REVIEWS
Opportunities and challenges in the therapeutic activation of
human energy expenditure and thermogenesis to manage
obesity
Published, Papers in Press, December 30, 2019, DOI 10.1074/jbc.REV119.007363
X Kong Y. Chen1, X Robert J. Brychta, Zahraa Abdul Sater, Thomas M. Cassimatis, Cheryl Cero, X Laura A. Fletcher,
Nikita S. Israni, X James W. Johnson, Hannah J. Lea, Joyce D. Linderman, Alana E. O’Mara, Kenneth Y. Zhu,
and X Aaron M. Cypess2
From the Diabetes, Endocrinology, and Obesity Branch, Intramural Research Program, NIDDK, National Institutes of Health,
Bethesda, Maryland 20892
Edited by Jeffrey E. Pessin
The current obesity pandemic results from a physiological
imbalance in which energy intake chronically exceeds energy
expenditure (EE), and prevention and treatment strategies
remain generally ineffective. Approaches designed to increase
EE have been informed by decades of experiments in rodent
models designed to stimulate adaptive thermogenesis, a long-
term increase in metabolism, primarily induced by chronic cold
exposure. At the cellular level, thermogenesis is achieved
through increased rates of futile cycling, which are observed in
several systems, most notably the regulated uncoupling of oxi-
dative phosphorylation from ATP generation by uncoupling
protein 1, a tissue-specific protein present in mitochondria of
brown adipose tissue (BAT). Physiological activation of BAT
and other organ thermogenesis occurs through ␤-adrenergic
receptors (AR), and considerable effort over the past 5 decades
has been directed toward developing AR agonists capable of
safely achieving a net negative energy balance while avoiding
unwanted cardiovascular side effects. Recent discoveries of
other BAT futile cycles based on creatine and succinate have
provided additional targets. Complicating the current and
developing pharmacological-, cold-, and exercise-based meth-
ods to increase EE is the emerging evidence for strong physio-
logical drives toward restoring lost weight over the long term.
Future studies will need to address technical challenges such as
how to accurately measure individual tissue thermogenesis in
humans; how to safely activate BAT and other organ thermo-
genesis; and how to sustain a negative energy balance over many
years of treatment.
This work was supported by National Institutes of Health Intramural Research
Program of the NIDDK Grants DK075112, DK075115, DK075116,
DK071013, and DK071014. The authors declare that they have no conflicts
of interest with the contents of this article. The content is solely the respon-
sibility of the authors and does not necessarily represent the official views
of the National Institutes of Health.
1
To whom correspondence may be addressed: Diabetes, Endocrinology, and
Obesity Branch, Intramural Research Program, NIDDK, National Institutes
of Health, Bldg. 10-CRC, Rm. 5–5752, 10 Center Dr., Bethesda, MD 20892–
1613. Tel.: 301-451-1636; E-mail: kong.chen@nih.gov.
2
To whom correspondence may be addressed: Bldg. 10-CRC, Rm. 6 –3950, 10
Center Dr., Bethesda, MD 20892–1453. Tel.: 301-435-9267; E-mail:
aaron.cypess@nih.gov.
1926 J. Biol. Chem. (2020) 295(7) 1926 –1942
Published in the U.S.A.
cro
An alarming rise in the rates of obesity and the numerous
associated health complications, from diabetes to heart disease
and cancers, has occurred over the last 50 years. Prevention of
the multiple interrelated and even unknown causes of the obe-
sity pandemic has proven difficult to implement. The billions of
dollars spent on reversing obesity have not solved and perhaps
even worsened the pandemic. This bleak picture has encour-
aged creative responses, one of which is based on utilizing phys-
iological thermogenesis to achieve the necessary net negative
energy balance. Exercise is a key component, but is rarely effec-
tive enough. Although effective, bariatric surgery (1) comes
with a high initial cost, risk of long-term morbidities, and recid-
ivism (2). Therefore, the field is turning to environmental, phar-
macological, and other novel interventions to boost thermo-
genesis and treat obesity and its related health complications.
To appreciate the regulation of mammalian thermogenesis,
it is appropriate to start with fundamental principles. The sec-
ond law of thermodynamics— entropy always increases—stip-
ulates that for biological reactions in an organism to occur,
there must be a release and dilution of thermal energy. Thus,
thermogenesis is an essential component of animal physiology.
All mammals are endothermic, meaning they generate their
own heat rather than being at the mercy of the environment.
Most mammals are also homeothermic and maintain a tightly-
controlled, stable body temperature, which is advantageous for
consistent chemical reaction rates, blood pH, and enzymatic
functions, and it may help minimize parasitic fungal growth (3,
4). Thus such “warm-blooded” animals, or homeotherms, can
live and function similarly in widely varying thermal environ-
ments. In this review, we illustrate and promote the process of
thermogenesis, from the molecular interactions that generate
heat to its current heightened relevance at the clinical level. We
do this by first clarifying the lexicon of the field studying whole-
body thermogenesis and then detailing the sources of thermo-
genesis at the molecular level. With that background, we
describe the challenges of measuring human thermogenesis.
Understanding the mechanisms and methodologies enables
one to appreciate why activating thermogenesis is of such inter-
est and holds promise as a treatment for obesity-related dis-
eases. The background also helps the reader appreciate why
targeting thermogenesis has been fraught with disappoint-
 JBC REVIEWS: Therapeutic regulation of thermogenesis

Figure 1. Sources of human thermogenesis and pharmacological approaches to increase it. There are three principal sources of thermogenesis in adult
humans. Most derive from the BMR, which is the minimum energy required to perform all the basic chemical reactions of the body and is the primary
contributor (60 –75%) to total energy expenditure in an adult human. Movement-related thermogenesis includes exercise and nonexercise activity thermo-
genesis (10 –30%). Adaptive thermogenesis is a physiological feedback system in which energy demands are assessed over a longer period of time, and the
body responds by increasing energy expenditure. A related but different process is facultative thermogenesis, which is a temporary increase in energy
expenditure only when extra heat is required acutely, such as for defending body temperature. There are three principal pharmacological approaches to
stimulating human thermogenesis that use some combination of appetite suppression, impaired absorption of ingested food, and increased energy expend-
iture. Adapted from Ref. 67.

ments. In the final section of this review, we provide our per-
spective on what the future may hold for the field.
Concepts
Whole-body thermogenesis
Thermogenesis is generally defined as any metabolic process
that releases heat, so whole-body thermogenesis is equivalent
to total energy expenditure (EE).3 Total EE includes three prin-
cipal components: basal metabolic rate (BMR); thermic effect
of food (TEF); and activity EE (Fig. 1). The BMR is regarded as
the minimum energy required to perform all of the basic chem-
ical reactions of the body and is the primary contributor (60 –
75%) to total EE in a typical human adult. The BMR remains
relatively constant, is mainly determined by lean body mass,
and can be regulated by hormones. TEF is the heat generated
during digestion of macronutrients. Activity-related EE is nec-
essary for movement and is the most variable contributor to
total EE. These components of EE are not for the specific pur-
pose of heat generation, so thermogenesis from them is an
obligatory by-product. For the context of this paper, we define
the term thermogenesis more functionally as any additional
metabolism used for heat production, either for defending body
temperature or to burn off calories determined to be in excess
3
The abbreviations used are: EE, energy expenditure; BMR, basal metabolic
rate; ETC, electron transport chain; AR, adrenoreceptor; DNP, 2,4-dinitro-
phenol; CRMP, controlled-release mitochondrial protonophore; TRP, tran-
sient receptor potential; BAT, brown adipose tissue; CIT, cold-induced ther-
mogenesis; W-S, warm-sensitive; TEF, thermic effect of food; TNZ,
thermoneutral zone; NST, nonshivering thermogenesis; WAT, white adi-
pose tissue; NE, norepinephrine; PKA, protein kinase A; TPM, topiramate;
FDA, Food and Drug Administration; GABA, ␥-aminobutyric acid; CT, com-
puted tomography; AMPA, ␣-amino-3-hydroxy-5-methyl-4-isoxazolepro-
pionic acid; TCA, tricarboxylic acid cycle; FFM, fat-free mass; MRI, magnetic
resonance imaging; 18F-FDG, [18F]fluorodeoxyglucose; EMG, electromyog-
raphy; SNS, sympathetic nervous system; PPAR, peroxisome proliferator-
activated receptor; LPL, lipoprotein lipase; PET, positron emission tomog-
raphy; CNS, central nervous system; REE, resting energy expenditure.
of the body’s needs, a process known as diet-induced
thermogenesis.
Cannon and Nedergaard (5) categorized thermogenesis as
having both facultative and adaptive components. Facultative
thermogenesis is activated when extra heat is required acutely,
such as for maintaining body temperature during short-term
cold exposure, whereas adaptive thermogenesis refers to meta-
bolic adaptation in response to additional heat needs over a
longer duration, such as during chronic or repeated cold expo-
sure. The detailed relationship between EE and environmental
temperature is largely based on classical animal studies by
Kleiber (6) and Scholander et al. (7), and more recently by Can-
non, Nedergaard, and co-workers (5, 8) and Abreu-Vieira et al.
(9). The thermoneutral zone (TNZ) is the environmental tem-
perature range over which resting EE is minimum and equal to
the BMR. The BMR helps to maintain the normal and optimal
human core temperature, 37 °C, which is also called the
“defended” body temperature. The lower and upper critical
temperatures are the environmental temperature limits of the
TNZ. Although resting metabolism is constant throughout the
TNZ, to maintain constant core temperature as the environ-
mental temperature drops from the upper to lower critical tem-
peratures, autonomic (e.g. vasoconstriction and piloerection)
and behavioral (e.g. huddling and environment selection)
responses occur to mitigate heat-loss without increasing heat
production. Thus, measures such as skin surface temperature
and heart rate will be different when assessed at the upper ver-
sus lower critical temperatures, reflecting these thermoregula-
tory responses. Below the lower critical temperature, heat con-
servation responses are insufficient to defend body
temperature, and EE must increase linearly as environmental
temperature drops. This increase above the BMR to maintain
core temperature is defined as cold-induced thermogenesis
(CIT). According to Fourier’s law of heat conduction, there is
no heat transfer at the x-intercept after the CIT line is extrap-

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JBC REVIEWS: Therapeutic regulation of thermogenesis
Figure 2. Summary of brown adipose tissue, white adipose tissue, and skeletal muscle characteristics and mechanisms related to thermogenesis.
Molecular, cellular, and physiological characteristics are shown in lightface text, and the molecular mechanisms are shown in bold text. Brown adipose tissue,
white adipose tissue, and skeletal muscle are represented by brown, yellow, and red circles, respectively. Characteristics and mechanisms relevant to two or
three tissues are shown in regions where the circles overlap.
olated, demonstrating that the environmental temperature is
equal to the defended body temperature (6). For greater detail,
a comparison of the EE responses to different environmental
temperatures in and around the TNZ in lean and obese young
men have been published recently (10).
The neuronal pathways involved in mammalian thermogen-
esis for thermoregulation are described by Morrison et al. (11).
These thermoregulated neuronal pathways can activate BAT
and skeletal muscle through thermoreceptors in the case of CIT
or through nonthermal means, such as stress. Thermal sensa-
tions on the skin are transmitted as signals through the dorsal
root ganglia and to the hypothalamic preoptic area where
warm-sensitive (W-S) neurons regulating BAT and skeletal
muscle are inhibited by cool-activated neurons in the lateral
part of the parabrachial nucleus. The W-S neurons function to
inhibit BAT sympathoexcitatory neurons, so when these neu-
rons are disinhibited in the cold, BAT and skeletal muscle sym-
pathoexcitatory neurons are stimulated (11).
Homeostatic regulation of heat conservation/dissipation and
heat production mechanisms results in constant body temper-
ature. Loss of body temperature control can cause death from
either hypothermia or hyperthermia. A rise of 1 °C in body tem-
perature due to fever is associated with a 13% increase of heat
production (12), albeit with large individual variability.
1928 J. Biol. Chem. (2020) 295(7) 1926 –1942
Cellular thermogenesis
The principal organs involved in adaptive thermogenesis are
skeletal muscle, BAT, and likely WAT (Fig. 2). The majority of
reactions regulating biological energy production occurs in the
mitochondria (Fig. 3). Energy stored in dietary nutrients is
released through the tricarboxylic acid (TCA) cycle and the
electron transport chain (ETC). These processes are normally
facilitated through interconnected enzyme-facilitated reac-
tions, which release energy stored in chemical bonds to fuel
ATP synthesis (13). ATP can then be shuttled throughout the
cell to provide the energy to drive essential processes, notably
macromolecular synthesis, intermembrane ion pump function,
protein folding, and metabolite store mobilization (14).
This typical mitochondrial energy conversion does not break
down all energy intake efficiently despite being considered
“coupled.” Nevertheless, there are other cellular processes that
are considered entirely “uncoupled” or futile, as energy is only
expended and released as excess heat. Cation leakage across
concentration gradients is a common example of “uncoupled”
reactions which occurs in all cells, and this is the fate of up to
20% of all mitochondrial energy (15). During cation leakage, the
ETC and TCA cycle work faster to pump protons out of the
mitochondrion, which requires more ATP hydrolysis and asso-
 JBC REVIEWS: Therapeutic regulation of thermogenesis

Figure 3. Molecular mechanisms underlying adaptive cellular thermogenesis. Mechanisms relevant to coupled respiration, which occurs in most tissues,
are illustrated within the box. In the mitochondrial inner membrane, succinate dehydrogenase (SDH) forms complex II of the ETC and is one of the enzymes of
the TCA cycle. Brown adipocytes expressing uncoupling protein 1 (UCP1) in response to ␤-adrenergic signaling can uncouple the tricarboxylic acid cycle (TCA)
and oxidative phosphorylation by the electron transport chain, composed of coenzyme Q (CoQ), cytochrome c (Cyt C), and complexes I–IV, increasing the rates
of the associated exergonic reactions and generating heat instead of harnessing it to make ATP. In beige/brite fat, thermogenic hydrolysis of ETC-generated
ATP occurs when the mitochondrial ADP/ATP carrier transports ATP from the mitochondrial matrix into the intermembrane space where mitochondrial CK
(Mi-CK) catalyzes the conversion of creatine to phosphocreatine, which is then hydrolyzed by enzymes to generate heat.

ciated thermogenesis. Heat is released from collisional interac-
tions as protons move out of the mitochondrion or potentially
from the amount of energy required to maintain the appropri-
ate concentration of enzymes to drive futile cycling.
Muscle tissue can also expend energy through nonmitochon-
drial futile cycling (Fig. 4). These include Ca2⫹ and Na⫹ chan-
nel action; actin–myosin cycling during muscle contraction;
the heat produced due to mechanical friction; and triglyceride/
fatty acid cycling (16). All of these processes involve futile
cycling, which generates heat from the same basic principle:
ATP hydrolysis. The futile cycle results from an uncoupling
process that causes the ETC and TCA cycle to speed up, thus
generating heat as a result. Energy lost from triglyceride/fatty-
acid cycling comes from hydrolysis of ester bonds in triglycer-
ides (17), and it has been advanced as the source of thermogen-
esis in acute burns (18), cancer cachexia (19), and following
exercise (20).
Thermogenesis from shivering, the involuntary contraction
of muscles caused by cold exposure is the main contributor to
heat production in moderate to extreme cold (21). Nonshiver-
ing thermogenesis (NST), however, is any heat production inde-
pendent of shivering, and can be both facultative and adaptive
(5). There are thought to be two contributors to NST: brown
adipose tissue (BAT) via uncoupling protein 1 (UCP1) and skel-
etal muscle via sarcolipin. Both of these processes cause futile
cycling with ATP hydrolysis and therefore generate heat
through an exergonic reaction. UCP1 releases energy as heat
during the dissipation of the proton-motive force across the
mitochondrial membrane. Sarcolipin controls thermogenesis
in skeletal muscle by mediating heat production from the sarco/
endoplasmic reticulum Ca2⫹-ATPase pump. Despite a wealth
of recent articles about NST and BAT, the capacity of, physio-
logical mechanism behind, and primary contributor to NST in
humans all remain to be determined (22).
The thermodynamic inefficiency of mammalian energy
metabolism may offer flexibility for various cellular processes
(16), but the proton leak regulated by UCP1 in human BAT
serves a distinct purpose. UCP1 is found in brown and beige/
brite fat, made up of “brown-able” adipocytes that develop in
white fat, and it permits proton flow from the intermembrane
space to the mitochondrial matrix (23). This results in the
uncoupling of ATP production from the proton gradient estab-
lished by the ETC. The UCP1-mediated proton leak is thereby
specific to BAT thermogenesis: a diminished proton gradient
permits an increased rate in the series of exothermic reactions
generating the protein gradient, from the TCA cycle through
the ETC, and increases the rate of collisions between protons
and other molecules, generating substantial heat (24). Mito-
chondrial dysfunction and age-related hormonal changes that
regulate UCP1 expression may also explain why BAT activation
correlates negatively with age (25).
Recent advancements have identified alternative mecha-
nisms for facultative and adaptive thermogenesis in BAT (26).
One of these is a mitochondrial substrate futile cycle based on
creatine. Creatine, an amino acid found predominantly in skel-
etal muscle, supports substrate futile cycling by increasing
ADP-dependent respiration in mitochondria of beige fat (27),
which shares many functional similarities with brown fat. Such

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JBC REVIEWS: Therapeutic regulation of thermogenesis

Figure 4. Muscle-specific mechanisms of thermogenesis and therapies that can increase thermogenesis. Repeated excitation– contraction cycling with
actin and myosin is stimulated by the release of sarcoplasmic calcium through the ryanodine receptor and is used by skeletal muscle for shivering thermo-
genesis. Muscular nonshivering thermogenesis is mediated by sarco/endoplasmic reticulum Ca2⫹-ATPase (SERCA) and sarcolipin. Triglyceride/fatty acid
synthesis and lipolysis, which occur in skeletal muscle and other tissues, are parts of a thermogenic futile cycle. Certain therapies, such as ␤3-adrenergic
receptor agonists, up-regulate cellular signaling pathways that lead to increased lipolysis and thus thermogenesis. Much like UCP1, DNP, and controlled-
release mitochondrial protonophore (CRMP) uncouple the ETC from ATP synthesis, increasing thermogenesis.

a pathway requires creatine and creatine kinase–mediated hy-
drolysis of ATP to drive a catalytic mechanism that stimulates
cycling of ATP production and consumption (28). Both in vivo
and genetic evidence support the role of creatine in thermogen-
esis (28, 29). Additionally, it has been recently shown that the
TCA cycle and ETC intermediate succinate is present in higher
levels in rodent BAT after cold exposure. This is specific to
succinate and not other related metabolites, and this process
occurs through transport from the extracellular milieu. Succi-
nate therefore can specifically drive mitochondrial respiration
in a dose-dependent fashion and stimulates BAT thermogene-
sis via succinate dehydrogenase, which oxidizes succinate to
drive this process (30). Of note, studies of these mechanisms
have been completed in rodent models, and it still needs to be
determined what contribution they have toward thermogenesis
in humans as methods for measuring tissue and organ thermo-
genesis are being developed.
Methods to measure human thermogenesis
It is clear from the previous sections that the past decades
have witnessed advances in the mechanistic understanding of
cellular thermogenesis, and its measurement has become more
precise. Where a key challenge arises is in integrating the pro-
cesses occurring in each cell to accurately describe what is hap-
pening at the level of individual organs and the entire body. This
section describes the methods currently used to measure both
whole-body energy expenditure and tissue/organ metabolism.
The goal is 2-fold: the first is to explicate how the quantification
is done, and second is to justify why measuring human thermo-
genesis needs to be considered differently from measuring
other cellular processes at the whole-body level. As will be dem-
onstrated, measuring whole-body thermogenesis requires rig-
orous control of external factors in study design and accuracy
and precision of calorimetry methods. Although human ther-
mogenesis has been investigated for more than two centuries,
technological advancements have improved the measurement
precision that is critical for quantifying small, but significant,
components of total energy expenditure (31). A better under-
standing of potential mechanisms of human thermogenesis can
be gained by combining measurement of whole-body energy
expenditure with in vivo quantification of organ and tissue met-
abolic processes and fuel utilization via minimally-invasive
imaging methodologies. In the summary, we will revisit these
methods when assessing the state of the field and identify areas
that require the most attention.
Body size is known to be the major determinant of whole-
body EE. Thus, allometric scaling is necessary when comparing
thermogenesis between species and between individuals of the
same species. The simplest method to normalize metabolism to
body size is to divide by body mass, as proposed by Brody and
Procter (32) and by Kleiber (33), or body surface area, as pro-
posed by Benedict (34) and Rubner (35). Normalizing to body
weight is a common approach when comparing the metabolism

1930 J. Biol. Chem. (2020) 295(7) 1926 –1942


of animals of different weights (36), whereas the surface area is
often used to scale parameters of human heat loss and produc-
tion (e.g. W/m2) (37, 38). Although body mass and surface area
are easy to obtain—the latter is typically derived from predic-
tive equations from height, body mass, and other characteris-
tics—these allometric scaling approaches are known to reflect
between subject differences less accurately, especially those
attributed to age, sex, and race. Alternatively, Scholander et al.
(7) suggested expressing CIT as a percentage of BMR, which is
useful for cross-species comparisons because CIT magnitude
varies drastically on account of the differences in surface–to–
volume ratio and thermal physiology. A more physiologically-
based approach is to use detailed measures of body composition
to scale metabolic rate. Multiple regression analysis shows that
fat-free mass (FFM), which consists of all nonadipose tissue
such as muscle, bone, and viscera, is the main determinant of
BMR, followed by sex, fat mass, age, and race (39). However,
expressing metabolic rate as a simple quotient, e.g. BMR/FFM,
creates artifacts because such models contain nonzero inter-
cepts as constants. Thus, it is recommended to scale metabo-
lism, particularly BMR, by using FFM and other factors as cova-
riates. Going one step further, investigators can use organ and
tissue masses measured with computed tomography (CT) or
magnetic resonance imaging (MRI) to explain more of the var-
iability in BMR. For example, Heymsfield et al. (40) showed that
using masses of organs and tissues such as brain, liver, skeletal
muscles, and adipose tissue can predict individual BMR with
18% less error than using FFM alone, and the regression inter-
cept is close to zero, suggesting this is a more biologically accu-
rate scaling model. Thus, to minimize the influence of body
composition on metabolism, it is essential to use the most accu-
rate measurements of body composition available, which cur-
rently are performed via dual-energy X-ray absorptiometry,
CT, MRI, or other validated methodologies. The goal is to scale
metabolism when comparing human subjects of different body
size or composition or when assessing change in metabolism
resulting from an intervention that may alter body composi-
tion. In summary, understanding of obesity requires measure-
ment of EE, which itself depends on the accurate measure of
body composition.
Measurement accuracy and precision of thermogenesis also
depend on the specific methodology used to quantify energy
expenditure. Direct and indirect calorimetry have been used to
measure heat loss and EE, respectively, as reviewed in detail
elsewhere (31). Direct calorimetry quantifies heat exchange
with the environment using well-controlled environmental
chambers. Limitations of this method include the high cost of
equipment and complex engineering. Thus, most studies of
human thermogenesis are done via indirect calorimetry,
whereby thermogenesis is quantified by measuring the amount
of oxygen consumed and carbon dioxide produced, with the
ratio being the respiratory quotient that provides information
about substrate utilization, i.e. carbohydrate and fat oxidation.
Lavoisier (41) was the first to note that oxygen consumption
in resting men increased in cold temperatures. Classic studies
performed in the 1930s to the 1950s extended our understand-
ing of the effects of environmental temperature on human
metabolism by using whole-room calorimeters capable of mea-
JBC REVIEWS: Therapeutic regulation of thermogenesis
suring direct heat loss and indirect gas exchange simultane-
ously (42–46). Because of the technical limitations of these
early calorimeters, EE measurements were labor-intensive.
Thus, studies were limited; subjects were few; and documented
CIT was small to moderate in magnitude (0 –36%). More recent
studies of CIT have involved EE measurement via indirect cal-
orimetry either using portable carts with canopies/hoods for
short exposure periods or calorimetry rooms for exposures up
to 24 h. Despite the improved precision of newer measurement
devices, reported CIT has varied considerably, from 0 to 280%
and peaking at 500% of the BMR at “peak shivering” (47), which
is likely dependent on experimental conditions and subject
characteristics. Greater detail of the variations in CIT measure-
ment is provided elsewhere (31). These variations demonstrate
the need for standardized protocols to measure CIT and other
changes in metabolism. Current best practices include ensuring
careful measurement of the BMR in thermoneutral tempera-
tures with standardized clothing while minimizing energetic
contributions from activity and diet. In addition, it is essential
to employ systematic intervention protocols, e.g. uniform dos-
ing of cold exposure or pharmacological agents, optimized tim-
ing for measuring changes in energy expenditure, and appro-
priate study power and sample size to detect clinically
meaningful changes. When designing such protocols, research-
ers should also recognize the limited temporal resolution of
room calorimeters and the greater time–to–steady-state for
metabolic cart measurements— both requiring ⬃30 min of
steady-state energy-expenditure measurement at each inter-
vention stage to accurately quantify changes in metabolism.
Organ-level measurement of thermogenesis is necessary to
better understand the mechanisms underlying CIT and other
metabolic changes and to design more targeted drugs capable
of selectively elevating metabolism from these organs. How-
ever, as with BMR, organ-level contributions to CIT are cur-
rently difficult to quantify. As discussed previously, skeletal
muscle, through shivering thermogenesis, and BAT, through
NST, are thought to be the main contributors to human CIT
(21). Given BAT’s prominence in rodent energy expenditure
and its potential for treating obesity and the associated meta-
bolic diseases, substantial focus over the past decade has been
devoted to measuring its volume and metabolic activity. The
challenges, pitfalls, and successes have been discussed in several
extensive reviews and consensus papers (48 –51) and therefore
will not be addressed in detail here. In brief, the principal chal-
lenges to accurately assess human BAT’s contributions to
energy expenditure are anatomical and technical. First,
although human BAT is a solid organ, the individual thermo-
genic adipocytes are mixed with different combinations of met-
abolically quiet white adipocytes and dormant brown and
beige/brite adipocytes that can be activated with cold exposure
or chronic treatment with adrenergic agonists (27, 52–54). Sec-
ond, because the thermogenic adipocytes are distributed
throughout the body, any imaging whose goal is to characterize
whole-body BAT activity needs to sample from the base of the
skull to the umbilicus via PET computed tomography (PET/
CT) (55). Among the radiotracers available that reflect oxygen
consumption, the most commonly used is 2-deoxy-2-[18F]fluo-
roglucose ([18F]fluorodeoxyglucose (18F-FDG)), which behaves
J. Biol. Chem. (2020) 295(7) 1926 –1942 1931
JBC REVIEWS: Therapeutic regulation of thermogenesis
similarly to blood glucose yet gets trapped into most metaboli-
cally-active cells; after entry and phosphorylation to become
fluorodeoxyglucose 6-phosphate, it can proceed no further
through glycolysis and cannot be dephosphorylated in most
cells because they lack glucose-6-phosphatase. Because glucose
uptake is a real-time marker of tissue oxygen consumption (56),
18
F-FDG is a useful biomarker of tissue energy expenditure in
the fasted state. The principal drawback of 18F-FDG is that it
does not provide a quantitative measure of cellular EE. Other
tracers that are more reflective include [11C]acetate (57), which
measures oxidative phosphorylation, and 15O2, which provides
a direct measure of oxygen consumption (58, 59). Because the
latter two molecules have much shorter half-lives (seconds to a
few minutes), are not routinely produced for clinical use, and
can be visualized only in a small region of the body during a
single scan, studies using them are more limited in number but
quite promising in terms of learning about the therapeutic
potential of human BAT (60). MRI-based methods are also
gaining in interest and application toward measuring thermo-
genesis. In addition to assessing changes in tissue fat fraction to
detect changes in BAT fuel consumption (61, 62), MRI and
functional MRI have the ability to directly measure thermogen-
esis (63). Given the absence of ionizing radiation and the wide
range of MRI pulse-sequences that can be developed, it is likely
that in the future substantial advances in understanding human
thermogenesis will rely on MRI-based techniques.
Shivering thermogenesis, which can consume more calories
that the BMR itself (64), is also difficult to measure due to inher-
ent technical limitations and highly-variable muscle recruit-
ment patterns during shivering. Traditional methods to quan-
tify shivering include using indwelling and surface-based
sensors (21) to measure muscle electrical activity, or electro-
myography (EMG), rather than thermogenesis directly. EMG
sensors primarily record from superficial, but not deeper, mus-
cle. Alternatively, the same PET/CT-based imaging techniques
used to quantify BAT metabolic activity can also be used to
quantify the metabolic activity of shivering skeletal muscle.
Concurrent measures of surface EMGs and PET/CT imaging
demonstrate that the two methods are correlated (64). How-
ever, PET/CT has also demonstrated that surface and deep
muscles are involved in shivering-based heat production (65).
In summary, the methods used over the past decades to mea-
sure thermogenesis have enabled multiple advances in under-
standing human physiology, the development of obesity, and a
characterization of how the body adapts to weight loss. What is
lacking is the ability to actively manipulate and then accurately
measure processes happening at the individual tissue and cel-
lular level. One critical area in this regard relates to human
BAT. Estimates of energy expenditure in response to BAT acti-
vation span over 2 orders of magnitude (60), which makes it
currently impossible to determine BAT’s roles in human phys-
iology. Beyond BAT, the field of metabolism is in great need of
noninvasive measures to study the intercommunication among
the organs’ regulation energy storage and utilization. The
breakthroughs will likely come through new radiotracers and
stable isotopes (66). The needs—and the potential discover-
ies—are vast.
1932 J. Biol. Chem. (2020) 295(7) 1926 –1942
Pharmacological interventions
Having discussed the origins and function of mammalian
thermogenesis, we now turn to pharmacological regulation of
thermogenesis. The various classes of drugs that attempt to
alter the caloric balance by suppressing appetite, inhibiting fat
absorption, or increasing energy consumption (Fig. 1) have
been summarized (67, 68). The activation of BAT is of particu-
lar interest because it is an organ whose principal physiological
role is thermogenesis. An extensive treatment of the transla-
tional pharmacology involved in human BAT activation has
been recently published (69). What follows here is a more
focused discussion of the cellular physiology underlying phar-
macological activation of thermogenesis and includes human
BAT.
Adrenergic receptors
The sympathetic nervous system (SNS) is the principal net-
work that regulates thermogenesis. The receptors of the SNS
can be divided into two main types based on their function, the
␣- and the ␤-adrenoreceptors (ARs). There are at least two
types of ␣-ARs, ␣1-AR and ␣2-AR, and there are three types of
␤-ARs, ␤1-, ␤2-, and ␤3-ARs (70, 71). The ␣-AR and ␤-AR
differ in their specificity for coupling to the heterotrimeric
G-proteins, which results in complex and multidimensional
stimulatory and inhibitory signaling pathways. ␣1-ARs couple
mainly to G␣q/11 proteins that activate phospholipase C to gen-
erate inositol trisphosphate and diacylglycerol. These two sec-
ond messengers increase intracellular Ca2⫹ and protein kinase
C, respectively, which stimulate a myriad of intracellular pro-
cesses specific to each distinct cell type (70, 71). In contrast,
␣2-AR couples primarily to G␣i/o to inhibit adenylyl cyclase.
␤-ARs predominantly couple to G␣s and activate adenylyl
cyclase to increase intracellular cyclic adenosine monophos-
phate (cAMP) and protein kinase A (PKA). The endogenous
ligands of ARs are catecholamines, principally norepinephrine
(NE), a neurotransmitter released from the sympathetic nerve
endings as well as directly into the blood by the adrenal
medulla, and/or epinephrine, a hormone synthesized only in
the adrenal medulla and released into the systemic circulation.
A detailed description of the molecular interactions underlying
AR ligand binding can be seen in Refs. 72, 73 and additional
references for downstream signaling (74 –76).
In adipose tissue, ␤-ARs stimulate physiologically-relevant
thermogenesis and bind NE to acutely increase cellular catab-
olism by stimulating lipolysis in white adipocytes and coupled
lipolysis and thermogenesis in brown adipocytes. Activation of
the mitochondrial protein UCP1 in BAT generates heat by
allowing protons in the mitochondrial intermembrane space to
re-enter the matrix without uncoupling the respiratory chain,
accelerating substrate oxidation and ATP hydrolysis, and
allowing energy to be released as heat rather than ATP (77).
PKA phosphorylates hormone-sensitive lipase, a key enzyme in
lipolysis, and induces UCP1 activation in two ways: 1) fatty
acids released by lipolysis, which, besides being fuel for oxida-
tion within the mitochondria, also bind to UCP1 to activate and
increase its function (23, 71, 78 –80); and 2) PKA phosphory-
lates and activates cAMP-response element-binding protein

and the p38 MAPK pathway. p38 MAPK activates PGC1␣ that,
together with PPAR␣ and PPAR␥, stimulates transcription of
UCP1 and other thermogenic genes (71, 81).
In rodents, all three ␤-ARs are expressed in brown adi-
pocytes, with ␤1/␤2/␤3-AR mRNA transcripts at a ratio of 3:1:
150 (82), suggesting that the ␤3-AR plays a dominant role in
BAT metabolism. Although ␤3-ARs are thought to be the main
contributors to BAT activation and NST, each member of
␤-ARs contributes to BAT thermogenesis at a different magni-
tude (83), and all are physiologically relevant in mediating ␤-AR
signal transduction in BAT. Gene knockout of the individual
␤-ARs results in increased obesity, possibly due to the incom-
plete functional redundancy of the ␤-ARs in adipocytes (84 –
88). Disruption of all three ␤-ARs produces “␤-less mice,”
which increases their susceptibility to cold-induced hypother-
mia and diet-induced obesity (89, 90). However, knocking out
␤3-AR (␤3AR-KO) increases ␤1-AR mRNA in adipocytes,
brown more than white, suggesting cross-talk between ␤3-AR
and ␤1-AR. These mice displayed only a modest increase in fat
stores, suggesting compensatory mechanisms in response to
␤3-AR deficiency to maintain BAT function (84). In fact, dele-
tion of ␤1-AR has also caused cold-induced hypothermia,
decreased catecholamine-stimulated BAT response, and sus-
ceptibility to diet-induced obesity, suggesting that the ␤1-AR
plays an important role in SNS stimulation of adaptive thermo-
genesis (91). Moreover, following cold exposure, compared
with WT, ␤3AR-KO display the same thermogenic genes
expression (Ucp1, Pgc1a, Dio2, and Cidea) in BAT and WAT,
indicating that the ␤3-AR is dispensable for browning of the
adipose tissue (92). These animal data suggest that increased EE
through activation of NST is not exclusively mediated via
␤3-AR. Translation and comparison of studies on rodent
␤-ARs to humans is progressing as well, as several epidemiolog-
ical and mechanistic studies have linked mutations in the
␤3-AR to obesity and insulin resistance, although the precise
mechanisms remain to be determined (93–96).
Sympathomimetics
Ephedrine was one of the earliest sympathomimetic drugs
used to increase EE in rodents and humans (97–104). It medi-
ates its thermogenic effects by directly activating ␤-ARs (105)
and indirectly enhancing the release of NE and epinephrine
from sympathetic nerve terminals (106). The substantial
increase in EE does not come from activation of human BAT
(107, 108), but more likely is from activation of skeletal muscle
(98). While chronic administration of ephedrine does lead to a
net increase in EE, there is a reduction in BAT activity in
response to the greater muscle thermogenesis (109). Most trials
utilizing ephedrine for weight loss rely on its central suppres-
sion of appetite in addition to its sympathomimetic properties
and have been short-term (less than 6 months), so the long-
term effects are not well-known. A meta-analysis of 20 clinical
trials using ephedrine and ephedra (with and without caffeine,
discussed below) for weight loss found they were associated
with a 2 to 3 times increased risk of heart palpitations as well as
psychiatric, autonomic, and upper gastrointestinal symptoms
(110). As will be seen in the upcoming discussions, the experi-
ence with ephedrine for obesity treatment has a profile similar
JBC REVIEWS: Therapeutic regulation of thermogenesis
to several other classic drugs described here in other places:
short-term increases in energy expenditure; early reductions in
weight without evidence of long-term efficacy; cardiovascular
side effects; and several types of long-term risks.
Caffeine is an extremely popular drug that is thought to
increase thermogenesis by inhibiting the phosphodiesterase-
induced degradation of intracellular cAMP (111), and its effects
on human energy expenditure are well-documented (101, 112,
113). In nonhuman animal models, ephedrine and caffeine
combined are stimulatory thermogenic agents that cause NST
via ␤-AR– cAMP-mediated BAT activation (100, 101, 114,
115). Aside from the increase in energy expenditure, ephedrine
and caffeine have also been reported to decrease fat accumula-
tion (106). Conflicting human data have been reported on the
effects on body weight with some studies reporting significant
decreases (116, 117), whereas others report negligible effects
(118). An elegant study using innervated interscapular BAT in
control and chemically-sympathectomized rats showed that
both ephedrine and caffeine have a dose-dependent synergistic
action (119). At low concentrations, the thermogenic effects of
both are due to presynaptic NE release from nerve terminals,
whereas in higher doses (1 ␮M ephedrine and 2 mM caffeine),
BAT stimulation is postsynaptic (119). The thermogenic effects
of ephedrine and caffeine are regulated by two negative feed-
back mechanisms: 1) extracellular via adenosine and prosta-
glandin binding to Gi-coupled heptahelical receptors (119,
120),and 2) intracellular by phosphodiesterase degradation of
cAMP (120). Therefore, the effect of ephedrine and caffeine is
further exaggerated when combined with aspirin, 8-phe-
nyltheophylline (a potent adenosine receptor antagonist), and
3-propylxanthine (an inhibitor of phosphodiesterase) (120).
Interestingly, the effect of ephedrine and caffeine is attenuated
in obesity, consistent with the growing body of literature dem-
onstrating catecholamine resistance in obese rodent models
(121). This resistance was eliminated by adding aspirin,
through a mechanism that is not fully understood (122). This
could be explained by obesity-mediated PDE3B up-regulation
(121) that causes a reduction in cAMP and reduced BAT activ-
ity in an obese animal after ephedrine stimulation (108, 109,
121, 122).
Like caffeine and ephedrine, the sympathomimetic amine
phentermine has been available for decades for weight loss.
Phentermine targets the CNS by modulating catecholamines in
the satiety centers of the hypothalamus to act as an anorectic
agent that negatively regulates energy balance (123). It has been
used as a short-term management of obesity (123) and is
approved for short-term (up to 12 weeks) weight management.
Like other sympathomimetic agents, phentermine is associated
with elevations of blood pressure and heart rate and is not rec-
ommended in individuals with preexisting cardiac issues (124).
A retrospective cohort study (125) found that cardiovascular
disease was rare in individuals taking phentermine for 12 and 24
months, although a slight increase in heart rate was observed.
Current recommendations do not support long-term adminis-
tration of this drug.
For several decades, it has been observed that animals treated
with nicotine gain less weight and at a slower rate compared
with untreated animals. This is achieved by increasing their
J. Biol. Chem. (2020) 295(7) 1926 –1942 1933
JBC REVIEWS: Therapeutic regulation of thermogenesis
energy expenditure without decreasing food intake (126). Sim-
ilarly, smokers have been reported to have a higher resting met-
abolic rate compared with nonsmokers, and when they stop
smoking, their metabolic rate appears to decrease (127). Mech-
anistically, nicotine increases EE by stimulating the SNS,
increasing NE turnover and blood concentrations of NE and
epinephrine, and by increasing the binding of the purine nucle-
otide GDP to BAT mitochondria (128) promoting thermogen-
esis and consequently weight loss. In mice, nicotine was
reported to increase BAT weight and, when combined with
caffeine, increase BAT thermogenesis (129, 130). In a clinical
study evaluating the effect of smoking on energy expenditure,
nicotine exposure caused a 10% increase in total 24-h energy
expenditure with a significantly higher mean diurnal urinary
excretion of NE in cigarette smokers. This suggests that nico-
tine induces its thermogenic effects via increased NE secretion
(131) that could likely be due to activation of the sympathetic
central outflow, as reported in rodents (128). A second mecha-
nism proposed for nicotine-induced weight loss and increased
thermogenesis in rodents and humans is by inactivation of the
hypothalamic AMP-activated protein kinase (AMPK)/BAT
axis. This is a pathway in which reduced AMPK levels in the
ventromedial nucleus of the hypothalamus activate the SNS to
stimulate BAT thermogenesis (132). Nicotine also induces an
increase in anorexic signaling in the hypothalamus, decreasing
hunger and feeding, and an increase in physical activity and
substrate oxidation, leading to increased NST (132–134). Nic-
otine and liraglutide, a glucagon-like peptide 1 (GLP-1) recep-
tor agonist, promote body weight reduction via increasing sati-
ety and mediating BAT thermogenesis through the
hypothalamic AMPK axis (131, 134 –136). The principal limi-
tations of nicotine are the stimulation of the cardiovascular
system and its ability to cause physical and psychological addic-
tion (137). Smoking is also specifically associated with an
increased risk for developing various cancers (127).
Topiramate (TPM) was initially approved in 1996 for—and
primarily used to treat—CNS disorders, including epilepsy,
migraines, bipolar disorder, and neuropathic pain (138).
Patients receiving TPM displayed significant weight loss, lead-
ing to the drug’s subsequent approval by the FDA as an anti-
obesity drug. TPM exerts multiple mechanisms of action: it
increases the opening of GABA-mediated chloride channels
(139, 140); decreases the action of glutamate at kainite/AMPA
receptors (141); decreases L-type voltage-sensitive calcium cur-
rents (142); inhibits carbonic anhydrase (143); and increases
potassium conductance (144). The negative effect of TPM on
body weight is thought to be mainly achieved by the modulation
of GABA and antagonizing AMPA/PKA receptors. Studies in
lean and obese rodent models show that TPM reduces fat accu-
mulation independent of either diet or food intake (145, 146) by
reducing appetite and decreasing lipoprotein lipase (LPL) activ-
ity in WAT depots (145). Although no thermogenic action of
TPM has been demonstrated yet, a possible mechanism could
be the increased LPL activity in BAT, skeletal muscle, and car-
diac muscle, thus potentially increasing substrate oxidation and
thermogenesis (147, 148). Because both phentermine and TPM
reduce appetite, an extended-release combination therapy
(Qsymia威 by Vivus) was approved by the FDA in 2012 for the
1934 J. Biol. Chem. (2020) 295(7) 1926 –1942
treatment of obesity. This combination has been shown to be
efficacious in inducing and maintaining negative energy bal-
ance alongside improved lipid profile and blood pressure (149).
These long-term effects suggest an increase in metabolic rate,
yet no effects on BAT thermogenesis have been reported.
The class of ␤3-AR agonists has been a focus of the pharma-
ceutical industry for over 3 decades as a drug target for stimu-
lating fatty acid oxidation and thermogenesis (150 –152). To
date, no drug has been approved for that indication, yet the high
expression of the ␤3-AR on urinary bladder smooth muscle
facilitated its approval to treat overactive bladder. ␤3-AR ago-
nists such as mirabegron cause relaxation of the bladder’s
smooth muscle, thereby allowing greater urine capacity and
mitigating the effects of overactive bladder. The commercial
availability of mirabegron led to the testing of the ability of this
highly-selective ␤3-AR agonist to activate human BAT thermo-
genesis and WAT lipolysis. A single oral dose of 200 mg in
young healthy men increased EE by 203 kcal/day (⫹13%) and
stimulated BAT thermogenesis (153). While encouraging,
there was an increase in heart rate and blood pressure that were
not seen at the maximum approved dosage of 50 mg daily,
which itself did not affect EE (154). It remains to be determined
whether other doses of mirabegron will be clinically effective
and safe, both acutely (155) and after chronic treatment (156).
In summary, sympathomimetics are logical choices for stim-
ulating thermogenic EE, suppressing appetite, and ultimately
treating obesity. Although these drug options have achieved
desired metabolic effects, such as weight loss, increased energy
expenditure, increased BAT activity, or decreased food intake,
the sympathetic innervation–activation of ␤1- and ␤2-AR leads
to an increase in heart rate and blood pressure that have nega-
tive health effects. Although the prolonged use of such agents
leads to chronic stimulation of the SNS, the long-term patho-
logical effects to humans are not easily predicted nor are they
restricted to elevated BP. Fisher et al. (157) summarized the
consequences to include the following: vascular effects (hyper-
tension and atherosclerosis), metabolic effects (insulin resis-
tance and dyslipidemia), cardiac effects (arrhythmia and tach-
ycardia), and/or renal effects (renal vasoconstriction and
glomerulosclerosis). Similar consequences are also described in
middle- to older-age adults when chronic SNS activation
occurs as an intended physiological response to stimulate ther-
mogenesis (158). Therefore, despite the conceptual appeal,
anti-obesity drugs have been developed and mostly withdrawn
due to adverse effects affecting their safety and tolerability (68).
Uncoupling agents
NST is achieved by mitochondrial uncoupling mediated by
UCP1 in BAT. Uncoupling can be also induced by ionophores
such as 2,4-dinitrophenol (DNP), which generates heat by
allowing protons to shuttle more freely across the inner mito-
chondrial membrane into the matrix. As with UCP1, when
uncouplers reduce the backpressure from the protons in the
intermembrane space, the TCA cycle and electron transport
chain run faster, generating heat through the increased rate of
exothermic processes and intermolecular friction (23). In con-
trast to UCP1, DNP’s actions occur in every cell and are unreg-
ulated, which leads to uncontrolled hyperthermia (159).

Despite its success in reducing body weight (up to 3 lbs per
week) in high doses, DNP caused substantial side effects,
including rashes, cataracts, and even death due to hyperthermia
(160). Nevertheless, DNP was used as an off-label weight-loss
medication in the 1930s (160) and has the distinction of being
one of the first drugs banned by the FDA (161). Besides direct
uncoupling of oxidative phosphorylation, DNP increases intra-
cellular cAMP, likely through the activation of adenylyl cyclase
and/or inhibition of phosphodiesterase activity (160). Elevated
cAMP could then activate PKA and then downstream lipolysis
and thermogenesis. The door appears to be shut on the possi-
bility of using ionophores to treat obesity due to the numerous
studies demonstrating adverse reactions indicative of toxicity
in the muscle, liver, and heart when people took DNP (161).
However, recent studies by the Shulman and co-workers (162)
have focused on using a controlled-release oral formulation of
DNP, called CRMP (controlled-release mitochondrial protono-
phore). In a proof–of–concept rat model, CRMP produced mild
hepatic mitochondrial uncoupling and ameliorated hypertriglyc-
eridemia, insulin resistance, hepatic steatosis, and diabetes (162).
TRP superfamily
Transient receptor potential channels are a family of inter-
membrane ion channels that play a role in sensory reception
and can be thermally or chemically activated. The chemorecep-
tive properties of the channels provide a target for pharmaco-
logical interventions affecting sensory reception of tempera-
ture. Capsaicin is the compound responsible for the burning
sensation associated with hot peppers. It belongs to a family of
chemicals known as capsaicinoids present in all species of Cap-
sicum peppers (163). Capsaicin binds transient receptor poten-
tial vanilloid receptor 1 (TRPVR1), which detects painful heat
and harmful chemicals (164), and is currently approved by the
FDA as a topical agent for the treatment of neuropathic pain
associated with post-herpetic neuralgia. Another class of
TRPV1 receptor agonists found in Capsicum peppers are
known as capsinoids and lack the pungency of capsaicin (165).
Both capsaicinoids and capsinoids are thought to increase
energy expenditure through TRPV1 receptor-mediated sympa-
thetic nervous system response (166) and release of adrenal
catecholamines (167). The effect of capsaicin and capsinoids on
human metabolism is not entirely clear. Many studies are con-
ducted using extracts of red peppers and other natural prod-
ucts, which makes it difficult to determine which chemical
agent induced the observed effects. Pure capsaicin was evalu-
ated in a study of weight maintenance after weight loss in 140
overweight men and women. The group that consumed 22.5
mg of capsaicin had a significantly higher increase in resting
energy expenditure (REE) (167 ⫾ 120 kcal/day) than controls
(48 ⫾ 120 kcal/day) (168). Overall results have been mixed,
however. Another study of 78 healthy men who ingested 3 mg
of dihydrocapsiate for 28 days had a nonsignificant increase in
REE compared with controls, whereas another study of 13 men
found no changes in metabolic rate with the consumption of 1,
3, 6, and 12 mg of capsinoid capsules over a 5-day inpatient stay
(169). Capsaicin has also been associated with BAT activation
(170), although there has been no demonstration that capsaicin
activates human BAT, either directly through cell-surface
JBC REVIEWS: Therapeutic regulation of thermogenesis
receptors or indirectly via the SNS. Thus, despite the large interest
in this natural compound, it is unclear whether it has any potential
utility in treating obesity-related energy imbalance.
Menthol, also known as mint camphor, is a compound iso-
lated from the plant genus Mentha that is responsible for the
cooling sensation associated with mint extracts (171). Menthol
binds the transient receptor potential melatstatin-8 (TRPM8)
on peripheral nerve fibers, which detect environmental cold
(172). These nerves transverse the dorsal horn of the spinal cord
to the lateral parabrachial nucleus in the dorsolateral pons and
then on to the preoptic area of the hypothalamus (173). Efferent
signals leave the brain descending the spinal cord to sympa-
thetic nerves that release norepinephrine causing vasoconstric-
tion in blood vessels and BAT activity. TRPM8 receptors have
been found to be expressed on the surface of both mouse brown
and white adipocytes as well (174, 175). Treatment of mouse
white adipocytes with menthol increased UCP1 expression,
thought to be due to TRPM8 activation. Mice fed a high-fat diet
with 1% menthol for 18 weeks had a significantly-reduced
weight gain compared with high-fat diet mice (174). TRPM8
expression has been detected in human white adipocytes as
well, and when treated with menthol the adipocytes showed an
increase in UCP1 expression, mitochondrial membrane poten-
tial, and heat production, displaying a similarity to brown adi-
pose tissue during cold exposure (176). Although there have yet
to be any in vivo human studies on the effect of menthol and
energy expenditure, these results show potential for menthol-
induced increases in REE.
In summary, it is useful to conceptualize the pharmacological
treatment of energy imbalanced-induced obesity as one would
approach other chronic conditions such as essential hyperten-
sion and insulin resistance. The undesirable retention of food
calories is similarly multigenic and produced by multiple inter-
actions between genetic background and environment. Success
routinely requires several medications from distinct classes that
address the different contributors to the chronic illnesses. Just
as hypertension is often treated with combinations of sympa-
tholytics, ion channel blockers, and enzyme inhibitors, the
pharmacological approach to obesity will likely require a com-
bination of drugs that suppress appetite, impair absorption, and
increase energy expenditure (Fig. 1). Given the challenges asso-
ciated with combating the strong evolutionary drive to preserve
caloric stores, focus should be toward treating obesity-related
metabolic disease. Success is more likely in this arena where
substantial advances have already been made in reducing insu-
lin resistance, hypertension, and dyslipidemia.
Impacts of pharmacological regulation of energy
balance, overweight, and obesity
Metabolic adaptations
As the previous section shows, there is great interest in devel-
oping pharmacological approaches to achieving a net negative
energy balance and treating obesity. However, the small num-
ber of approved anti-obesity drugs reflect many conceptual and
practical inadequacies. The limitations are not just safety or
even short-term efficacy. A larger challenge is the need over the
long term to combat homeostatic drives within humans to
J. Biol. Chem. (2020) 295(7) 1926 –1942 1935
JBC REVIEWS: Therapeutic regulation of thermogenesis
return to higher weights. Despite a seemingly simple equation,
“energy in less than energy out,” there are complex adaptations
to energy regulation. Although body weight can be modulated
acutely, it remains difficult to achieve long-term weight loss as
the body tends to adapt or resist by modulating energy expend-
iture, hormonal, and psychological drive.
Even in short-duration studies of energy deficit, energy bal-
ance tends to reestablish. For example, in a 1-day diet-induced
or exercise-induced net-negative energy balance, subjects the
following day compensated calorically to the energy lost on the
previous day and returned to energy balance after 48 h (177). In
cases where energy expenditure increases due to exercise train-
ing, there is evidence to suggest that energy intake will also
compensatively increase (178, 179), and activity outside voli-
tional exercise tends to decrease (180). Similarly, in mice, cold-
induced increases in energy expenditure lead to increased food
intake in a dose-dependent manner (181). Although the rela-
tionship between energy expenditure and energy intake may be
unclear, energy maintenance is still tightly regulated (182). It is
true that with longer-term energy deficits, there is weight loss.
However, decreases in weight are accompanied by reductions
in circulating leptin, peptide YY, cholecystokinin, and amylin
and increases in ghrelin—a coordinated hormonal response
that promotes weight gain. Even after the initial dynamic phase
of weight loss, these changes are maintained, likely playing a part
in the body’s continual resistance to weight loss (183). In fact, hor-
monal regulations that alter intake and satiety can persist for
greater than a year after a 10-week very low energy diet (183).
To the frustration of most dieters, there is a lowering of REE
with weight loss. It is a widely-held but false belief that a daily
energy deficit of 500 kcal leads to a loss of a pound of fat per
week and over 50 lbs per year (184). Rather, weight loss is more
asymptotic, and a larger energy deficit is required to con-
tinue losing weight at the same rate (https://www.niddk.nih.
gov/health-information/weight-management/body-weight-
planner) (185). The extent of weight change has both hormonal
and genetic components (186 –188). At first, the body can
adjust energy expenditure, up or down, according to a 10%
weight gain or loss, respectively (189). However, this adaptation
is only able to adjust to a certain level: in subjects who lost 20%
of their initial weight, REE did not decrease any further, sug-
gesting a maximal adaptation to the maintenance of reduced
body weight (189). In subjects who lost over one-third of their
initial body weight and maintained adequate fat-free mass dur-
ing the “Biggest Loser” competition, the measured BMR
decreased by 504 kcal/day more than that predicted based on
fat-free mass, fat mass, age, and sex (190). The degree of meta-
bolic adaptation was inversely correlated with changes in thy-
roid-stimulating hormone levels but was not correlated to
changes in triiodothyronine levels, which declined with weight
loss. This pattern suggests that metabolic adaptation was cen-
trally mediated with the hypothalamic–pituitary–thyroid axis
potentially playing a large role (190). Other studies have shown
that leptin, an anorexigenic adipokine, may play a role in met-
abolic adaptation (191–193). Metabolic slowing not only adds
to the difficulty of losing weight but may also contribute to
weight regain. For instance, in a subset of the “Biggest Loser”
contestants measured 6 years after their initial weight loss, the
1936 J. Biol. Chem. (2020) 295(7) 1926 –1942
percentage of original weight regained was directly related to
the amount of metabolic adaptation, i.e. the difference between
the measured and predicted BMR at 6 years (194). Interestingly,
the amount of weight regained by the participants after 6 years
was not correlated with a change from pre-weight loss energy
intake but was inversely correlated with changes from pre-
weight loss physical activity levels. These observations suggest
that physical activity, although not necessarily effective as the
primary approach for weight loss, is important for successfully
preventing the regaining of lost weight (195).
Approaches to maximize thermogenesis
Given that humans and related mammals are physiologically
designed to resist weight loss, it raises the following question:
does the method of altered energy intake or output change met-
abolic responses? This was addressed in rats whose weight loss
from diet was compared with exercise. Both groups had similar
reductions in adiposity, but the exercised rats displayed
improvements in insulin resistance, greater insulin sensitivity,
and lower low-density lipoprotein (196), and they showed
increased mitochondrial functioning in BAT (196). Other
reports on exercise suggest that endurance exercise promotes
high rates of oxidative metabolism in skeletal muscle. With
endurance exercise, there is a shift to type I myofibers with high
mitochondrial content and thus fatty-acid oxidation profile
(197). This switch is similar to the one that occurs in skeletal
muscle from cold exposure, where cold exposure increases
expression of PGC-1␣ in skeletal muscle promoting mitochon-
drial biogenesis and a switch to oxidative fibers (198).
Besides reduced oral caloric consumption and increased
exercise, cold exposure is another intervention that can lead to
a net negative energy balance. Mice exposed intermittently to
cold for 0, 1, 4, or 8 h a day three times a week for 10 weeks saw
an increase in total energy expenditure (181). Joy (199) tested
human subjects repeatedly exposed to cold temperatures (5 °C)
for 8 h over the course of 5 weeks. The cold-adapted subjects
could further increase their metabolic rates in response to an
infusion of NE, demonstrating an increase in the body’s ability
to perform nonshivering thermogenesis. These early findings
were corroborated by studies of subjects who were exposed to
17 °C for 2 h daily over 6 weeks, which resulted in increased
BAT activity and an ⬃167% increase in the CIT response to
acute exposure to 19 °C (170). Further study by Lee et al. (200)
demonstrated that sleeping in a 19 °C room at night for 1 month
increased BAT volume and activity compared with 1 month of
sleeping in 24 °C. Physiological responses in these subjects also
included increased expression of adiponectin and GLUT4 in
subcutaneous WAT. White adipocyte insulin resistance
decreased, and the Matsuda index for insulin sensitivity
increased (200). However, as with increased exercise and
reduced caloric intake, the increased metabolism in response to
cold may only be temporary “adjustments” seen in those who
normally live in a thermoneutral climate. Over the longer term,
the body undergoes “adaptations” that lead to blunted meta-
bolic rate increases (201). Additionally, people with obesity, for
whom therapeutic BAT activation would be desirable, have less
activated BAT than lean men after cold exposure, despite a
greater amount of fat in BAT-containing depots (55).

Thus, depending on the type and amount of exposure to cold,
caloric changes, and exercise regimen, there are multiple ways
the body will manipulate cellular energy expenditure, hor-
mones, and physiological responses to re-achieve a perceived
homeostasis. The body, over chronic periods of energy abun-
dance or deprivation, will adapt. The decreasing return on
investment, whether it be to lose weight, improve the lipopro-
tein profile, etc., posits a question for how often and frequently
we can manipulate our actions and environments to receive the
desired results.
The future and conclusions
In summary, the prospect of using pharmacological and
other nonsurgical means to increase thermogenesis and reduce
obesity is in a state of equipoise. Current methodologies to mea-
sure whole-body energy expenditure are quite precise, yet
advances are urgently needed in the area of measuring thermo-
genesis at the level of the individual tissue. Available
approaches to stimulate thermogenesis are effective acutely,
but long-term efficacy and safety are still not assured. There
remains promise in new approaches to increasing EE, particu-
larly human BAT as it was only recently determined to be func-
tional in adult humans. Much remains to be learned about its
roles in human physiology, both in terms of thermogenesis and
other contributions. Finally, as with any intervention that per-
turbs homeostasis, solutions are needed for the physiological
compensation that occurs when a negative energy balance is
achieved. It may be that small, sustained increases in energy
expenditure or reducing metabolic adaptation will be the
most effective over the years to achieve and maintain lower
weights.
These sober perspectives will remain the fate of the field
unless— or until—the ultimate breakthrough in mammalian
energy balance is discovered: how the body knows and main-
tains its own weight. As described above, numerous studies
point to hypothalamic nuclei as regions where the brain
receives input from the periphery regarding energy stores. It
has also been demonstrated that the brain contains the sites
where metabolic adaptation slows metabolism after weight
loss. If new research determines how to directly adjust the
body’s “baristat,” then the therapeutic activation of human
energy expenditure and thermogenesis to treat obesity would
be attainable. Such systems have already been described and
manipulated beneficially to treat other endocrine disorders,
from the thyroid to the reproductive axes. The same may be
true for the regulation of energy balance, yet the big discoveries
await. The obesity pandemic means the demand for treatments
is high, and so must be the ingenuity and resourcefulness
among those in the field.
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