insulin resistance: mechanisms and role of intestinal
insulin sensitivity. Atheroscler Suppl. 2008;9(2):7–13.
70. Lewis GF, Carpentier A, Adeli K, et al. Disordered fat storage and mobilization in the pathogenesis of insulin resistance
and type 2 diabetes. Endocr Rev. 2002;23(2):201–229.
71. Tomiyama AJ, Hunger JM, Nguyen-Cuu J, et al. Misclassification of cardiometabolic health when using body mass index
categories in NHANES 2005–2012. Int J Obes (Lond). 2016;40(5):883–886.
72. Muñoz-Garach A, Cornejo-Pareja I, Tinahones FJ. Does metabolically healthy obesity exist? pii: E320. Nutrients. 2016;8
(6): http://dx.doi.org/10.3390/nu8060320.
73. Pinhas-Hamiel O, Zeitler P. Clinical presentation and treatment of type 2 diabetes in children. Pediatr Diabetes. 2007;8
(Suppl. 9):S16–S27.
74. Lipton RB, Drum ML, Danielson KK, et al. Onset features and subsequent clinical evolution of childhood diabetes over
several years. Pediatr Diabetes. 2011;12(4 Pt 1):326–334.
75. Milani D, Cerutti M, Pezzani L, et al. Syndromic obesity: clinical implications of a correct diagnosis. Ital J Pediatr. 2014;40
(1):33. http://dx.doi.org/10.1186/1824-7288-40-33.
76. Sharda S, Panigrahi I, Marwaha RK. MOMO syndrome with holoprosencephaly and cryptorchidism: expanding the
spectrum of the new obesity syndrome. Case Rep Genet. 2011;2011:839650. http://dx.doi.org/10.1155/2011/839650.
77. Syndromes{C}. Genetics Home Reference. https://ghr.nim.nih.gov. [Assessed 3 December 2017].
78. Hamdy{C} O. Obesity Work-up Published on Line with Medscape Internet. Updated Oct. 11, 2017.
79. Levy E, Saenger AK, Steffes MW, et al. Pediatric obesity and cardiometabolic disorders: risk factors and biomarkers.
EJIFCC. 2017;28(1):6–24.
80. Hadizadeh F, Faghihimani E, Adibi P. Nonalcoholic fatty liver disease: diagnostic biomarkers. World J Gastrointest
Pathophysiol. 2017;8:11–26.
81. Ochiai H, Shirasawa T, Nishimura R, et al. Abdominal obesity and serum adiponectin complexes among
population-based elementary school children in Japan: a cross-sectional study. BMC Pediatr. 2014;14:
81. http://dx.doi.org/10.1186/1471-2431-14-81.
82. Panagopoulou P, Galli-Tsinopoulou A, Fleva A, et al. Adiponectin and insulin resistance in childhood obesity. J Pediatr
Gastroenterol Nutr. 2008;47(3):356–362.
83. Helba M, Binkovitz LA. Pediatric body composition analysis with dual-energy X-ray absorptiometry. Pediatr Radiol.
2009;39(7):647–656.
84. Fursevich DM, LiMarzi GM, O’Dell MC, et al. Bariatric CT imaging: challenges and solutions. Radiographics. 2016;36(4):
1076–1086.
85. Villarroya MA, Esquivel JM, Tomás C, et al. Assessment of the medial longitudinal arch in children and adolescents with
obesity: footprints and radiographic study. Eur J Pediatr. 2009;168(5):559–567.
86. Pulgarón ER. Childhood obesity: a review of increased risk for physical and psychological comorbidities. Clin Ther.
2013;35(1):A18–A32.
87. Llewellyn A, Simmonds M, Owen CG, et al. Childhood obesity as a predictor of morbidity in adulthood: a systematic
review and meta-analysis. Obes Rev. 2016;17(1):56–67.
88. Gibson LY, Allen KL, Davis E, et al. The psychosocial burden of childhood overweight and obesity: evidence for persisting
difficulties in boys and girls. Eur J Pediatr. 2017;176(7):925–933.
89. Ames M, Leadbeater B. Overweight and isolated: The interpersonal problems of youth who are overweight from
adolescence into young adulthood. Int J Behav Dev. 2017;41(3):390–404.
90. Sánchez-Villegas A, Pimenta AM, Beunza JJ, et al. Childhood and Young Adult Overweight/Obesity and Incidence of
Depression in the SUN Project, 18. Obesity (Silver Spring); 2010; p 1443–1448.
91. McLeod GF, Fergusson DM, Horwood JL, et al. Adiposity and psychosocial outcomes at ages 30 and 35. Soc Psychiatry
Psychiatr Epidemiol. 2016;51(2):309–318.
92. Li J, Olsen J, Vestergaard M, et al. Prenatal stress exposure related to maternal bereavement and risk of childhood
overweight. PLoS One. 2010;5(7):e11896. http://dx.doi.org/10.1371/journal.pone.0011896.
93. Barrett KJ, Thompson AL, Bentley ME. The influence of maternal psychosocial characteristics on infant feeding styles.
Appetite. 2016;103:396–402.
94. Braungart-Rieker JM, Lefever JB, Planalp EM, et al. Body mass index at 3 years of age: cascading effects of prenatal
maternal depression and mother-infant dynamics. J Pediatr. 2016;177:128–132.
95. Stang J, Loth KA. Parenting style and child feeding practices: potential mitigating factors in the etiology of childhood
obesity. J Am Diet Assoc. 2011;111(9):1301–1305.
96. Gemmill AW, Worotniuk T, Holt CJ, et al. Maternal psychological factors and controlled child feeding practices in
relation to child body mass index. Child Obes. 2013;9(4):326–337.
97. Wilson SM, Sato AF. Stress and paediatric obesity: what we know and where to go. Stress Health. 2014;30(2):91–102.
98. Garasky S, Stewart SD, Gundersen C, et al. Family stressors and child obesity. Soc Sci Res. 2009;38(4):755–766.
99. Björntorp P. Do stress reactions cause abdominal obesity and comorbidities? Obes Rev. 2001;2(2):73–86.
100. Bi S, Haak EA, Gilbert LR, et al. Children exposed to marital conflict exhibit more disordered eating behaviors: Child
emotional insecurity and anxiety as mechanisms of risk. J Child Fam Stud. 2017. http://dx.doi.org/10.1007/s10826-017-
0811-8.
101. Tate AD, Trofholz A, Rudasill KM, et al. Does child temperament modify the overweight risk associated with parent
feeding behaviors and child eating behaviors? An exploratory study. Appetite. 2016;101:178–183.
102. Wu T, Dixon WE Jr. Dalton WT 3rd, et al. Joint effects of child temperament and maternal sensitivity on the development
of childhood obesity. Matern Child Health J. 2011;15(4):469–477.
103. Pervanidou P, Chrousos GP. Stress and obesity/metabolic syndrome in childhood and adolescence. Int J Pediatr Obes.
2011;1(Suppl):21–28.
104. Suglia SF, Duarte CS, Chambers EC, et al. Social and behavioral risk factors for obesity in early childhood. J Dev Behav
Pediatr. 2013;34(8):549–556.
105. Hemmingsson E, Johansson K, Reynisdottir S. Effects of childhood abuse on adult obesity: a systematic review and meta-
analysis. Obes Rev. 2014;15(11):882–893.
106. Marmorstein NR, Iacono WG, Legrand L. Obesity and depression in adolescence and beyond: reciprocal risks. Int J Obes.
2014;38(7):906–911.
107. Olive LS, Telford RM, Byrne DG, et al. Symptoms of stress and depression effect percentage of body fat and insulin
resistance in healthy youth: LOOK longitudinal study. Health Psychol. 2017;36(8):749–759.
108. Meule A, Hofmann J, Weghuber D, et al. Impulsivity, perceived self-regulatory success in dieting, and body mass in
children and adolescents: a moderated mediation model. Appetite. 2016;107:15–20.
109. Davis C. Psychobiological traits in the risk profile for overeating and weight gain. Int J Obes (Lond). 2009;33(Suppl 2):
S49–S53.
110. Vander Wal JS, Mitchell ER. Psychological complications of pediatric obesity. Pediatr Clin North Am. 2011;58(6):
1393–1401.
111. Puhl RM, Latner JD. Stigma, obesity, and the health of the nation’s children. Psychol Bull. 2007;133(4):557–580.
112. Haines J, Hannan PJ, Van Den Berg P, et al. Weight-related teasing from adolescence to young adulthood: Longitudinal
and secular trends between 1999 and 2010. E428–E434. Obesity. 2013;21(9): http://dx.doi.org/10.1002/oby.20092.
113. Harrist AW, Swindle TM, Hubbs‐Tait L, et al. The social and emotional lives of overweight, obese, and severely obese
children. Child Dev. 2016;87(5):1564–1580.
114. Madowitz J, Knatz S, Maginot T, et al. Teasing, depression and unhealthy weight control behaviour in obese children.
Pediatr Obes. 2012;7(6):446–452.
115. Storch EA, Ledley DR. Peer victimization and psychosocial adjustment in children: current knowledge and future
directions. Clin Pediatr. 2005;44(1):29–38.
116. Eisenberg ME, Neumark-Sztainer D, Story M. Associations of weight-based teasing and emotional well-being among
adolescents. Arch Pediatr Adolesc Med. 2003;157(8):733–738.
117. Franklin J, Denyer G, Steinbeck KS, et al. Obesity and risk of low self-esteem: a statewide survey of Australian children.
Pediatrics. 2006;118(6):2481–2487.
118. Gibson LY, Byrne SM, Blair E, et al. Clustering of psychosocial symptoms in overweight children. Aust N Z J Psychiatry.
2008;42(2):118–125.
119. Rankin J, Matthews L, Cobley S, et al. Psychological consequences of childhood obesity: psychiatric comorbidity and
prevention. Adolesc Health Med Ther. 2016;7:125–146.
120. Lanza HI, Grella CE, Chung PJ. Adolescent obesity and future substance use: incorporating the psychosocial context.
J Adolesc. 2015;45:20–30.
121. Omar HA, Greydanus DE, Patel DR, Merrick J. Obesity and Adolescence: A Public Health Concern. 295 pages. NY: Nova
Science Publishers; 2009.
122. Lazar-Antman MA, Leet AI. Effects of obesity on pediatric care and management. J Bone Joint Surg Am. 2012;94(9):
855–861.
123. Azziz R, Woods KS, Reyna R, et al. The prevalence and features of the polycystic ovary syndrome in an unselected
population. J Clin Endocrinol Metab. 2004;89(6):2745–2749.
124. Fauser BC, Tarlatzis BC, Rebar RW, et al. Consensus on women's health aspects of polycystic ovary syndrome (PCOS): the
Amsterdam ESHRE/ASRM-Sponsored 3rd PCOS Consensus Workshop Group. Fertil Steril. 2012;97(1):28–38. e25.
125. Hart R, Doherty DA. The potential implications of a PCOS diagnosis on a woman's long- term health using data linkage. J
Clin Endocrinol Metab. 2015;100(3):911–919. Epub 2014/12/23.
126. Witchel SF, Oberfield S, Rosenfield RL, et al. The diagnosis of polycystic ovary syndrome during adolescence. hormone
research in paediatrics. Horm Res Paediatr. 2015;83:376–389.
127. Javed A, Chelvakumar G, Bonny AE. Polycystic ovary syndrome in adolescents: a review of past year evidence. Curr Opin
Obstet Gynecol. 2016;28(5):373–380. Epub 2016/07/19.
128. Legro RS, Arslanian SA, Ehrmann DA, et al. Diagnosis and treatment of polycystic ovary syndrome: an endocrine society
clinical practice guideline. J Clin Endocrinol Metab. 2013;98(12):4565–4592.
129. Dumesic DA, Oberfield SE, Stener-Victorin E, et al. Scientific statement on the diagnostic criteria, epidemiology,
pathophysiology, and molecular genetics of polycystic ovary syndrome. Endocr Rev. 2015;36(5):487–525.
130. Zawadzki JK, Dunaif A. Diagnostic criteria for polycystic ovary syndrome: towards a rational approach. In: Dunaif A,
Givens GR, Haseltine F, Merriam GR, eds. Polycystic Ovary Syndrome. Boston, MA: Blackwell Scientific Publications; 1992:
377–384.
131. Rotterdam ESHRE/ASRM-sponsored PCOS consensus workshop group. Revised 2003 consensus on diagnostic criteria
and long-term health risks related to polycystic ovary syndrome. Fertil Steril. 2004;81(1):19–25.
132. Azziz R, Carmina E, Dewailly D, et al. Positions statement: criteria for defining polycystic ovary syndrome as a
predominantly hyperandrogenic syndrome: an Androgen Excess Society guideline. J Clin Endocrinol Metab. 2006;91(11):
4237–4245.
133. National Institutes of Health. Evidence-based Methodology Workshop on Polycystic Ovary Syndrome December 3–5,
2012. 2012.
134. Codner E, Villarroel C, Eyzaguirre FC, et al. Polycystic ovarian morphology in postmenarchal adolescents. Fertil Steril.
2011;95(2): 702-6 e1-2.
135. Blank SK, Helm KD, McCartney CR, et al. Polycystic ovary syndrome in adolescence. Ann N Y Acad Sci. 2008;1135:76–84.
136. Fanelli F, Gambineri A, Mezzullo M, et al. Revisiting hyper- and hypo-androgenism by tandem mass spectrometry. org/.
Rev Endocr Metab Disord. 2013;14:185. http://dx.doi.org/10.1007/s11154-013-9243-y.
137. Kamboj MK, Patel DR. Polycystic ovarian syndrome: a diagnostic and therapeutic challenge. J Pediatric Sci. 2010;2:
e4. http://www.pediatricsciences.com/ojs/index.php/jps/article/view/28/pdf_21.
138. Bremer AA. Polycystic ovary syndrome in the pediatric population. Metab Syndr Relat Disord. 2010;8(5):375–394.
139. Buggs C, Rosenfield RL. Polycystic ovary syndrome in adolescence. Endocrinol Metab Clin North Am. 2005;34(3):677–705.
140. Marzouk TM, Sayed Ahmed WA. Effect of dietary weight loss on menstrual regularity in obese young adult women with
polycystic ovary syndrome. J Pediatr Adolesc Gynecol. 2015;28(6):457–461.
141. Fields EL, Trent ME. Treatment considerations for the cardiometabolic signs of polycystic ovary syndrome: a review of
the literature since the 2013 endocrine society clinical practice guidelines. JAMA Pediatr. 2016;170(5):502–507.
142. Lass N, Kleber M, Winkel K, et al. Effect of lifestyle intervention on features of polycystic ovarian syndrome, metabolic
syndrome, and intima-media thickness in obese adolescent girls. J Clin Endocrinol Metab. 2011;96(11):3533–3540.
143. Martin KA, Chang RJ, Ehrmann DA, et al. Evaluation and treatment of hirsutism in premenopausal women: an endocrine
society clinical practice guideline. J Clin Endocrinol Metab. 2008;93(4):1105–1120.
144. Al Khalifah RA, Florez ID, Dennis B, et al. Metformin or oral contraceptives for adolescents with polycystic ovarian
xyndrome: a meta-analysis. Pediatrics. 2016;137(5):e20154089. http://dx.doi.org/10.1542/peds.2015-4089.
145. Writing Group for the SEARCH for Diabetes in Youth Study Group, Dabelea D, Bell RA, D'Agostino RB Jr. Dabelea D, Bell
RA, D'Agostino RB Jr, et al. Incidence of diabetes in youth in the United States. JAMA. 2007;297(24):2716–2724.
146. Fagot-Campagna A, Pettitt DJ, Engelgau MM, et al. Type 2 diabetes among North American children and adolescents: an
epidemiologic review and a public health perspective. J Pediatr. 2000;136(5):664–672.
147. Centers for Disease Control and Prevention. National Diabetes Statistics Report, 2017. Estimates of diabetes and its
burden in the United States. Atlanta, CA. https://www.cdc.gov/diabetes/pdfs/data/statistics/national-diabetes-statistics-
report.pdf. [Accessed 23 November 17].
148. American Diabetes Association. Classification and diagnosis of diabetes. Diabetes Care. 2017;40(Suppl 1):S11–S24.
149. Rajjo T, Mohammed K, Alsawas M, et al. Treatment of pediatric obesity: an umbrella systematic review. J Clin Endocrinol
Metab. 2017;102(3):763–775.
150. Parikh Y, Mason M, Williams K. Researchers’ Perspectives on pediatric obesity research participant recruitment. Clin
Transl Med. 2016;5:20. http://dx.doi.org/10.1186/s40169-016-0099-0.
151. Steinbeck K. Childhood obesity. Treatment options. Best Pract Res Clin Endocrinol Metab. 2005;19(3):455–469.
152. Epstein LH, Wing RR, Penner BC, et al. Effect of diet and controlled exercise on weight loss in obese children. J Pediatr.
1985;107:358–361.
153. No authors listed. Obesity. preventing and managing the global epidemic. Report of a WHO consultation. World Health
Organ Tech Rep Ser. 2000;894:1–253. i-xii.
154. Eisenmann JC. Assessment of obese children and adolescents: a survey of pediatric obesity- management programs.
Pediatrics. 2011;128(Suppl. 2):S51–S58.
155. Redfern J, Enright G, Raadsma S, et al. Effectiveness of a behavioral incentive scheme linked to goal achievement: study
protocol for a randomised controlled trial. Trial. 2016;17:33. http://dx.doi.org/10.1186/s13063-016-1161-3.
156. Wake M, Lycett K, Sabin MA, et al. A shared-care model of obesity treatment for 3- 10 year old children: protocol for the
HopSCOTCH randomized controlled trial. BMC Pediatr. 2012;12:39. http://dx.doi.org/10.1186/1471-2431-12-39.
157. Wake M, Lycett K, Clifford S, et al. Shared care obesity mangement in 3 -10 year old children: 12 month outcomes of
HopSCOTCH randomized trial. BMJ. 2013;346:f3092. http://dx.doi.org/10.1136/bmj.f3092.
158. Christie D, Hudson L, Mathiot A, et al. Assessing the efficacy of the healthy eating and lifestyle programme (HELP)
compared with enhanced standard care of the obese adolescent in the community: study protocol for a randomized
controlled trial. Trials. 2011;12:242. http://dx.doi.org/10.1186/1745-6215-12-242.
159. Christie D, Hudson LD, Kinra S, et al. A community-based motivational personalized lifestyle intervention to reduce BMI
in obese adolescents: results from the health eating and lifestyle programme (HELP) randomized controlled trial. Arch
Dis Child. 2017;102(8):695–701.
160. Gomez SF, Casas R, Palomo VT, et al. Study protocol: effects of the THAO-child health intervention program on the
prevention of childhood obesity – The POIBC study. BMC Pediatr. 2014;14:215. http://dx.doi.org/10.1186/1471-
2431-14-215.
161. Santiago F, Santiago R, Gil-Antuñano N. ThaO-Child Health Programme: community- based interventions for healthy
lifestyles promotion to children and families: results of a cohort study. Nutr Hosp. 2015;32(6):2584–2587.
162. Rui L. Brain regulation of energy balance and body weight. Rev Endocr Metab Disord. 2013;14(4):387–407.
163. Faulconbridge LF, Hayes MR. Regulation of energy balance and body weight by the brain: a distributed system prone to
disruption. Psychiatr Clin North Am. 2011;34(4):733–745.
164. McDuffie JR, Calis KA, Uwaifo GI, et al. Efficacy of orlistat as an adjunct to behavioral treatment in overweight African
American and Caucasian adolescents with obesity-related co-morbid conditions. J Pediatr Endocrinol Metab. 2004;17:
307–319.
165. Greydanus DE, Bricker LA, Patel DR. The benefits of sports participation in childhood and adolescence to prevent obesity
in adolescents and adults. Asian J Paediatric Practice. 2006;9(4):1–7.
166. Greydanus DE, Bhave S. Obesity in the adolescent. Indian Pediatrics. 2004;41(6):545–550.
167. Greydanus DE, Feucht C, Patel DR. Pharmacology for Obese Adolescents. Int J Child and Human Development. 2008;1(4):
385–394.
168. Greydanus DE, Bricker L, Feucht C. Pharmacology for Obese Adolescents. Pediatric Clin No Amer. 2011;58(1):
139–153. PMID: 2128153.
169. Dixon JB. Weight loss medications—where do they fit in? Aust Fam Physician. 2006;35(8):576–579.
170. Ryan DH, Bray GA. Pharmacologic treatment options for obesity: what is old is new again. Curr Hypertens Rep. 2013;
15(3):182–189.
171. Curry SA. Obesity epidemic: pharmaceutical weight loss. R I Med J (2013). 2017;100(2):18–20.
172. Kirk S, Scott BJ, Daniels SR. Pediatric obesity epidemic: treatment options. J Am Diet Assoc. 2005;105(5 Suppl. 1): S44-
S51.
173. Eneli I, Mantinan KD. “Managing the overweight child”. ch 9. In: Fitzgerald HE, Mousouli V, eds. Obesity in Childhood and
Adolescence., vol. 2. Westport, CT: Praeger Publishers; 2008:191–225.
174. Webb E, Viner R. Should metformin be prescribed to overweight adolescents in whom dietary/behavioural
modifications have not helped? Arch Dis Child. 2006;91:793–794.
175. Bosanquet N. The European Medicines Evaluation Agency. BMJ. 1994;308(6926):430.
176. Berntgen M, Gourvil A, Pavlovic M, et al. Improving the contribution of regulatory assessment reports to health
technology assessments—a collaboration between European Medicines Agency and the European network for Health
Technology Assessment. Value Health. 2014;17(5):634–641.
177. Hendricks EJ. Off-label drugs for weight management. Diabetes Metab Syndr Obes. 2017;10:223–234.
178. Hainer V. Overview of new antiobesity drugs. Expert Opin Pharmacother. 2014;15(14):1975–1978.
179. Verhaegen AA, Van Gaal LF. Drug-induced obesity and its metabolic consequences: a review with a focus on
mechanisms and possible therapeutic options. J Endocrinol Invest. 2017. http://dx.doi.org/10.1007/s40618-017-0719-6.
180. Wilding JPH. Medication use for the treatment of diabetes in obese individuals. Diabetologia May. http://dx.doi.org/10.
1007/s00125-017-4288-1.
181. Greydanus DE, Calles JL Jr., Patel DR, Nazeer A, Merrick J, editors. Clinical Aspects of Psychopharmacology in Childhood
and Adolescence. Second Edition. NY: Nova Science Publishers; 2017.
182. Rodríquez JE, Campbell KM. Past, present and future of pharmacologic therapy in obesity. Prim Care 2016;43(1):61-67.
183. Shettar V, Patel S, Kidambi S. Epidemiology of obesity and pharmacologic treatment options. Nutr Clin Pract. 2017;32(4):
441–462.
184. Kim S. Drugs to treat obesity: do they work? Postgrad Med J. 2016;92(1089):401–406.
185. Yanovski SZ, Yanovski JA. Obesity. N Engl J Med. 2002;346(8):591–602.
186. Mead E, Atkinson G, Richter B, et al. Drug interventions for the treatment of obesity in children and adolescents.
Cochrane Database Syst Rev. 2016:11. CD012436.
187. Silverstone T. Appetite suppressants. A review. Drugs. 1992;43(6):820–836.
188. White B, Jamieson L, Clifford S, et al. Adolescent experiences of anti-obesity drugs. Clin Obes. 2015;5(3):116–126.
189. Barlow SE, the Expert Committee. Expert committee recommendations regarding prevention, assessment, and
treatment of child and adolescent overweight and obesity: Summary report. Pediatrics. 2007;120(Suppl. 4):S164–S192.
190. Velazquez A, Apovian CM. Pharmacological management of obesity. Minerva Endocrinol. 2017. http://dx.doi.org/
10.23736/S0391-1977.17.02654-2.
191. Khorassani FE, Misher A, Garris S. Past and present antiobesity agents: focus on monoamine modulators. Am J Health
Syst Pharm. 2015;72(9):697–706.
192. Saunders KH, Shukla AP, Igel LI, et al. Pharmacotherapy for obesity. Endocrinol Metab Clin North Am. 2016;45(3):
521–538.
193. Bray GA. Drug insight: appetite suppressants. Nat Clin Pract Gastroenterol Hepatol. 2005;2(2):89–95.
194. Gurevich-Panigraphi T, Panigraphi S, Wiechec E, Los M. Obesity: pathophysiology and clinical management. Curr Med
Chem. 2009;16(4):506–521.
195. Seaton DA, Rose K, Duncan LJ. Current therapeutics. 203. Sustained-action chlorphentermine in the correction of
refractory obesity. Practitioner. 1964;193:698–702.
196. No authors listed. Phentermine: an appetite-suppressant amphetamine classified as a narcotic in France. Is a
combination with topiramate on the horizon? Prescrire Int. 2012 Sep;21(130):209.
197. Ioannides-Demos LL, Piccenna L, McNeil JJ. Pharmacotherapies for obesity: past, current and future therapies. J Obes.
2011;2011:179674. http://dx.doi.org/10.1155/2011/179674.
198. Hampp C, Kang EM, Borders-Hemphill V. Use of prescription antiobesity drugs in the United States. Pharmacotherapy.
2013;33(12):1299–1307.
199. Fujioka K. Current and emerging medications for overweight or obesity in people with comorbidities. Diabetes Obes
Metab. 2015;17(11):1021–1032.
200. Decina L, Tanyol H. Treatment of obesity with a new anorexiant, diethylpropion, without special stress on diet. N Y State
J Med. 1960;60:2702–2705.
201. No Authors listed. Diethylpropion, an appetite suppressant. Med Lett Drugs Ther 1971;12(25):101-2.
202. Cabrerizo Garcia l, Ramos-Levi A, Moreno Lopera C, et al. Update on pharmacology of obesity: benefits and risks. Nutr
Hosp. 2013;28(Suppl 5):121–127.
203. Garcia-Mijares M, Bernardes AM, Silva MT. Diethylpropion produces psychostimulant and reward effects. Pharmacol
Biochem Behav. 2009;91(4):621–628.
204. Lucchetta RC, Riveros BS, Pontarolo R, et al. Diethylpropion and mazindol: an end to the discussion? Rev Assoc Med Bras
(1992). 2017;63(3):203–206.
205. Kalyanasundar B, Solorio J, Perez Cl, et al. The efficacy of the appetite suppressant, diethylpropion, is dependent on both
when it is given (day vs. night) and under conditions of high fat dietary restriction. Appetite. 2016;100:152–161.
206. Cercato C, Roizenblatt VA, Leança CC, et al. A randomized double-blind placebo-controlled study of the long term
efficacy and safety of diethylpropion in the treatment of obese subjects. Int J Obes. 2009;33(8):857–865.
207. Soto-Molina H, Pizarro-Castellanos M, Rosado-Pérez J, et al. Six-month efficacy and safety of amfepramone in obese
Mexican patients: a double-blinded, randomized controlled trail. Int J Clin Pharmacol Ther. 2015;53(7):541–549.
http://dx.doi.org/10.5414/CP202135.
208. Arias HR, Santamaría A, Ali SF. Pharmacological and neurotoxicological actions mediated by bupropion and
diethylpropion. Int Rev Neurobiol. 2009;88:223–255.
209. Suplicy H, Boguszewski CL, dos Santos CM, et al. A comparative study of five centrally acting drugs on the pharmacologic
treatment of obesity. Int J Obes. 2014;38(8):1097–1103.
210. Austin ED, Loyd JE, Phillips JA II. Heritable pulmonary arterial hypertension. GeneReviews [Internet]. Seattle (WA):
University of Washington. Seattle; 1993-2017. 2002. [Updated 2015 Jun 11].
211. No authors listed. Diethylpropion psychosis. Med J Aust 1970;2(23):1052-1053.
212. Carney MW. Diethylpropion and psychosis. Clin Neuropharmacol. 1988;11(2):183–188.
213. Simkin B, Wallace L. A controlled clinical trial of benzphetamine (didrex) in the management of obesity. Curr Ther Res
Clin Exp. 1960;2:33–38.
214. King LA. New phenethylamines in Europe. Drug Test Anal. 2014;6(7-8):808–818.
215. Phear D. Phenmetrazine in the treatment of obesity. Practitioner. 1959;183:62–63.
216. Poindexter A. Appetite suppressant drugs: a controlled clinical comparison of benzphetamine, phenmetrazine,
d-amphetamine and placebo. Curr Ther Res Clin Exp. 1960;2:354–363.
217. Cass LJ. Evaluation of phenmetrazine bitartrate as an appetite suppressant. Can Med Assoc J. 1961;84:1114–1116.
218. Evans J. Psychosis and addiction to phenmetrazine (preludin). Lancet. 1959;2(7095):152–155.
219. Hood I, Monforte J, Gault R, Mirchandani H. Fatality from illicit phendimetrazine use. J Toxicol Clin Toxicol. 1988;26(3-4):
249–255.
220. Landau D, Jackson J, Gonzalez G. A case of demand ischemia from phendimetrazine. Cases J. 2008;1(1):
105. http://dx.doi.org/10.1186/1757-1626-1-105.
221. Boland CL, Harris JB, Harris KB. Pharmacological management of obesity in pediatric patients. Ann Pharmacother.
2015;49(2):220–232.
222. Sweeting AN, Tabet E, Caterson ID, et al. Management of obesity and cardiometabolic risk – role of phentermine/
extended release topiramate. Diabetes Metab Syndr Obes. 2014;7:35–44.
223. Garvey WT, Ryan DH, Look M, et al. Two-year sustained weight loss and metabolic benefits with controlled-release
phentermine/topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase
3 extension study. Am J Clin Nutr. 2012;95(2):297–308.
224. Halpern B, Mancini MC. Safety assessment of combination therapies in the treatment of obesity: focus on naltrexone/
bupropion and phentermine-topiramate extended release. Expert Opin Drug Saf. 2017;16(1):27–39.
225. Bays H. Phentermine, topiramate and their combination for the treatment of adiposopathy (‘sick fat’) and metabolic
disease. Expert Rev Cardiovasc Ther. 2010;8(12):1777–1778.
226. Hainer V, Aldhoon-Hainerová I. Tolerability and safety of the new anti-obesity medications. Drug Saf. 2014;37(9):
693–702.
227. Kumar RB, Aronne LJ. Efficacy comparison of medications approved for chronic weight management. Obesity (Silver
Spring). 2015;23(Suppl 1):S4–S7.
228. Khera R, Murad MH, Chandar AK, et al. Association of pharmacological treatments for obesity with weight loss and
adverse effects: a systematic review and meta-analysis. JAMA. 2016;315(22):2424–2434.
229. Nuffer W, Trujillo JM, Megyeri J. A comparison of new pharmacological agents for the treatment of obesity. Ann
Pharmacother. 2016;50(5):376–388.
230. Shyh G, Heng-Lai C, New A. obesity agents: lorcaserin (Belviq) and phentermine/ topiramate ER (Qsymia). Cardio Rev.
2014;22(1):43–50.
231. Cunningham JW, Wiviott SD. Modern obesity pharmacotherapy: weighing cardiovascular risk and benefit. Clin Cardiol.
2014;37(11):693–699.
232. Guo F, Garvey WT. Cardiometabolic disease predicts effectiveness of weight-loss therapy to prevent type 2 diabetes:
pooled results from Phase III clinical trials assessing phentermine/topiramate extended release. Diabetes Care. 2017;
40(7):856–862.
233. Antza C, Stabouli S, Natsis M, et al. Obesity-induced hypertension: new insights. Curr Pharm Des. 2017. http://dx.doi.org/
10.2174/1381612823666170608083343.
234. No authors listed. Topiramate þ phentermine. An excessively dangerous appetite-suppressant combination. Prescrire
Int 2013;22(136):61-64.
235. Kelly EM, Tungol AA, Wesolowicz LA. Formulary management of 2 new agents: lorcaserin and phentermine/topiramate
for weight loss. J Manag Care Pharm. 2013;19(8):642–654.
236. Woloshin S, Schwartz LM. The new weight-loss drugs, lorcaserin and phentermine-topiramate: slim pickings? JAMA
Intern Med. 2014;174(4):615–619.
237. Verpeut JL, Bello NT. Drug safety evaluation of naltrexone/bupropion for the treatment of obesity. Expert Opin Drug Saf.
2014;13(6):831–841.
238. Luna-Tortós C, Rambeck B, Jurgens UH, et al. The antiepileptic drug topiramate is a substrate for human P-glycoprotein
but not multidrug resistance protein. Pharm Res. 2009;26:2464–2470.
239. Mercer SL. ACS chemical neuroscience molecule spotlight on contrave. ACS Chem Neurosci. 2011;2(9):484–486.
240. No authors listed. Contrave—a combination of bupropion and naltrexone for weight loss. Med Lett Drugs Ther 2014;56
(1455):112-114.
241. Ali KF, Shukla AP, Aronne LJ. Bupropion-SR plus naltrexone-SR for the treatment of mild-to-moderate obesity. Expert Rev
Clin Pharmacol. 2016;9(1):27–34.
242. Padwal R. Contrave, a bupropion and naltrexone combination therapy for the potential treatment of obesity. Curr Opin
Investig Drugs. 2009;10(10):1117–1125.
243. No authors listed. Naltrexone/bupropion: Contrave (R): naltrexone SR/bupropion SR. Drugs R D 2010;10(1):25-32.
244. Apovian CM, Aronne L, Rubino D, et al. A randomized, phase 3 trial of naltrexone SR/bupropion SR on weight and
obesity-related risk factors (COR-II). Obesity (Silver Springs). 2013;21(5):935–943.
245. Greig SL, Keating GM. Naltrexone ER/Bupropion ER: a review in obesity management. Drugs. 2015;75(11):1269–1280.
246. Yanovski SZ, Yanovski JA. Naltrexone extended-release plus bupropion extended-release for treatment of obesity. JAMA.
2015;313(12):1213–1214.
247. O’Neil PM, Smith SR, Weissman NJ, et al. Randomized placebo-controlled clinical trial of lorcaserin for weight loss in
type 2 diabetes mellitus: the BLOOM-DM study. Obesity (Silver Spring) 20(7):1426-36.
248. Berlie HD, Hurren KM. Evaluation of lorcaserin for the treatment of obesity. Expert Opin Drug Metab Toxicol. 2013;9(8):
1053–1059.
249. Tronieri JS, Alfaris N, Chao AM, et al. Lorcaserin plus lifestyle modification for weight loss maintenance: rationale and
design for a randomized controlled trial. Contemp Clin Trials. 2017;59:105–112.
250. Hurren KM, Dunham MW. Pharmacokinetic drug evaluation of extended release lorcaserin for the treatment of obesity.
Expert Opin Drug Metabb Toxicol. 2017;13(8):891–896.
251. No authors listed. Two drugs for weight loss. Med Lett Dr Ther 2012; 54(1398):69-71.
252. Nigro SC, Luon D, Baker WL. Lorcaserin: a novel serotonin 2C agonist for the treatment of obesity. Curr Med Res Opin.
2013;29(7):839–848.
253. Aronne L, Shanahan W, Fain R, et al. Safety and efficacy of lorcaserin: a combined analysis of the BLOOM and BLOSSOM
trials. Postgrad Med. 2014;126(6):7–18.
254. Greenway FL, Shanahan W, Fain R, et al. Safety and tolerability review of lorcaserin in clinical trials. Clin Obes. 2016;6(5):
285–295.
255. Smith SR, Garvey WT, Greenway FL, et al. Coadministration of lorcaserin and phentermine for weight management: a
12-week, randomized, pilot safety study. Obesity (Silver Spring). 2017;25(5):857–865.
256. Mehta A, Marso SP, Neeland IJ. Liraglutide for weight management: a critical review of the evidence. Obes Sci Pract
2017;3(1):3-14.
257. Konstantinos L, Karavis M, Mastorakos G, et al. New molecular targets for the pharmacotherapy of obesity. Editors: De
Groot LJ, Chrousos G, Dungan K, Feinfold KR, Grossman A, Hershman JM, et al. Endotext (internet). South Dartmouth
(MA): MDText.com, Inc; 2000-2015 Apr 8.
258. Prasad-Reddy L, Isaacs D. A clinical review of GLP-1 receptor agonists: efficacy and safety in diabetes and beyond. Drugs
Context 2015 Jul 9:212283. http://dx.doi.org/10.7573/dic.212283.
259. Bareti M, Troskot R. How to fight obesity with antidiabetic drugs: targeting gut or kidney? Minerva Endocrinol. 2015;40
(1):71–83.
260. Hocking S, Dear A, Cowley MA. Current and emerging pharmacotherapies in Australia. Obes Res Clin Pract 2017 Aug 14.
pii: S1871-403X(17)30065-0. http://dx.doi.org/10.1016/j.orcp.2017.07.002.
261. Rowlett JR. “Obesity in the adolescent”. ch. 31. In: Essential Adolescent, editor. Medicine. NY: McGraw-Hill Medical
Publishers; 2006:651–665.
262. Davidson MH, et al. Weight control and risk factor reduction in obese subjects treated for 2 years with orlistat: A
randomized trial. JAMA. 1999;281:235–242.
263. Orlistat for obesity. Med Lett Drugs Ther;1999. 41:55.
264. Freemark M, Kiess W. Anti-obesity medication use in adolescents: risks and benefits. Pediatr Endocrinol Rev. 2004;2
(Suppl. 1):S168–S170.
265. Snow V, Barry P, Fitterman N, et al. Pharmacologic and surgical management of obesity in primary care: A clinical
practice guideline from the American College of Physicians. Ann Intern Med. 2005;142:525–531.
266. Chanoine JP, Hampl S, Jensen C, et al. Effect of orlistat on weight and body composition in obese adolescents: a
randomized controlled trial. JAMA. 2005;293(23):2873–2883.
267. Dunican KC, Desilets AR, Montalbano JK. Pharmacotherapeutic options for overweight adolescents. Ann Pharmacother.
2007;41:1445–1455.
268. Orlistat OTC for weight loss. Med Lett Drugs Ther 2007; 49:49.
269. Bray GA. Are non-prescription medications needed for weight control? Obesity (Silver Spring). 2008;16(3):509–514.
270. Anderson JW. Low-dose orlistat effects on body weight of mildly to moderately overweight individuals: a 16 week,
double-blind, placebo-controlled trial. Ann Pharmacother. 2006;40(10):1717–1723.
271. Maahs D, de Serna DG, Kolotkin RL, et al. Randomized, double-blind, placebo- controlled trial of orlistat for weight loss
in adolescents. Endocr Pract. 2006;12:18–28.
272. Ali Khan R, Kapur P, Jain A, et al. Effect of orlistat on periostin, adiponectin, inflammatory markers and ultrasound
grades of fatty liver in obese NAFLD patients. Ther Clin Risk Manag. 2017;13:139–149.
273. Ozkan B, Bereket A, Turan S, et al. Addition of orlistat to conventional treatment in adolescents with severe obesity.
European J Pediatr. 2004;163(12):738–741.
274. Wilding J. Orlistat: should we worry about liver inflammation? BMJ. 2013;346:f2777. http://dx.doi.org/10.1136/
bmj.f2777.
275. Sali D, Wang J, Rashkin M, Welch M, Droege C, Schauer D. Orlistat-induced fulminant hepatic failure. Clin Obes. 2014;4
(6):342–347.
276. Buysschaert B, Aydin S, Morelle J, et al. Weight loss at a high cost: Orlistat-induced late-onset severe kidney disease.
Diabetes Metab. 2016;42(1):62–64.
277. Chaudhari D, Crisostomo C, Ganote C, et al. Acute oxalate nephropathy associated with orlistat: a case report with a
review of the literature. Case Rep Nephrol. 2013;2013:124604. http://dx.doi.org/10.1155/2013/124604.
278. Coutinho AK, Glancey GR. Orlistat, an under-recognized cause of progressive renal impairment. iv172-4. Nephrol Dial
Transplant. 2013;28(Suppl. 4): http://dx.doi.org/10.1093/ndt/gft066.
279. Carter R, Mouralidarane A, Ray S, et al. Recent advancements in drug treatment of obesty. Clin Med (Lond). 2012;12(5):
456–460.
280. Cheung BM, Cheung TT, Samaranayake NR. Safety of antiobesity drugs. Ther Adv Drug Saf. 2013;4(4):171–181.
281. Fleischman A, Rhodes ET. Management of type 2 diabetes and prediabetes in children and adolescents. Adolesc Med.
2017;28(2):406–422.
282. Laube H. Acarbose, a reliable therapeutic principle. [Article in German]. Med Klin (Munich). 2003;98(Suppl. 1):S2–S6.
283. Wettergreen SA, Sheth S, Malveaux J. Effects of the addition of acarbose to insulin and non-insulin regimens with type
2 diabetes mellitus. Pharm Pract. 2016;14(4):832. http://dx.doi.org/10.18549/PharmPract.2016.04.832.
284. Zhang W, Kim D, Philip E, et al. A multinational, observational study to investigate the efficacy, safety and tolerability of
acarbose as add-on or monotherapy in a range of patients: the Gluco VIP study. Clin Drug Investig. 2013;3(4):263–274.
285. Vos RC, van Avendonk MJ, Jansen H, et al. Insulin monotherapy compared with the addition of oral glucose-lowering
agents to insulin for people with type 2 diabetes already on insulin therapy and inadequate glycaemic control. Cochrane
Database Syst Rev. 2016:9. CD006992.
286. Yang W, Liu J, Shan Z, et al. Acarbose compared with metformin as initial therapy in patients with newly diagnosed type
2 diabetes: an open-label, non-inferiority randomized trial. Lancet Diabetes Endocrinol. 2014;2(1):46–55.
287. Gu S, Shi J, Tang Z, et al. Comparison of glucose lowering effect of meformin and acarbose in type 2 diabetes mellitus: a
meta-analysis. e0126704. PLoS One. 2015;10(5): http://dx.doi.org/10.1371/journal.pone.0126704.
288. Zhang YY, Hou LQ, Zhao TY. Effects of acarbose on polycystic ovary syndrome: a meta-analysis. Exp Clin Endocrinol
Diabetes. 2014;122(6):373–378.
289. Derosa G, Maffioli P. Efficacy and safety profile evaluation of acarbose along and in association with other antidiabetic
drugs: a systematic review. Clin Ther. 2012;34(6):1221–1236.
290. Sugimoto S, Nakajima H, Kosaka K, et al. Review: miglitol has potential as a therapeutic drug against obesity. Nutr Metab
(Lond). 2015 1;12:51. http://dx.doi.org/10.1186/s12986-015-0048-8.
291. Pedersen J. The effect of metformin on weight loss in obesity. Acta Endocrinol (Copenh). 1965;49:479–486.
292. Pedersen J, Olesen ES. Observations on the mechanism of increased weight loss during metformin administration in
obesity. Acta Endocrinol (Copenh). 1968;57:683–688.
293. Douglas JG, Munro JF. Drug treatment and obesity. Pharmacol Ther. 1982;18(3):351–373.
294. Golay A. Metformin and body weight. Int J Obes. 2008;32(1):61–72.
295. Kujawska-Luczak M, Musialik K, Szulińska M, et al. The effect of orlistat versus metformin on body composition and
insulin resistance in obese premenopausal women: 3-month randomized prospective open-label study. Arch Med Sci.
2017;13(4):725–731.
296. Freemark M. Pharmacotherapy of childhood obesity: an evidence-based, conceptual approach. Diabetes Care. 2007;30:
395–402.
297. Srinivasan S, Ambler GR, Baur LA, et al. Randomized, controlled trial of metformin for obesity and insulin resistance in
children and adolescents: Improvement in body composition and fasting insulin. J Clin Endocrinol Metabol. 2006;91(6):
2074–2080.
298. Nestler JE. Metformin for the treatment of polycystic ovary syndrome. N Engl J Med. 2008;358(1):47–54.
299. Hoppin AG, Katz ES, Kaplan LM, et al. Case 31-2006: A 15-year-old girl with severe obesity. N Engl J Med. 2006;355(15):
1593–1602.
300. Harborne L, Fleming R, Lyall H, et al. Metformin or antiandrogen in the treatment of hirsutism in polycystic ovary
syndrome. J Clin Endocrinol Metabol. 2003;88:4116–4123.
301. Zhou L, Cai X, Yang W, et al. The magnitude of weight loss induced by meformin is independently associated with BMI at
baseline in newly diagnosed type 2 diabetes: post- hoc analysis from data of a phase IV open-labeled trial. Adv Clin Exp
Med. 2017 27. http://dx.doi.org/10.17219/acem/63025e.
302. Li S, Li H, Wang R, Zhang JP. The effect of sitagliptin on obese patients with insulin treatment-induced diabetes mellitus.
Eur Rev Med Pharmacol Sci. 2017;21(15):3490–3495.
303. Munir KM, Lamos EM. Diabetes type 2 management: what are the differences between DPP-4 inhibitors and how do
you choose? Expert Opin Pharmacother. 2017;18(9):839–841.
304. Gómez Huelgas R. Weight and type 2 diabetes: new recommendations. Med Clin. 2016;147:17–21.
305. Esquivel MA, Lansang MC. Optimizing diabetes treatment in the presence of obesity. Cleve Clin J Med. 2017;
84(7 Suppl. 1): S22-S29.
306. Steen O, Goldenberg RM. The role of sodium-glucose cotransporter 2 inhibitors in the management of type 2 diabetes.
Can J Diabetes. 2017;41(5):517–523.
307. Blevins TC, Farooki A. Bone effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type
2 diabetes mellitus. Postgrad Med. 2017;129(1):159–168.
308. Press release: FDA confirms increased risk of leg and foot amputations with diabetes mellitus medicine canagliflozin.
Fox Business 05/16/2017. [Assessed 20 November 2017].
309. Hollander P, Bays HE, Rosenstock J, et al. Coadministration of canagliflozin and phentermine for weight management in
overweight and obese individuals without diabetes: a randomized clinical trial. Diabetes Care. 2017;40(5):632–639.
310. Hay DL, Chen S, Lutz TA, et al. Amylin: pharmacology, physiology, and clinical potential. Pharmacol Rev. 2015;67(3):
564–600.
311. Ryan GJ, Jobe JL, Martin R. Pramlintide in the treatment of type 1 and type 2 diabetes mellitus. Clin Ther. 2005;27(10):
1500–1512.
312. Lidell ME, Betz MJ, Enerbäck S. Brown adipose tissue and its therapeutic potential. J Intern Med. 2014;276(4):364–377.
313. Zafir B. Brown adipose tissue: research milestones of a potential player in human energy balance and obesity. Horm
Metab Res. 2013;45(11):774–785.
314. Calmasini FB, de Oliveira MG, Alexandre EC, et al. Long-term treatment with the beta-3 adrenoceptor agonist,
mirabegron ameliorates detrusor overactivity and restores cyclic adenosine monophosphate (cAMP) levels in obese
mice. Neurourol Urodyn. 2017;36(6):1511–1518.
315. Hainer V. Beta3-adrenoreceptor agonist mirabegron – a potential antiobesity drug? Expert Opin Pharmacother. 2016;17
(16):2125–2127.
316. Pino MF, Divoux A, Simmonds AV, et al. Investigating the effects of Orexin-A on thermogenesis in human deep neck
brown adipose tissue. Int J Obes. 2017. http://dx.doi.org/10.1038/ijo.2017.155.
317. Mele L, Bidault G, Mena P, et al. Dietary (poly)phenols, brown adipose tissue activation, and energy expenditure: a
narrative review. Adv Nutr. 2017;8(5):694–704.
318. Fernández-Quintela A, Milton-Laskibar I, González M, et al. Antibody effects of resveratrol; which tissues are involved.
Ann N Y Acad Sci. 2017;1403(1):118–131.
319. Aguirre L, Fernández-Quintela A, Arias N, et al. Resveratrol: anti-obesity mechanisms of action. Molecules. 2014;19(11):
18632–18655.
320. Fluoxetine (Prozac) and other drugs for treatment of obesity. Med Lett Drugs Ther; 1994;36(936):107.
321. Nazeer A, Calles JL Jr. ch 14. In: Greydanus DE, Patel DR, Omar HA, Feucht C, Merrick J, eds. Anxiety disorders. In:
Adolescent Medicine: Pharmacotherapeutics in General, Mental and Sexual Health. Berlin/Boston: Walter de Gruyter GmbH
& Co.; 2012:255–267.
322. Seferian A, Chaumais MC, Savale L, et al. Drugs Induced Pulmonary Arterial Hypertension, 42. Presse Med; 2013; p
e303–e310.
323. Halpern A, Mancini MC. Treatment of obesity: an update on anti-obesity medications. Obes Rev. 2004;4(1):25–42.
324. Bessessen DH, Van Gaal FL. Progress and challenges in anti-obesity pharmacotherapy. pii: S2213-8587(17)30236-X.
Lancet Diabetes Endocrinol. 2017. http://dx.doi.org/10.1016/S2213-8587(17)30236-X.
325. Wren AM, Blood SR. Gut hormones and appetite control. Gastroenterology. 2007;132(6):2116–2130.
326. Stasi C, Milani S. Functions of ghrelin in brain, gut and liver. CNS Neurol Disord Drug Targets. 2016;15(8):956–963.
327. Steinert RE, Feinle-Bisset C, Asarian L, et al. Ghrelin, CCK, GLP-1, and PYY (3-36): secretary controls and physiological
roles in eating and glycemia in health, obesity, and after RYGB. Physiol Rev. 2017;97(1):411–463.
328. Chaudhri OB, Field BC, Bloom SR. Gastrointestinal satiety signals. Int J Obes. 2008;32(Suppl. 7):S28–S31.
329. Ghigo E, Broglio F, Arvat E, et al. Ghrelin: more than a natural GH secretagogue and/or an orexigenic factor. Clin
Endocrinol. 2005;62(1):1–17.
330. Andarini S, Kangsaputra FB, Handayani D. Pre-and posprandial acylated ghrelin in obese and normal weight men. Asia
Pac J Clin Nutr. 2017;26(Suppl. 1):S85–S91.
331. Nguo K, Walker KZ, Bonham MP, et al. Systematic review and meta-analysis of the effect of meal intake on postprandial
appetite-related gastrointestinal hormones in obese children. Int J Obes (Lond). 2016;40(4):555–563.
332. Abegg K, Bernasconi L, Hutter M, et al. Ghrelin receptor inverse agonists as a novel therapeutic approach against
obesity-related metabolic disease. Diabetes Obes Metab. 2017. http://dx.doi.org/10.1111/dom.13020.
333. Xing YX, Yang L, Kuang HY, et al. Function of obestatin in the digestive system. Nutrition. 2017;34:21–28.
334. Corgosinho FC, Almeida SS, Tock L, et al. LEPR polymorphism may affect energy balance during weight loss among
Brazilians obese adolescents. pii: S0143-4179(17) 30029-X. Neuropeptides. 2017. http://dx.doi.org/10.1016/j.npep.
2017.07.007.
335. Zheng H, Lenard NR, Shin AC, et al. Appetite control and energy balance regulation in the modern world: reward-driven
brain overrides repletion signals. Int J Obes. 2009;33(Suppl. 2):S8–S13.
336. Sinha MK, Caro JF. Clinical aspects of leptin. Vitam Horm. 1998;54:1–30.
337. Jéquier E. Leptin signaling, adiposity and energy balance. Ann N Y Acad Sci. 2002;967:379–388.
338. Rostás I, Pótó L, Mátrai P, et al. In middle-aged and old obese patients, training intervention reduces leptin level: a meta-
analysis. PLoS One. 2017;12(8):e0182801. http://dx.doi.org/10.1371/journal.pone.0182801.
339. de Carvalho-Ferreira JP, Masquio DC, da Silveira Campos RM, et al. Is there a role for leptin in the reduction of depression
symptoms during weight loss therapy in obese adolescent girls and boys? Peptides. 2015;65:20–28.
340. Dâmaso AR, de Piano A, Sanches PL, et al. Hyperleptinemia in obese adolescents deregulates neuropeptides during
weight loss. Peptides. 2011;32(7):1384–1391.
341. Van Swieten MM, Pandit R, Adan RA, et al. The neuroanatomical function of leptin in the hypothalamus. J Chem
Neuroanat. 2014;61-62:207–220.
342. Wilson JL, Enriori PJ. A talk between fat tissue, gut, pancreas and brain to control body weight. Mol Cell Endocrinol.
2015;418(Pt 2):108–119.
343. Bhat SP, Sharma A. Current drug targets in obesity pharmacotherapy – a review. Curr Drug Targets. 2017;18(8):983–993.
344. Brown RJ, Meehan CA, Cochran E, et al. Effect of metreleptin in pediatric patients with lipodystrophy. J Clin Endocrinol
Metab. 2017;102(5):1511–1519.
345. Cescão R, Fonseca JE, Moita LF. Celastrol: a spectrum of treatment opportunities in chronic diseases. Front Med
(Lausanne). 2017;4:69. http://dx.doi.org/10.3389/fmed.2017.00069.
346. Venkatesha SH, Moudgil KD. Celastrol and its role in controlling chronic diseases. Adv Exp Med Biol. 2016;928:267–289.
347. Rehfeld JF. Cholecystokinin-from local gut hormone to ubiquitous messenger. Front Endocrinol (Lausanne). 2017;8:
47. http://dx.doi.org/10.3389/fendo.2017.00047.
348. Miller LJ, Desai AJ. Metabolic actions of the type 1 cholecystokinin receptors: its potential as a therapeutic target. Trends
Endocrinol Metab. 2016;27(9):609–619.
349. Emilien C, Hollis JH. A brief review of salient factors influencing adult eating behavior. Nutr Res Rev. 2017:
1–14. http://dx.doi.org/10.1017/S0954422417000099.
350. Biermasz NR. New medical therapies on the horizon: oral octreotide. Pituitary. 2017;20(1):149–153.
351. Lustig RH. Hypothalamic obesity: causes, consequences, treatment. Pediatr Endocrinol Rev. 2008;6(2):220–227.
352. Xu S, Xue Y. Pediatric obesity: causes, symptoms, prevention and treatment. Exp Ther Med. 2016;11(1):15–20.
353. Liu R, Wei N, Guo W, et al. Octreotide alleviates obesity by reducing intestinal glucose absorption and inhibiting low-
grade inflammation. Eur J Nutr. 2013;52(3):1067–1075.
354. Rose-John S. Interleukin-6 family cytokines. Cold Spring Harb Perspect Biol. 2017:a028415. http://dx.doi.org/
10.1101/cshperspect.a028415.
355. Stefater MA, MacLennan AJ, Lee N, et al. The anorectic effect of CNTF does not require action in leptin-responsive
neurons. Endocrinology. 2012;153(6):2647–2654.
356. Xu B, Xie X. Neurotrophic factor control of satiety and body weight. Nat Rev Neurosci. 2016;17(5):282–292.
357. Kim HJ, Min KB, Min JY. Neuropeptide Y gene-by-psychosocial stress interaction effect is associated with obesity in a
Korean population. Psychoneuroendocrinology. 2016;69:10–15.
358. Gumbs MC, van den Heuvel JK, la Fleur SE. The effect of obesogenic diets on brain neuropeptide Y. Physiol Behav.
2016;162:161–173.
359. Seo M, Kim J, Moon SS, et al. Intraventricular administration of Tenebrio molitor larvae extract regulates food intake and
body weight in mice with high-fat diet-induced obesity. Nutr Res. 2017;44:18–26.
360. Choudhury SM, Tan TM, Bloom SR. Gastrointestinal hormones and their role in obesity. Curr Opin Endocrinol Diabetes
Obes. 2016;23(1):18–22.
361. Batterham RL, Cohen MA, Ellis SM, et al. Inhibition of food intake in obese subjects by peptide YY3-36. N Engl J Med.
2003;349(10):941–948.
362. Small CJ, Bloom SR. The therapeutic potential of gut hormone peptide YY3-36 in the treatment of obesity. Expert Opin
Investig Drugs. 2005;14(5):647–653.
363. https://en.wikipedia.org/wiki/Bombesin. [Assessed 20 November 2017].
364. González N, Moody TW, Igarashi H, et al. Bombesin-related peptides and their receptors: recent advances in their role in
physiology and disease states. Curr Opin Endocrinol Diabetes Obes. 2008;15(1):58–64.
365. González N, Moreno P, Jensen RT. Bombesin receptor subtype 3as a potential target for obesity and diabetes. Expert Opin
Ther Targets. 2015;19(9):1153–1170.
366. González N, Martín-Duce A, Martínez-Arrieta F, et al. Effect of bombesin receptor subtype-3 and its synthetic agonist on
signaling, glucose transport and metabolism in myocytes from patients with obesity and type 2 diabetes. Int J Mol Med.
2015;35(4):925–931.
367. Ramos-Álvarez I, Martín-Duce A, Moreno-Villegas Z, et al. Bombesin receptor subtype-3 (BRS-3), a novel candidate as
therapeutic molecular target in obesity and diabetes. Mol Cell Endocrinol. 2013;367(1-2):109–115.
368. Blalock JE, Bost KL, Smith EM. Neuroendocrine peptide hormones and their receptors in the immune system.
Production, processing and action. J Neuroimmunol. 1985;10(1):31–40.
369. Kapahi P, Kaeberlein M, Hansen M. Dietary restriction and lifespan: lessons from invertebrate models. Ageing Res Rev.
2017;39:3–14.
370. Singh CK, Chhabra G, Ndiaye M, et al. The role of sirtuins in antioxidant and redox signaling. Antioxid Redox Signal. 2017
11. http://dx.doi.org/10.1089/ars.2017.7290.
371. Aditya R, Kiran AR, Varma DS, et al. A review of SIRtuins in diabetes. Curr Pharm Des. 2017;23(16):2299–2307.
372. Iyer RN, Shah KH, Venkataraman K. A synthesis of prunetin. Curr Sci. 1949;18(11):404–406.
373. Walter ED. Genistin (an isoflavone glucoside) and its aglucone, genistein, from soybeans. J Amer Chem Soc. 1941;63(12):
3273–3276.
374. Setchell KD, Cassidy A. Dietary isoflavones: biological effects and relevance to human health. J Nutr. 1999;129(3):
758S–767S.
375. Behloul N, Wu G. Genistein: a promising therapeutic agent for obesity and diabetes treatment. Eur J Pharmacol.
2013;698(1-3):31–38.
376. Gilbert ER, Liu D. Anti-diabetic functions of soy isoflavone genistein: mechanisms underlying its effects on pancreatic β-
cell function. Food Funct. 2013;4(2):200–212.
377. Deierlein AL, Wolff MS, Pajak A, et al. Phenol concentrations during childhood and subsequent measures of adiposity
among young girls. Am J Epidemiol. 2017;186(5):581–592.
378. Frankenfeld CL, Atkinson C, Wähälä K, et al. Obesity prevalence in relation to gut microbial environments capable of
producing equol or O-desmethylangolensin from the isoflavone daidzein. Eur J Clin Nutr. 2014;68(4):526–530.
379. Howland RH. Aspergillus, angiogenesis, and obesity: the story behind beloranib. J Psychosoc Nurs Ment Health Serv.
2015;53(3):13–16.
380. Joharapurkar AA, Dhanesha NA, Jain MR. Inhibition of the methioninem aminopeptidase 2 enzyme for the treatment of
obesity. Diabetes Metab Syndr Obes. 2014;7:73–84.
381. Maksimov ML, Svistunov AA, Tarasov VV, et al. Approaches for the development of drugs for treatment of obesity and
metabolic syndrome. Curr Pharm Des. 2016;22(7):895–903.
382. Kim DD, Krishnarajah J, Lillioja S, et al. Efficacy and safety of beloranib for weight loss in obese adults: a randomized
controlled trial. Diabetes Obes Metab. 2015;17(6):566–572.
383. Shoemaker A, Proietto J, Abuzzahab MJ, et al. A randomized, placebo-controlled trial of beloranib for the treatment of
hypothalamic injury-associated obesity. Diabetes Obes Metab. 2017;19(8):1165–1170.
384. McCandless SE, Yanovski JA, Miller J, et al. Effects of MetAP2 inhibition on hyperphagia and body weight in Prader-
Syndrome: a randomized, double-blind, placebo-controlled trial. Diabetes Obes Metab. 2017. http://dx.doi.org/10.1111/
dom.13021.
385. Hughes TE, Kim DD, Marjason J, et al. Ascending Dose-Controlled Trial of Beloranib, A Novel Obesity Treatment for Safety,
Tolerability, and Weight Loss in Obese Women, 21. Obesity (Silver Spring); 2013; p 1782–1788.
386. Steele JM. Primum non nocere: first do no harm. Med Times. 1957;85(7):729–731.
387. Bello NT, Zahner MR. Tesofensine, a monoamine reuptake inhibitor for treatment of obesity. Curr Opin Investig Drugs.
2009;10:1105–1116. 10.
388. Nielsen AL, Larsen TM, Madsbad S, et al. The effect of tesofensine on body weight and body composition in obese
subjects—secondary publication [Article in Danish]. Ugeskr Laeger. 2009;171(41):2974–2977.
389. George M, Rajaram M, Shanmugam E. New and emerging drug molecules against obesity. J Cardiovasc Pharmacol Ther.
2014;19(1):65–76.
390. Axel AM, Mikkelsen JD, Hansen HH. Tesofensine, a novel triple monoamine reuptake inhibitor, induces appetite
suppression by indirect stimulation of alpha1 adrenoceptor and dopamine D1 receptor pathways in the diet-induced
obese rat. Neuropsychopharmacology. 2010;35:1464–1476.
391. Hansen HH, Jensen MM, Overgaard A, et al. Tesofensine induces appetite suppression and weight loss with reversal of
low forebrain dopamine levels in the diet-induced obese rat. Pharmacol Biochem Behav. 2013;110:265–271.
392. Gilbert JA, Gasteyger C, Raben A, et al. The Effect of Tesofensine on Appetite Sensations, 20. Obesity (Silver Spring); 2012; p
553–561.
393. Appel L, Bergström M, Buus Lassen J, et al. Tesofensine, a novel triple monoamine reuptake inhibitor with anti-obesity
effects: dopamine transporter occupancy as measured by PET. Eur Neuropsychopharmacol. 2014;24(2):251–261.
394. Astrup A, Madsbad S, Breum L, et al. Under-reporting of adverse effects of tesofensine. Lancet. 2013;382(9887):
127. http://dx.doi.org/10.1016/S0140-6736(13)61563-9.
395. Tunç S, Demir K, Tükün FA, et al. Melanocortin-4 receptor gene mutations in a group of Turkish obese children and
adolescents. J Clin Res Pediatr Endocrinol. 2017;9(3):216–221.
396. Hinney A, Volckmar AL, Knoll N. Melanocortin-4 receptor in energy homeostasis and obesity pathogenesis. Prog Mol Biol
Transl Sci. 2013;114:147–191.
397. Adan RA, Tiesjema B, Hillebrand JJ, et al. The MC4 receptor and control of appetite. Br J Pharmacol. 2006;149(7):815–827.
398. Mul JD, van Boxtel R, Bergen DJ, et al. Melanocortin Receptor 4 Deficiency Affects Body Weight Regulation, Grooming
Behavior, and Substrate Preference in the Rat, 20. Obesity (Silver Spring); 2012; p 612–621.
399. Shen WJ, Yao T, Kong X, et al. Melanocortin neurons: multiple routes to regulation of metabolism. Biochim Biophys Acta.
2017;1863:2477–2485. 10 Pt A.
400. Chen KY, Muniyappa R, Abel BS, et al. RM 493, a melanocortin-4 receptor (MC4R) agonist, increases resting energy in
obese individuals. J Clin Endocrinol Metab. 2015;100(4):1639–1645.
401. Kievit P, Halem H, Marks DL, et al. Chronic treatment with a melanocortin-4 receptor agonist causes weight loss,
reduces insulin resistance, and improves cardiovascular function in diet-induced obese rhesus macaques. Diabetes.
2013;62(2):490–497.
402. Fosgerau K, Raun K, Nilsson C, et al. Novel α-MSH analog causes weight loss in obese rats and minipigs and improves
insulin sensitivity. J Endocrinol. 2014;220(2):97–107.
403. Fani L, Bak S, Delhanty P, et al. The melanocortin-4 receptor as target for obesity treatment: a systematic review of
emerging pharmacological therapeutic options. Int J Obes. 2014;38(2):163–169.
404. Lee EC, Carpino PA. Melanocortin-4 receptor modulators for the treatment of obesity: a patent analysis (2008-2014).
Pharm Pat Anal. 2015;4(2):95–104.
405. Patek R. Vaccines. Cal State J Med. 1909;7(5):177–181.
406. Mark C, Rigau-Pérez JG. The world’s first immunization campaign: the Spanish smallpox vaccine expedition,1803-1813.
Bull Hist Med. 2009;83:63–94.
407. Reid M, Fleck F. The immunization programme that save millions of lives. Bull World Health Organ. 2014;92(5):314–315.
408. McCarthy M. US vaccine program will prevent 732,000 deaths, CDC says. BMJ. 2014;348:2978.
409. Lernout T, Theeten H, Leuridan E, et al. Do vaccines save lives? Yes they do!. Acta Med Port. 2014;27(2):160–162.
410. Darrow JJ, Kesselheim AS. A new wave of vaccines for non-communicable diseases: what are the regulatory challenges?
Food Drug Law J. 2015;70(2):243–258.
411. Zorrilla EP, Iwasaki S, Moss JA, et al. Vaccination against weight gain. Proc Natl Acad Sci USA. 2006;103(35):13226–13231.
412. Na HN, Kim H, Nam JH. Prophylactic and therapeutic vaccines for obesity. Clin Exp Vaccine Res. 2014;3(1):37–41.
413. Monteiro MP. Obesity vaccines. Hum Vaccin Immunother. 2014;10(4):887–895.
414. Zjacic-Rotkvic V. Endocrinology and immunology of obesity, obesity vaccines. Curr Clin Pharmacol. 2013;8(3):232–237.
415. Monteiro MP. Anti-ghrelin vaccine for obesity: a feasible alternative to dieting? Expert Rev Vaccines. 2011;10(10):
1363–1365.
416. Altabas V, Zjačić-Rotkvić V. Anti-ghrelin antibodies in appetite suppression: recent advances in obesity pharmacother-
apy. Immunotargets Ther. 2015;4:123–130.
417. Fan W, Chen XF, Shen C, et al. Hepatitis B vaccine response in obesity: a meta-analysis. Vaccine. 2016;34(40):4835–4841.
418. Tagliabue C, Principi N, Giavoli C, et al. Obesity: impact of infections and response to vaccines. Eur J Clin Microbiol Infect
Dis. 2016;35(3):325–331.
419. Kelishadi R, Roufarshbaf M, Soheili S, et al. Association of childhood obesity and the immune system: a systematic
review of reviews. Child Obes. 2017;13(4):332–346.
420. Kilborn LG. Chinese medicine; ancient and modern. Can Hosp. 1946;23(2):39–42.
421. Roy A. The merits of the Ayurvedic system of medicine. Ind Med Gaz. 1923;58(2):66–68.
422. Ayyar PR. The eternal glory of Ayurveda. Curr Sci. 1946;15:177–179.
423. Sivarajan VV, Balachandran I. Plant resources for Ayurveda: an outlook for the future. Anc Sci Life. 1983;3(1):45–47.
424. Finlayson J. Ancient Egyptian medicine: [A bibliographical demonstration in the library of the faculty of Physicians and
Surgeons, Glasgow, January 12th. 1893]. Br Med J. 1983;1(1684):748–752.
425. Scholl R. Der Papyrus Ebers. Die grösste Buchrolle zur Heilkunde Altägyptens (Schriften aus der Universitätsbibliothek 7),
Leipzig, Germany; 2002.
426. Porter R. The Greatest Benefit of Mankind: A Medical History of Humanity. New York, NY: WW Norton & Co.; 1998.
427. Kinch MS, Haynesworth A, Kinch SL, et al. An overview of FDA-approved new molecular entities: 1827-2013. Drug Discov
Today. 2014;19(8):1033–1039.
428. Talalay P, Talalay P. The importance of using scientific principles in the development of medicinal agents from plants.
Acad Med. 2001;76(3):175–184.
429. Barkan ID. Industry invites regulation: the passage of the Pure Food and Drug Act of 1906. Am J Public Health. 1985;75
(1):18–26.
430. Cooper DE. Adequate controls for new drugs: good manufacturing practice and the 1938 federal Food, Drug, and
Cosmetic Act. Pharm Hist. 2002;44(1):12–23.
431. Peltzman S. An evaluation of consumer protection legislation: the 1962 drug amendments. J Political Econ. 1973;81(5):
1049–1091.
432. Swann JP. The history of efforts to regulate dietary supplements in the USA. Drug Test Anal. 2016;8(3-4):271–282.
433. Pawar RS, Grundel E. Overview of regulation of dietary supplements in the USA and issues of adulteration with
phenethylamines (PEAs). Drug Test Anal. 2017;9(3):500–517.
434. Roller ST, Pippins RR, Ngai JW. FDA’s expanding postmarket authority to monitor and publicize food and consumer
health product risks: the need for procedural safeguards to reduce “transparency” policy harms in the post-9/11
regulatory environments. Food Drug Law J. 2009;64(3):577–598.
435. Frankos VH, Street DA, O’Neill RK. FDA regulation of dietary supplements and requirements regarding adverse event
reporting. Clin Pharmacol Ther. 2010;87(2):239–244.
436. Evans BJ. The ethics of postmarketing observational studies of drug safety under section 505(o)(3) of the Food, Drug,
and Cosmetic Act. Am J Law Med. 2012;38(4):577–606.
437. Hasani-Ranjbar S, Jouyandeh Z, Abdollahi M. A systematic review of anti-obesity medicinal plants-an update. J Diabetes
Metab Disord. 2013;12(1):28. http://dx.doi.org/10.1186/2251-6581-12-28.
438. Mopuri R, Islam MS. Medicinal plants and phytochemicals with anti-obesogenic potentials: A review. Biomed
Pharmacother. 2017;89:1442–1452.
439. Harpaz E, Tamir S, Weinstein A, et al. The effect of caffeine on energy balance. J Basic Clin Physiol Pharmacol. 2017;28(1):
1–10.
440. Wu L, Meng J, Shen Q, et al. Caffeine inhibits hypothalamic A1R to excite oxytocin neuron and ameliorate dietary obesity
in mice. Nat Commun. 2017;8:15904.
441. Dangol M, Kim S, Fakhaei Lahiji S, et al. Anti-obesity effect of a novel caffeine-loaded dissolving microneedle patch in
high-fat obese C57BL/6J mice. pii: SO168-3659(16)30857-4. J Control Release. 2017 4. http://dx.doi.org/10.1016/j.
jconrel.2017.03.400).
442. Greydanus DE, Feucht C. Performance-enhancing drugs and supplements. ch 7. In: Patel DR, Greydanus DE, Baker RJ,
eds. Pediatric Practice: Sports Medicine. NY: McGraw-Hill Medical; 2009:63–77.
443. Bonsignore A, Sblano S, Pozzi F, et al. A case of suicide by ingestion of caffeine. Forensic Sci Med Pathol. 2014;10(3):
448–451.
444. Jurgens TM, Whelan AM, Killian L, et al. Green tea for weight loss and weight maintenance in overweight or abuse
adults. Cochrane Database Syst Rev. 2012:12.
445. Pastoriza S, Mesias M, Cabrera C, et al. Healthy properties of green and white teas: an update. Food Funct. 2017;8(8):
2650–2662.
446. Haghighatdoost F, Nobakht M, Gh BF, Hariri M. Effect of green tea on plasma leptin and ghrelin levels: a systematic
review and meta-analysis of randomized controlled clinical trials. Nutrition. 2018;45:17–23.
447. Hasani-Ranjbar S, Jouyandeh Z, Abdollahi M. A systemic review of anti-obesity medicinal plants-an update. J Diabetes
Metab Disord. 2013;12(1):28. http://dx.doi.org/10.1186/2251-6581-12-28.
448. Hursel R, Westerterp-Plantenga MS. Green tea catechin plus caffeine supplementation to a high-protein diet has no
additional effect on body weight maintenance after weight loss. Am J Clin Nutr. 2009;89(3):822–830.
449. Santos RM, Lima DR. Coffee consumption, obesity and type 2 diabetes: a mini-review. Eur J Nutr. 2016;55(4):1345–1358.
450. Alves RC, Almeida IM, Casal S, Oliveira MB. Isoflavones in coffee: influence of species, roast degree, and brewing method.
J Agric Food Chem. 2010;58(5):3002–3007.
451. Sakamoto Y, Kanatsu J, Toh M, et al. The dietary isoflavone daidzein reduces expression of pro-inflammatory genes
through PPARα/γ and JNK pathways in adipocyte and macrophage co-cultures. PLoS One. 2016; 22;11(2):
e0149676. http://dx.doi.org/10.1371/journal.pone.0149676.
452. Bahijri SM, Alsheikh L, Ajabnoor G, et al. Effect of supplemetation with chitosan on weight, cardiometabolic, and other
risk indices in Wistar rats fed normal and high- fat/high-cholesterol diets ad libitum. 1178638817710666. Nutr Metab
Insights. 2017 22. http://dx.doi.org/10.1177/1178638817710666.
453. Si X, Strappe P, Blanchard C, et al. Enhanced anti-obesity of complex of resistant starch and chitosan in high fat diet fed
rats. Carbohydr Polym. 2017;157:834–841.
454. Jull AB, Ni Mhurchu C, Bennett DA, et al. Chitosan for overweight or obesity. CD003892. Cochrane Database Syst Rev.
2008. http://dx.doi.org/10.1002/14651858.CD003892.pub 3.
455. Mhurchu C, Dunshea-Mooij CA, Bennett D, et al. Effect of chitosan on weight loss in overweight and obese individuals: a
systematic review of /randomized controlled trials. Obes Rev. 2005;6(1):35–42.
456. Rodrigues MR, de Oliveira HP. Use of chitosan in the treatment of obesity: evaluation of interaction with vitamin B12. Int
J Food Sci Nutr. 2012;63(5):548–552.
457. Tian H, Guo X, Wang X, et al. Chromium picolinate supplementation for overweight or obese adults. CD010063.
Cochrane Database Syst Rev. 2013. http://dx.doi.org/10.1002/14651858. CD010063.pub 2.
458. Stohs SJ, Preuss HG, Shara M. The safety of Citrus aurantium (bitter orange) and its primary protoalkaloid p-synephrine.
Phytother Res. 2011;25(10):1421–1428.
459. Zheng X, Guo L, Want D, et al. p-Synephrine: a novel agonist for neuromedin U2 receptor. Biol Pharm Bull. 2014;37(5):
764–770.
460. Stohs SJ, Preuss HG, Shara M. A review of the human clinical studies involving Citrus aurantium (bitter orange) extract
and its primary protoalkaloid p-synephrine. Int J Med Sci. 2012;9(7):527–538.
461. Kaats GR, Miller H, Preuss HG, et al. A 60 day double-blind, placebo-controlled safety study involving Citrus aurantium
(bitter orange) extract. Food Chem Toxicol. 2013;55:358–362.
462. Astell KJ, Mathai ML, Su XQ. A review on botanical species and compounds with appetite suppressing properties for
body weight control. Plant Foods Hum Nutr. 2013;68(3):213–221.
463. Pawar RS, Grundel E. Overview of regulation of dietary supplements in the USA and issues of adulteration with
phenethylamines (PEAs). Drug Test Anal. 2017;9(3):500–517.
464. Pooyandjoo M, Nouhi M, Shab-Bidar S, et al. The efetfect of (L-)carnitive on weight loss in adults: a systematic review
and meta-analysis of randomized controlled trials. Obes Rev. 2016;17(10):970–976.
465. Costa I, Mendonça MD, Cruz E, Silva V, et al. Herbal supplements association with reversible cerebral vasoconstriction
syndrome: a case report. J Stroke Cardiovasc Dis. 2017;26(3):673–676.
466. Semwal RB, Semwal DK, Vermaak I, et al. A comprehensive scientific overview of Garcinia cambogia. Fitoterapia.
2015;102:134–148.
467. Márquez F, Babio N, Bulló M, et al. Evaluation of the safety and efficacy of hydroxycitric acid or Garcinia cambogia
extracts in humans. Crit Rev Food Sci Nutr. 2012;52(7):585–594.
468. Lunsford KE, Bodzin AS, Reino DC, et al. Dangerous dietary supplements: Garcinia cambogia-associated hepatic failure
requiring transplantation. World J Gastroenterol. 2016;22(45):10071–10076.
469. Corey R, Werner KT, Singer A, et al. Acute liver failure associated with Garcina cambogia use. Ann Hepatol. 2016;15(1):
123–126.
470. Allen SF, Godley RW, Evron JM, et al. Acute necrotizing eosinophilic myocarditis in a patient taking Garcia
cambogia extract successfully treated with high-dose corticosteroids. e12-5. Can J Cardiol. 2014;30(12):
1732. http://dx.doi.org/10.1016/j.cjca.2014.08.025.
471. Hendrickson BP, Shaikh N, Occhiogrosso M, et al. Mania induced by Garcinia cambogia: a case series. Prim Care
Companion CNS Disorfd. 2016;18(2): http://dx.doi.org/10.4088/PCC.15101890.
472. Hasani-Ranjbar S, Nayebi N, Larijani B, et al. A systemic review of the efficacy and safety of herbal medicines used in the
treatment of obesity. World J Gastroenterol. 2009;15(25):3073–3085.
473. Astell KJ, Mathai ML, McAinch AJ, et al. A pilot study investigating the effect of Caralluma fimbriata extract on the risk
factors of metabolic syndrome in overweight and obese subjects: a randomized, controlled clinical trial. Complement
Ther Med. 2013;21(3):180–189.
474. van Heerden FR. Hoodia gordonii: a natural appetite suppressant. J Ethnopharmacol. 2008;119(3):434–437.
475. Rios-Hoyo A, Gutiérrez-Salmeán G. New dietary supplements for obesity: what we currently know. Curr Obes Rep.
2016;5(2):262–270.
476. Landor M, Benami A, Segev N, et al. Efficacy and acceptance of a commercial Hoodia parviflora product for support of
appetite and weight control in a consumer trial. Med Food. 2015;18(2):250–258.
477. Smith C, Krygsman A. Hoodia gordonii: to eat, or not to eat. J Ethnopharmacol. 2014;155(2):987–991.
478. Whelan AM, Jurgens TM, Szeto V. Case report. Efficacy of Hoodia for weight loss: is there evidence to support the
efficacy claims? J Clin Pharm Ther. 2010;35(5):609–612.
479. Alkhatib A, Atcheson R. Yerba maté (Ilex paraguariensis) metabolic, satiety, and mood state effects at rest and during
prolonged exercise. pii: E882. Nutrients. 2017 15;9(8): http://dx.doi.org/10.3390/nu9080882.
480. Alkhatib A. Yerba maté (Illex paraguariensis) ingestion augments fat oxidation and energy expenditures during exercise
at various submaximal intensities. Nutr Metab (Lond). 2014 2;11:42. http://dx.doi.org/10.1186/1743-7075-11-42.
481. Pittler MH, Schmidt K, Ernst E. Adverse events of herbal food supplements for body weight reduction: systematic
review. Obes Rev. 2005;6(2):93–111.
482. Barrella MV, Heringer OA, Cardoso PMM, et al. Metals content in herbal supplements. Biol Trace Elem Res. 2017;175(2):
488–494.
483. Yoo YH, Lee EJ, Kwak CK, et al. Clinical trial of herbal formula on weight loss in obese Korean children. Am J Chin Med.
2005;33:713–722.
484. Jeong SJ, Yoo SR, Seo CS, et al. Traditional medicine yanggyuksanhwa-tang inhibits adipogenesis and suppresses
proliferator-activated receptor gamma expression in 3T3-L1 cells. Pharmacogn Mag. 2015;11(43):502–508.
485. Seamon M, Clauson K. Ephedra: yesterday, DSHEA, and tomorrow-a ten-year perspective on the dietary supplement
health and education act of 1994. J Herb Pharmacotherapy. 2005;5:67–86.
486. Elangbam CS. Review paper: current strategies in the development of anti-obesity drugs and their safety concerns. Vet
Pathol. 2009;46(1):10–24.
487. Ioannides-Demos LL, Proietto J, Tonkin AM, et al. Safety of drug therapies used for weight loss and treatment of obesity.
Drug Saf. 2006;29(4):277–302.
488. Blankfield RP, Iftikhar IH. Food and drug administration regulation of drugs that raise blood pressure. J Cardiovasc
Pharmacol Ther. 2015;20(1):5–8.
489. Barst RJ, Abenhaim L. Fatal pulmonary arterial hypertension associated with phenylpropanolamine exposure. Heart.
2004;90(7):e42.
490. Ahmad SR. Adverse drug event monitoring at the Food and Drug Administration. J Gen Inter Med. 2003;18:57–60.
491. Yau WP, Mitchell AA, Lin KJ, et al. Use of decongestants during pregnancy and the risk of birth defects. Am J Epidemiol.
2013;178(2):198–208.
492. Garg L, Akbar G, Agrawal S, Agarwal M, Khaddour L, Handa R, Garg A, Shah M, et al. Drug-induced pulmonary artery
hypertension: a review. Heart Fail Rev. 2017;22(3):289–297.
493. Sibutramine for obesity. Med Lett Dr Ther 1998;40:32.
494. Krentz AJ, Fujioka K, Hompesch M. Evolution of pharmacological obesity treatments: focus on adverse side-effect
profiles. Diabetes Obes Metab. 2016;18(6):558–570.
495. Rosenbohm A, Bux CJ, Connemann BJ. Psychosis with sibutramine. J Clin Psychopharmacol. 2007;27(3):315–317.
496. Waszkiewicz N, Zalewska-Szajda B, Szajda SD, et al. BMC Psychiatry. 2012 18;12:43. http://dx.doi.org/
10.1186/1471-244X-12-43.
497. Araldi RP, Santos NP, Mendes TB, et al. Can Spirulina maxima reduce the mutagenic potential of sibutramine? Genet Mol
Res. 2015;14(4):18452–18464.
498. Siebenhofer A, Jeitler K, Horvath K, et al. Long-term effects of weight-reducing drugs in people with hypertension.
Cochrane Data Syst Rev. 2016 2:3. CD007654.
499. Venhuis BJ, Zwaagstra ME, Keizers PH, et al. Dose-to-dose variations with single packages of counterfeit medicines and
adulterated dietary supplements as a potential source of false negatives and inaccurate health risk assessments. J Pharm
Biomed Anal. 2014;89:158–165.
500. Mathon C, Ankli A, Reich E, et al. Screening and determination of sibutramine in adulterated herbal slimming
supplements by HPTLC-UV densitometry. Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2014;31(1):
15–20.
501. Kim HJ, Lee JH, Park HJ, et al. Monitoring of 29 weight loss compounds in foods and dietary supplement by LC-MS/MS.
Food Addit Contam Part A Chem Anal Control Expo Risk Assess. 2014;31(5):777–783.
502. Shapira B, Goldstein L, Reshef A, et al. A rare case of psychomotor disturbances linked to the use of an adulterated
dietary supplement containing subutramine. Clin Neuropharmacol. 2016;39(3):154–156.
503. Pagotto U, Pasquali R. Fighting obesity and associated risk factors by antagonizing cannabinoid type 1 receptors. Lancet.
2005;365:1363–1364.
504. Pi-Sunyer FX, Arrone LJ, Heshmati HM, et al. Effect of rimonabant, a cannabinoid-1- receptor blocker on weight and
cardiometabolic risk factors in overweight or obese patients. JAMA. 2006;295:761–775.
505. Maldonado R, Valverde O, Berrendero F. Involvement of the endocannabinoid system in drug addiction. Trends Neurosci.
2006;29(4):225–232.
506. Huestis MA, Gorelick DA, Heishman SJ, et al. Blockage of effects of smoked marijuana by the CB1-selective cannabinoid
receptor antagonist SR141716. Arch Gen Psychiatr. 2001;58(4):322–328.
507. FDA Briefing Document NDA 21-888 Zimulti (rimonabant) tablets, 20. FDA. June 13, 2007. [Assessed 20 November 2017].
508. Carmo-Silva S, Cavadas C. Hypothalamic dysfunction in obesity and metabolic disorders. Adv Neurobiol. 2017;19:73–116.
509. Khajavi N, Biebermann H, Tschöp M, DiMarchi R. Treatment of diabetes and obesity by rationally designed peptide
agonists functioning at multiple metabolic receptors. Endocr Dev. 2017;32:165–182.
510. Agahi A, Murphy KG. Models and strategies in the development of antiobesity drugs. Vet Pathol. 2014;51(3):695–706.
511. Anandhakrishnan A, Korbonits M. Glucagon-like peptide 1 in the pathophysiology and pharmacotherapy of clinical
obesity. World J Diabetes. 2016;7(20):572–598.
512. Gotthardt JD, Bello NT. Can we win the war on obesity with pharmacotherapy? Expert Rev Clin Pharmacol. 2016:1–9.
513. Padwal R, Li SK, Lau DC. Long-term pharmacotherapy for obesity and overweight. Cochrane Database Syst Rev. 2004(3):
CD004094.
514. Gadde KM, Pritham Raj Y. Pharmacotherapy of obesity: clinical trials to clinical practice. Curr Diab Res. 2017;17(5):
34. http://dx.doi.org/10.1007/s11892-017-0859-2.
515. Saunders KH, Umashanker D, Igel LI, et al. Obesity pharmacotherapy. Med Clin North Am. 2018;102(1):135–148.
516. Nguyen NT, Scott-Conner CEH, editors. The SAGES Manual: Volume 2 577 Advanced Laparoscopy and Endoscopy.
Springer Science Business Media, LLC; 2012. http://dx.doi.org/10.1007/978-1-4614-2347-8_39.
517. Pratt JSA, Lenders CM, Dionne EA, et al. Best practice updates for pediatric/adolescent weight loss surgery. Obesity.
2009;17:901–910.
518. Treadwell JR, Sun F, Schoelles K. Systematic review and meta-analysis of bariatric surgery for pediatric obesity. Ann Surg.
2008;248(5):763–776.
519. Inge TH, Krebs NF, Garcia VF, Skelton JA, Guice KS, Strauss RS, et al. Bariatric Surgery for severely overweight
adolescents: concerns and recommendations. Pediatrics. 2004;114(1):217–223.
520. Inge, et al. Perioperative Outcome of Adolescents Undergoing Bariatric Surgery: The Teen Longitudinal Assessment of
Bariatric Surgery (Teen-LABS) Study. JAMA Pediatr. 2014;168(1):47–53.
521. Langer FB, Reza Hoda MA, Bohdjalian A, et al. Sleeve gastrectomy and gastric banding: effects on plasma ghrelin levels.
Obese Surg. 2005;15(7):1024–1029.
522. Alqahtani AR, Antonisamy B, Alamri H, et al. Laparoscopic sleeve gastrectomy in 108 obese children and adolescents
aged 5–21 years. Ann Surg. 2012;256:266–273.
523. Boza C, Viscido G, Salinas J, et al. Laparoscopic sleeve gastrectomy in obese adolescents: results in 51 patients. Surg Obes
Relat Dis. 2012;8:133–137.
524. Till HK, Muensterer O, Keller A, et al. Laparoscopic sleeve gastrectomy achieves substantial weight loss in an adolescent
girl with morbid obesity. Eur J Pediatr Surg. 2008;18(1):47–49.
525. Landau Z, Karplus G, Hanukoglu A, et al. Laparoscopic sleeve gastrectomy (LSG) in adolescents with morbid obesity.
Harefuah 2011;150(10):765-8, 816, 815.
526. Nadler EP, Barefoot LC, Qureshi FG. Early results after laparoscopic sleeve gastrectomy in adolescents with morbid
obesity. Surgery. 2012;152(2):212–217.
527. le Roux CW, Heneghan HM. Bariatric surgery for obesity. Med Clin North Am. 2018;102(1):165–182.
528. Strauss RS, Bradley LJ, Brolin RE. Gastric bypass surgery in adolescents with morbid obesity. J Pediatr. 2001;138(4):
499–504.
529. Sugerman HJ, Sugerman EL, DeMaria EJ, et al. Bariatric surgery for severely obese adolescents. J Gastrointest Surg.
2003;7:102–108.
530. Nadler EP, Youn HA, Ren CJ, et al. An update on 73 US obese pediatric patients treated with laparoscopic adjustable
gastric banding: comorbidity resolution and compliance data. J Pediatr Surg. 2008;43(1):141–146.
531. Dillard BE, Gorodner V, Galvani C, et al. Initial experience with the adjustable gastric band in morbidly obese US
adolescents and recommendations for further investigation. J Pediatr Gastroenterol Nutr. 2007;45(2):240–246.
532. Fittipaldi-Fernandez RJ, Guedes MR, Galvao Neto MP, et al. Efficacy of intragastric balloon treatment for adolescent
obesity. Obes Surg. 2017;27(10):2546–2551.
533. Mion F, Napoléon B, Roman S, et al. Effects of intragastric balloon on gastric emptying and plasma ghrelin levels in
nonmorbid obese patients. Obes Surg. 2005;15(4):510–516.
534. Loux TJ, Haricharan RN, Clements RH, et al. Health-related quality of life before and after bariatric surgery in
adolescents. J Pediatr Surg. 2008;43:1275–1279.
535. Inge TH, Miyano G, Bean J, et al. Reversal of type 2 diabetes mellitus and improvements in cardiovascular risk factors
after surgical weight loss in adolescents. Pediatrics. 2009;123(1):214–222.
536. Chandra V, Dutta S. Adolescent Bariatric Surgery. ch 48. In: Pitombo C, Jones K, Higa K, Pareja JC, eds. Obesity Surgery:
Principles and Practice. New York: McGraw-Hill; 2008. ch 48, www.accesssurgery.com/content.aspx?aID=145518.
[Accessed 3 December 2017].
537. Martínez Garcia RM, Al Jiménez Ortega, González Torres H, et al. Prevention of obesity from perinatal stage. [article in
Spanish]. Nutr Hosp. 2017;34(Suppl 4):53–57.
538. Dutton H, Borengasser SJ, Gaudet LM, et al. Obesity in pregnancy: optimizing outcomes for mom and baby. Med Clin
North Am. 2018;102(1):87–106.
539. Anderson KL. A review of the prevention and medical management of childhood obesity. Child Adolesc Psychiatr Clin N
Am. 2018;27(1):63–76.
540. Ryan DH, Kahan S. Guidelines recommendations for obesity management. Med Clin North Am. 2018;102(1):49–63.

Pediatric Obesity Current Concepts 2018

Uploaded by

Document Information

Original Description:

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Pediatric Obesity Current Concepts 2018

Uploaded by

Copyright:

Available Formats

Disease-a-Month ] (2018) ]]]–]]]

Contents lists available at ScienceDirect

journal homepage: www.elsevier.com/locate/disamonth

Pediatric obesity: Current concepts

This discussion reﬂects on concepts of obesity in children

Introduction: Historical perspectives

Aulus Cornelius Celsus (25 BC-50 AD

These early clinicians considered obesity to be a pathological condition in need of urgent

Ancient Persian/Arabic clinicians

Obesity and the Renaissance

Seventeenth to nineteenth centuries

Twentieth century developments

Denouement: historical issues in obesity

Underweight Less than 18.5

Category BMI percentile

Prevalence of obesity - Global perspective

Obesity in the United States

Social determinants of obesity

Obesity: diagnostic perspectives

Obesity: medical history perspectives

Laboratory perspectives in obesity

Syndrome Key features Genetics

Bardet-Biedl Vison loss, obesity, intellectual disability, learning problems, AR

Disproportionately ﬁne facial features

Impact of psychological and psychosocial factors on obesity

Impact of obesity on psychological functioning

Conclusion: psychosocial issues

Endocrine conditions associated with obesity

Polycystic ovarian syndrome (PCOS)

Polycystic Ovarian Syndrome/Ovarian hyperandrogenism

Dysregulation of glucose and insulin metabolism:

PCOS diagnostic considerations

history of pubertal development as well as progression and menarche. Symptomatology

PCOS Therapeutic management

• Lifestyle modiﬁcations and weight control strategies: Implementation of a healthy lifestyle to

include progestin-only preparations; gonadotropin releasing hormone (GnRH) agonists and

Associated with obesity is dysregulation of glucose and insulin with a spectrum of

1. Fasting blood glucose of ≥ 126 mg/dL;

Endocrine conditions associated with obesity

General Principles of Obesity Management

Treatment of obesity involves primary prevention of obesity and management of obesity

1. First or second degree relative with T2DM;

Perspectives on pediatric obesity programs

1. Family and study logistics

Pharmacotherapy for Pediatric Obesity

Sympathomimetics (with or without topiramate)

Adverse side effects

Average weight loss of 5%-10%

Adverse side effects

Black box warning for suicidality

blood pressure increase

Adverse side effects

Other proposed anti-obesity agents

Prescribed for type 2 diabetes mellitus, acarbose is an inhibitor of intestinal alpha-glucoside

Adverse side effects

Alpha-glucosidase inhibitors: acarbose, miglitol

Amylin receptor agonists: pramlintide

Brown fat activators

amylin (amylin analogues: pramlintide; davalintide)

hormone (adipokine) produced or released by adipose cells, stimulates receptors in the

Ciliary neurotrophic factor

MetAP2 inhibitors (i.e., beloranib)