1. What is/are the specific gene(s) that affect obesity? What are their products?

s? How are they expressed?

studies have identified variants in several genes that may contribute to obesity by increasing hunger and food
intake or by altering metabolic pathways
Rarely, a clear pattern of inherited obesity within a family is caused by a specific variant of a single gene
(monogenic obesity)
Most obesity probably results from complex interactions among multiple genes and environmental factors that
remain poorly understood (multifactorial obesity).
Candidate gene and genome-wide association studies have led to the discovery of
nine loci involved in Mendelian forms of obesity and 58 loci contributing to
polygenic obesity. (A review of progress in genetics of obesity Hlne
Choquet and David Meyre)

Monogenic Forms of Obesity

Helene Huvenne and Beatrice Dubern
Springer International Publishing Switzerland 2014 C. Nbrega, R. Rodriguez-Lpez (eds.), Molecular Mechanisms Underpinning
the Development of Obesity, DOI 10.1007/978-3-319-12766-8_2

Several clinical presentations are described in obesity depending on the involved genes:
a. Monogenic obesity described as rare and severe early-onset obesity associated with endocrine disorders. There are mainly due
to mutations in genes of the leptin/melanocortin axis involved in food intake regulation (genes of leptin (LEP) and its receptor
(LEPR), proopiomelanocortin (POMC), proconvertase 1 (PC1), etc).
x. Melanocortin 4 receptor (MC4R) linked obesity characterized by a variable severity of obesity and the absence of
specific phenotype. They are responsible for 23% of obesity in adults and children. [Genomewide association studies--illuminating
biologic pathways. Hirschhorn JN]: existence of a partially overlapping continuum between monogenic and polygenic forms of
obesity

b. Syndromic obesity corresponding to obesity associated with others genetic syndromes. Patients are clinically severely obese
and additionally distinguished by mental retardation, dysmorphic features and organ-specific developmental abnormalities. Prader-
Willi and Bardet-Biedl syndromes are the 2 most frequent. But more than 100 syndromes are now associated to obesity.
x. arises from discrete genetic defects or chromosomal abnormalities at several genes, and can be autosomal or X-linked
c. Polygenic obesity, which is the more common clinical situation (>95% of cases). Here each susceptibility gene, taken
individually, would only have a slight effect on weight. The cumulative contribution of these genes would become significant only in
an obesogenic lifestyle (such as overfeeding, sedentariness, stress).

Monogenic Obesity Due to Mutations in the Leptin/ Melanocortin Pathway

described in rodents, monogenic obesities are mainly due to mutations in the genes encoding proteins involved in the
leptin/melanocortin pathway that plays a pivotal role in the hypothalamic control of food intake
leptin/melanocortin pathway is activated following the systemic release of the adipokine LEP and its subsequent
interaction with its receptor LEPR located on the surface of neurons of the arcuate nucleus
downstream signals that regulate satiety and energy homeostasis are then propagated via POMC, cocaine-and-
amphetamine-related transcript (CART) and the melanocortin system
While POMC/ CART neurons synthesize the anorectic peptide -melanocyte stimulating hormone (-MSH), a separate
group of neurons express the orexigenic neuropeptide Y (NPY) and the agouti-related protein (AGRP), which acts as a
potent inhibitor of melanocortin 3 (MC3R) and MC4R receptors
nature of the POMC derived peptides depends on the type of endoproteolytic enzyme present in the specific brain region.
In the anterior pituitary, the presence of the PC1 enzyme produces ACTH (adrenocorticotropic hormone) and -lipotrophin
peptides, while the combined presence of PC1 and PC2 in the hypothalamus controls the production of -, -, -MSH and
- endorphins
Mutations in human genes coding for LEP, LEPR, POMC and PC1 lead to severe obesity occurring soon after birth, with
generally complete penetrance and autosomal recessive transmission (see table 2.1)

LEP and LEPR MUTATIONS LEADING TO DEFICIENCY

 Mutations in the human genes coding for LEP and LEPR lead to rapid and dramatic increase in weight since the first
months of life
Feeding behaviour is characterized by major hyperphagia and ravenous hunger
o major hyperphagia, hypogonadotrophic hypogonadism and thyrotrophic insufficiencies complete the phenotype

POMC and PCSK1 MUTATIONS

for POMC endocrine anomalies such as ACTH deficiency in addition to obesity. -MSH deficiency, so signals for
satiety are not produced
for PCSK1 rare mutation in the PCSK1 (proprotein convertase subtilisin/ kexin type 1) gene leading to PC1 deficiency,
have also endocrine anomalies in addition to severe obesity
o endocrine anomalies secondary to lack of POMC maturation
o delayed postprandial malaises are explained by the accumulation of proinsulin through lack of PC1, which is
involved in the synthesis of mature insulin from proinsulin (in addition to its involvement in production of a-MSH

o The absence of POMC maturation causes a dysfunction in the melanocortin pathway that explains the obese
phenotype
For polygenic obesity, Obesity is an Inherited Disorder of Central Regulation of Food Intake

o The association of the two major contributors to polygenic obesity (SNP rs17782313 near MC4R and SNP
rs1421085 / rs9939609 in FTO{fat mass and obesity associated gene}) with food intake / food behavior-related
endophenotypes has been well documented in the literature.
o Recent progress in the elucidation of polygenic predisposition to obesity also points to a key role of the central
nervous system in body weight regulation
o The obesity predisposing FTO variant was associated with increased total and fat dietary intake in children
[20, 21] as well as in adults [22]. The obesity risk variant was also associated with diminished satiety and / or
increased feeling of hunger in children [23] and in adults [24].
o The obesity predisposing SNP variant near MC4R was associated with increased feeling of hunger [25, 26],
increased snacking [25], decreased satiety [26], and increased total, fat and protein energy intake [25, 27], the
effects of the variant on food-related parameters being observed both in children and adults. responsible for up
to 6% of early-onset or severe adult obesity cases

For polygenic obesity, those suggested to work peripherally (outside the brain, more on adipose tissues)
TFAP2B (transcription factor activating enhancer-binding protein 2 ) preferentially expressed in
adipose tissue, which is involved in glucose transport, lipid accumulation, and adiponectin
expression
o specific for central fat accumulation
NCR3 (natural cytotoxicity triggering receptor 3) and PTER (phosphotriesterase related), which
might mediate their effect through the hypothesized low-grade inflammation of adipose tissue
c-MAF, a transcription factor involved in adipogenesis through the regulation of tissue-specific
gene expression, for instance of insulin and glucagon
interesting female-only association to LYPLAL1 (lysophospholipase-like-1) is caused by a lipase
with increased expression in subcutaneous adipose tissue
o specific for central fat accumulation
o supports previous hypotheses that there are sex-specific genes contributing to variation
of obesity-related traits and that genes account for more variance of fat distribution in
women than in men

2. How is this gene expression regulated? (6-9)

3. How much do these genes affect metabolism and lipid storage as opposed to modifiable factors? How do they interact
with each other? (10-13)
environmental influence on BMI, many researchers have focused on the identification of specific environmental
factors that interact with genetic predisposition to obesity. They based their investigations on epidemiological data
showing that physical activity, diet, educational status, age, gender and ethnicity among others modulate the risk for
obesity [77].
o genetic susceptibility to obesity can be blunted in part through physical activity; Thirteen independent
studies reported an interaction between the FTO obesity risk genotype and physical activity on BMI
variation or obesity risk including adults as well as adolescents
physical inactivity associated with a relatively large increase in BMI compared with that in
noncarriers and those heterozygous for the A-allele (FTO)
results indicate that high-fat diets and low physical activity levels may accentuate the
susceptibility to obesity by the FTO variant.
The findings of this study indicate that the genetic predisposition to obesity can be reduced by
approximately 40% by having a physically active lifestyle. The findings of this study suggest that,
while the whole population benefits from increased physical activity levels, individuals who are
genetically predisposed to obesity would benefit more than genetically protected individuals
Surprisingly, one LEP deficient Austrian girl has been recently described with more moderate
obesity (BMI 31.5 kg/m2 ), despite an increased consumption of calories in a test meal. The
phenotype was explained by extremely low daily calorie intake. Even if one takes into account a
substantial underreporting, this observation might suggest that despite LEP deficiency, it was
possible to control energy intake and thus to prevent extreme obesity. In that specific case, the
parents role was determinant by providing a favourable environment with vigorous control of the
patients eating behaviour from early infancy onward.
studies suggest that a high fat diet can amplify the effect of the FTO genotype on obesity risk
[79-81]

4. How can we maintain a healthy body weight/BMI despite genetic predisposition? (14-16)
To date, three main therapeutic options are proposed to treat obesity: lifestyle intervention, pharmacotherapy and
bariatric surgery. The aim of these therapeutics for obesity are to lose weight and maintain this weight-loss on the
long term and attenuate co-morbidities related to obesity. There is growing evidence that genetic factors not only
predispose to weight gain and development of obesity, but also modulate the response to therapeutic intervention in
terms of weight loss.
o Lifestyle Modifications: Individuals with MC4R or POMC monogenic conditions respond well to hypocaloric
dietary or multidisciplinary (exercise, behavior, nutrition therapy) interventions as do non-monogenic obese
subjects [100, 101] but MC4R individuals fail to maintain weight loss after intervention [101]. The major
gene variant contributing to polygenic obesity FTO does not modify the response to lifestyle intervention in
terms of weight loss [102], but may interact with specific components of the lifestyle intervention program
like the type of diet proposed during the caloric restriction program (high-fat, low-fat, Mediterranean diets)
[103, 104] or with physical activity [105] to modulate weight loss.
o Pharmacotherapy: individuals with congenital leptin deficiency can be treated with daily injections of
recombinant human leptin, which reverses the obesity and associated phenotypic abnormalities [106].
Leptin administration dramatically reduces food intake, fat mass, hyperinsulinemia, and hyperlipidemia,
restores normal pubertal development, endocrine and immune function and increases performances in
many neurocognitive domains
o Bariatric Surgery: Bariatric surgery is the most effective long-term treatment for severe obesity, reducing
obesity-associated co-morbidities but the mechanisms of weight loss after bariatric surgery and the role of
central energy homeostatic pathways in this weight loss process are not well understood