REVIEWS

Cognitive and autonomic determinants

of energy homeostasis in obesity
Denis Richard
Abstract | Obesity ensues from an imbalance between energy intake and expenditure that results from gene–
environment interactions, which favour a positive energy balance. A society that promotes unhealthy food and
encourages sedentary lifestyle (that is, an obesogenic environment) has become a major contributory factor
in excess fat deposition in individuals predisposed to obesity. Energy homeostasis relies upon control of
energy intake as well as expenditure, which is in part determined by the themogenesis of brown adipose tissue
and mediated by the sympathetic nervous system. Several areas of the brain that constitute cognitive and
autonomic brain systems, which in turn form networks involved in the control of appetite and thermogenesis,
also contribute to energy homeostasis. These networks include the dopamine mesolimbic circuit, as well
as the opioid, endocannabinoid and melanocortin systems. The activity of these networks is modulated by
peripheral factors such as hormones derived from adipose tissue and the gut, which access the brain via the
circulation and neuronal signalling pathways to inform the central nervous system about energy balance and
nutritional status. In this Review, I focus on the determinants of energy homeostasis that have emerged as
prominent factors relevant to obesity.
Richard, D. Nat. Rev. Endocrinol. 11, 489–501 (2015); published online 30 June 2015; doi:10.1038/nrendo.2015.103

Introduction
The high prevalence of obesity and an awareness of the been estimated to be between 40 and 70%7 and predispo-
impact that abdominal fat accretion has on health1 and sition to obesity is polygenic. Additionally, we currently
the cost of healthcare2 have stimulated much research on live in an ‘obesogenic’ environment, which promotes the
metabolism and increased our understanding of this con- marketing and provision of energy-dense foods and a
dition, which results from an imbalance between energy sedentary lifestyle, and consequently puts individuals at
intake and expenditure. The Latin origin of the word risk of developing obesity. Our modern lifestyle also pro-
obesity, obedere (constructed from ob, over and edere, to duces epi­genetic effects that contribute to obesity,8,9 and
eat), which literally means ‘eating in excess’ appropriately an obesogenic environment can imprint on the neuronal
describes this disequilibrium between intake and expendi- circuits involved in the regulation of energy balance.10–12
ture. Although less investigated than that of energy intake, Unhealthy eating can in fact lead to unfavourable neuro­
the role of energy expenditure in maintaining the energy plastic changes (that is, neurogenesis, synaptic plasticity
balance is nonetheless considerable. Energy expenditure is and dendritic arborisation).13 These changes can occur
generally assessed in terms of resting energy expenditure, during critical stages of development, as well as in adult-
the thermogenic effect of food and expenditure owing hood, and unfavorably alter energy balance regulation.11,12
to physical activity.3 Energy expenditure is partially con- Misprogramming of energy balance regulation during
trolled by the cognitive nervous system—for example, embryonic development has also been reported in rats
the decision to engage in physical activity is most cer- polygenetically predisposed to high fat diet-induced
tainly volitional. It also relies on autonomic mechanisms obesity.14,15 Finally, an obesogenic environment can alter
involved, for instance, in the control of thermogenesis in the microbiota composition in the gut, where it influences
brown adipose tissue (BAT), which modulates resting energy balance and when dysfunctional is associated with
energy expenditure, the thermic effect of food and pos- metabolic complications.16–18
sibly also energy expenditure during activity. This effect To fully understand the physiopathology of obesity,
might substantially impact the energy balance given the we require an extensive knowledge of the central
remarkable heat-producing potential of brown adipo­ nervous system (CNS) circuits involved in the regula-
cytes, 4 which are regulated by several brain regions tion of energy balance (that is, energy homeostasis) and
Institut Universitaire involved in energy homeostasis (Box 1 and Figure 1).5,6 the relationship between these circuits and the periph-
de Cardiologie Obesity results from gene–environment interactions. eral homeostatic signals, which inform the brain about
et de Pneumologie de
Québec, 2725 Chemin For examples, the heritability of excess fat deposition has the energy balance and nutritional status. The view
Sainte-Foy, Québec, that the brain regulates energy balance in obesity has
QC G1V 4G5, Canada.
denis.richard@ Competing interests received further support from an imposing genetic study
criucpq.ulaval.ca The author declares no competing interests. in which gene set enrichment analyses for associations

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REVIEWS

Key points the appetite and thermogenesis networks. 5,23,31–33

These networks include neurons which express recep-
■■ Obesity results from genetic and environmental factors that interfere with the
action of brain and peripheral networks involved in regulating energy balance
tors or produce chemical mediators that contribute to
■■ The control of energy expenditure is, in part, exerted on the activity of brown anabolic (fat deposition promoting) or catabolic (fat
adipose tissue, which might have a considerable thermogenic effect in the body deposition reducing) responses. 34 These mediators
■■ The controls of energy intake and expenditure are insured by interrelated and receptors include γ-aminobutyric acid (GABA),
cortical executive, reward and autonomic circuits in the brain glutamate, dopamine, opioids, endo­c annabinoids,
■■ The dopamine mesolimbic circuit and the opioid, endocannabinoid and pro-­o piomelanocortin (POMC), neuro­p eptide Y
melanocortin systems are key central nervous system elements in energy (NPY), agouti-related peptide (AgRP), steroidogenic
homeostasis
factor 1 (SF1) and melano­cortin receptor 4 (MC4R).34
■■ Leptin and ghrelin are peripheral homeostatic hormones that signal to the brain
to provide information on energy balance and nutritional status
Environmental cues or endo­genous or interoceptive
signals can influence food intake and energy expendi-
ture in response to changes in energy balance, and in
with body mass index (BMI) revealed that 27 out of 31 turn modulate activity in the brain networks that control
enriched tissues were in the CNS and include, together appetite and thermogenesis (Box 3).
with the hypo­thalamus, regions dedicated to learning,
cognition, emotion and memory. 19 In this Review, I Cortical executive circuits
outline the determinants of energy homeostasis regula- The decision to engage in eating or physical activity is
tion by the CNS in light of the new progress in the field controlled by the PFC and ACC and associated fore-
of obesity research. brain connections. The integrity of these structures
in achieving appropriate self-discipline towards food
The brain in energy balance ingestion and physical activity seems necessary to
The control of food intake and energy expenditure is maintain a healthy energy balance.27,35 Impaired or dys-
achieved via a highly coordinated communication functional PFC, ACC or connectivity between execu-
between the executive, reward and autonomic circuits in tive and reward circuits weakens self-discipline toward
the brain and circulating homeostatic signals (Box 2 and obesity-­preventing behaviours.35
Figure 2).20–31 The CNS circuits link the prefrontal cortex The importance of forebrain integrity in obesity
(PFC), anterior cingulate cortex (ACC), insula, stria- develop­ment is substantiated by the association between
tum, ventral pallidum (VPa), amygdala, hippo­campus, obesity and the loss of grey matter in these cortical
substantia nigra (SN), ventral tegmental area (VTA), regions.36–38 Whether the loss of grey matter follows or
hypothalamus, brainstem and spinal cord to constitute predates obesity is still under investigation. Obesity, at
least in its visceral form, might induce cortical thin-
ning, 36 which could be secondary to inflammatory
Box 1 | BAT thermogenesis processes.37 However, whether obesity-induced corti-
BAT dissipates chemical energy in the form of heat (via non-shivering cal thinning can lead to a loss of eating control (that is,
thermogenesis) and consequently contributes to energy homeostasis.203 impulsive eating) has yet to be corroborated. New data
BAT capacity for non-shivering thermogenesis is dependent on UCP1,204, 205 a which indicate that maintenance of weight loss follow-
protein uniquely expressed in the mitochondria of this tissue. UCP1 uncouples ing bariatric surgery depends on the ability to properly
ATP synthesis from substrate oxidation, promoting heat production and organize executive control, also support a role for the
enabling oxidative pathways to function without restriction.206 BAT is also highly
executive system in obesity.38
vascularized, which also contributes further to its thermogenic function.203
PFC and ACC-mediated self-discipline to control
BAT thermogenesis is physiologically controlled by the SNS,33 which extensively
eating is particularly important in an obesogenic
innervates this tissue. Sustained SNS stimulation of brown adipocytes enhances
thermogenic activity and capacity.207 Persistent adrenergic stimulation also leads
environ­ment, where reward-motivated responses to
to the development of brown adipocytes in WAT depots, a process referred as food-associated stimuli are heightened.35 The obesogenic
‘browning’.208,209 This transformation is further promoted by secreted factors such environment can increase a craving for food in individu-
as cardiac natriuretic peptides,210 FGF-21,211,212 and BMP7 and BMP8B.213,214 als with obesity, in particular those who report them-
Before molecular imaging studies revealed the presence of functional brown selves to be impulsive (that is, in those with a tendency to
adipocytes in humans,215–220 BAT was thought to be only present during neonatal act rapidly without attention to consequences).39 In fact,
life. Notably BAT can be detected with a near‑100% prevalence in healthy young self-reported impulsivity in individuals with obesity has
adults.221 The thermogenic activity of BAT in humans is increased by both cold been associated with a bias toward energy-dense foods.40
exposure and β3-adrenergic agonism.222–225 Individuals who are impulsive and obese seem in fact to
The role of BAT in energy balance regulation is supported by studies in which readily detect palatable foods, which enhances the risk
increases in metabolic efficiency leading to obesity in mice lacking either this for unhealthy eating.40 In this regard, impulsive children
tissue or UCP1 have been reported.226,227 Notably, BAT is controlled by brain
have enhanced susceptibility to food advertisements.41
regions involved in energy homeostasis.33,228 Inverse correlations between BMI,
body fat mass, or central obesity and BAT activity (inferred from 18FDG uptake)
Impulsivity has also emerged as a strong predictor of
have been reported.216,220,221,229,230 BAT might be exploited to potentially treat obesity in people demonstrating personality traits such
human obesity. 209,231–234 as high neuroticism and low conscientiousness.42 Finally,
Abbreviations: BAT, brown adipose tissue; BMP, bone morphogenetic protein; FGF, fibroblast individuals who restrict their calorie intake in order to
growth factor; SNS, sympathetic nervous system; UCP1, uncoupling protein 1; WAT, white lose weight are more likely to overeat if they have an
adipose tissue.
impulsive character.43

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a Hypothalamus ◀ Figure 1 | Control of thermogenesis in BAT. a | Brown

adipocyte thermogenesis is controlled by the autonomic
PVN
POA DMH
nervous system, specifically via the hypothalamus and the
LH brainstem, which control SNS activity. The efferent
VMH preganglionic neurons associated with thermogenesis
emerge from the IML in the vertebrae. Upon stimulation,
ARC SNS postganglionic nerves release noradrenaline in the
vicinity of BAT and trigger a cascade of events that ultimately
lead to the concomitant catabolism of intracellular TAG and
activation of UCP1, which generates heat. The intracellular
Brainstem
pool of TAG helps to sustain thermogenesis; replenishment
of this pool through de novo lipogenesis or the uptake of
PAG nonesterified FA is a metabolic priority of the stimulated
PBN brown adipocyte.207,222 b | Cold exposure and cold adaptation
stimulate brown fat in both rats and humans.207,222 The
RPa images from rats illustrate the tissue uptake of 18F-fluoro-6-
thia-heptadecanoic acid in cold-exposed/cold-adapted
animals.207 The images from humans illustrate the 18F-fluoro-
deoxyglucose uptake in response to cold-exposure.222
Vertebrae cross section Abbreviations: ARC, arcuate nucleus; BAT, brown adipose
tissue; DMH, dorsomedial hypothalamic nucleus; FA, fatty
acids; IML, intermediolateral nucleus; LH, lateral
hypothalamus; PAG, periaqueductal gray; PBN, parabrachial
IML nucleus; POA, preoptic area; PVN, paraventricular
hypothalamic nucleus; RPa, raphe pallidus; SNS,
sympathetic nervous system; TAG, triacylglycerol; UCP1,
uncoupling protein 1; VMH, ventromedial hypothalamus.
Permission for panel b obtained from FASEB © Labbe, S. M.
SNS signals et al. In vivo measurement of energy substrate contribution
BAT to cold-induced brown adipose tissue thermogenesis.
De novo lipogenesis Lipid storage
FASEB J. 29, 2046–2058 (2015) and the Endocrine Society
Glucose TAG Nonesterified FA © Blondin, D. P. et al. Increased brown adipose tissue
oxidative capacity in cold-acclimated humans. J. Clin.
UCP1
Endocrinol. Metab. 99, E438–E446 (2014).
Heat

Reward circuits
b Rat Human The reward circuits include neurons of the insula, stria-
tum, VPa, amygdala, hippocampus, VTA, SN, hypo-
thalamus and brainstem (Figure 2).23 These circuits have
been described as integrating incentive salience (that
is, ‘wanting’) and hedonic (that is ‘liking’) attributes.
Incentive salience can be defined as the brain’s repre-
sentation of the value (for example, in terms of attention
and motivation) of a rewarding prompt.23,44,45 Conversely,
hedonic refers to the pleasurable reactions or sensations
Control Cold-adapted Control Cold-adapted led to by reward-motivated behaviours.45,46 The insula and
Cold exposed Cold exposed
amygdala, which are highly sensitive to environ­mental
Cervical Interscapular Periaortic Clavicular Paraspinal Perirenal reward-inducing cues, provide the PFC (the orbito­frontal
cortex, in particular) and ACC with neuronal inputs that
modulate the overall value of food.23 The PFC, ACC,
Nature Reviews | Endocrinology
insula and amygdala, together with the striatum, VPa,
VTA, SN, hypothalamus and brainstem, work jointly
Box 2 | Brain circuits involved in energy homeostasis
to ultimately determine the subjective value of food-­
■■ Cortical executive circuits—responsible for the associated cues and establish the incentive salience for
self-control of eating, and engaging or adhering to
these cues.23 The insula also receives projections from the
physical activity
■■ Reward circuits—interconnected nuclei and neurons
oral cavity, hosts taste neurons, manages intero­ception
capable of encoding the pleasurable (hedonic) and and is sensitive to gut-related signals as well as hunger
motivational aspects and food-related cues sensation. 23,47 The ventral striatum, particularly the
■■ Autonomic energy balance regulation circuits medial shell of the nucleus accumbens (NAc), represents
—composed of hypothalamic and brainstem nuclei, an important entity in operating the ‘liking’ and ‘wanting’
which modulate the activity of the cortical executive components of the reward-motivated behaviours.30
and reward circuitries and govern expenditure The reward circuitry is continually stimulated in an
components such as thermogenesis
obesogenic environment that develops and advertises

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highly palatable energy-dense food while contribut- A rewarding eating experience activates the dopamine-
ing to reduce the imperative for physical activity.48 Our mediated mesocorticolimbic circuit, which in turn
modern lifestyle also includes stressful life-events, which enables food intake-related cues (flavour, smell, appear-
can lead to reward-motivated, obesity-promoting behav- ance, food advertising) to become conditioned to stimuli
iours while weakening self-regulation. Indeed, individu- that predict eating reward.23 Furthermore, the repeated
als tend to seek palatable energy-dense food to combat exposure to reward-associated eating prompts leads to
stress—so called, ‘comfort eating’.49,50 gradual enhancement of the dopamine response (sensiti-
zation) to conditioned stimuli, which reinforces incentive
The dopamine mesocorticolimbic circuit salience for food.23
A crucial input to the PFC, ACC, insula, striatum, Interestingly, obesity and overfeeding have been
amygdala and hippocampus are VTA and SN dopa- associated with a reduction in dopamine receptor D2
mine neurons,23 which constitute the dopamine meso- (DRD2) expression and signalling, for example, in
corticolimbic circuit and encode the ‘wanting’ for food humans with the Taq1A A1 allele polymorphism or
consumption.51 Increased dopaminergic activity induces rats overfed with palatable high-fat food.52,53 In rats,
the organism to engage in rewarding actions. It also ini- reduced DRD2 signalling leads to overfeeding on pal-
tiates a desire to transform neutral stimuli into condi- atable energy-dense food; similarly, striatal-specific
tioned stimuli and consequently reinforces behaviour.23 knockdown of DRD2 results in a drug addiction-like

ACC Insula
PFC

Hypothalamus

Executive

NAc VTA

Brainstem
Amygdala Anabolic control Catabolic control
AgRP/NPY POMC
GABA Glutamate
Hippocampus Dopamine SF1
Opioid MC4R
Reward Endocannabinoids Autonomic

CNS control

Peripheral control Ghrelin Leptin

(anabolic) (catabolic)

Muscle

Food Heat

Energy stores BAT

Figure 2 | Regulation of energy balance. Energy homeostasis relies on controls exerted on bothNature
energyReviews
intake and energy
| Endocrinology
expenditure. The control of energy expenditure can be exerted on the muscle activity as well as on BAT thermogenesis. Those
controls are insured by different brain structures that compose the cortical executive circuits, reward (that is, hedonism/
incentive salience) circuits and autonomic circuits. The neurons from these circuits shape networks controlling food intake
and energy expenditure and include anabolic and catabolic mediators or receptors that influence energy balance. The activity
of the brain networks is influenced by peripheral mediators (for example, leptin and ghrelin); variations in the circulating
levels of these signals inform the CNS about the body’s current energy balance. Abbreviations: ACC, anterior cingulate cortex;
AgRP, agouti-related peptide; BAT, brown adipose tissue; CNS, central nervous system; DVC, dorsal vagal complex; GABA,
γ-aminobutyric acid; MC4R, melanocortin receptor 4; NAc, nucleus accumbens; NPY, neuropeptide Y; PAG, periaqueductal
gray; PBN, parabrachial nucleus; PFC, prefrontal cortex; POMC, pro-opiomelanocortin; SF1, steroidogenic factor 1; SN,
substantia nigra; SNS, sympathetic nervous system; VTA, ventral tegmental area.

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neuroadaptive response in the reward circuitry, which Box 3 | Effects of obesity and an obesogenic environment
provokes overeating.53 How lowered DRD2 signalling
contributes to obesity has yet to be fully understood, but Increased
■■ Effect of reward prompts
reduced DRD2 signalling not only impairs motivation
■■ Appetite
(willingness to achieve effort-­demanding goals) but also
increases impulsivity.54 Assuming that overeating is an Decreased
impulsive behaviour,42 one might argue that low levels ■■ Activity and capacity of cortical executive networks
■■ Self-discipline
of DRD2 favours overeating. For example, diminished
■■ Physical activity
DRD2 density in the striatum in individuals with obesity ■■ Thermogenesis of brown adipose tissue
has been associated with a reduced metabolic activity
in the PFC areas that modulate the executive control of
food intake and possibly physical activity.55 Likewise,
DRD2 deficiency might result in learning difficulties, Autonomic regulation of energy balance
which in turn affect an individual’s capacity to under- Autonomic circuits in the brain can modulate CNS activ-
stand the consequences of overeating. 23 Compulsive ity in the rostral forebrain appetite network and control
eating also shares some analogies with compulsive drug- energy expenditure via thermogenesis (Figure 2). The
taking—both behaviours lead to overconsumption and autonomic energy balance regulation circuits mainly
unreceptiveness to unfavourable consequences.56 consist of hypothalamic and brainstem nuclei contain-
ing neurons, which are sensitive to signals that inform
The opioid and endocannabinoid systems the CNS of energy balance and nutritional status.22,34
Opioid and endocannabinoid systems are both involved The hypothalamus comprises many nuclei, which
in energy homeostasis.57–60 The opioid system produces are explicitly involved in the control of energy
endor­phins, enkephalins, dynorphins, endomorphins homeo­s tasis. 73,74 An important focus of research is
and includes neurons expressing opioid receptors that the arcuate nucleus (ARC), 75,76 a small structure of
include the μ (β-endorphins, met-enkephalins, leu- the mediobasal hypothalamus located on each side
enkephalins and endomorphins), δ (met-enkephalins and of the third ventricle. Neurons from the ARC send
leu-­enkephalins), and κ (dynorphins) opioid receptors.61 projections to various nuclei including the para-
The endocannabinoid system releases endocannabi­noids ventricular hypothalamic nucleus (PVH), which is
including anandamide and 2‑­arachidonoylglycerol, which responsible for major neuro­endocrine functions and
are produced ‘on-demand’ and act in the brain on the autonomic CNS control. The ARC and PVH work
cannabinoid 1 receptor (CB1).62 The opioid and endo­ together to control the energy balance (Figure 3).74,77
cannabinoid systems are both anabolic systems that Neurons from the ARC also terminate in the ventro-
promote energy deposition by increasing food intake and medial hypothalamic nucleus (VMH), lateral hypo-
likely decreasing BAT thermogenesis.63 thalamus (LH), dorso­m edial hypothalamic nucleus
Although the sites of action of opioids and endo­ (DMH) and preoptic area (POA), where they can
cannabinoids in the control of food intake and energy also influence both food intake and energy expendi-
expenditure are largely unknown, these agents can mod- ture.74 How the hypothalamus relays information on
ulate the activity of the reward circuitry by influencing energy homeostasis to the rostral forebrain appetite
both ‘liking’ and ‘wanting’ components.64 When injected network has yet to be fully investigated but might
into the dorsal medial shell of the NAc, agonists for the μ, function via a hypothalamic-thalamic-striatal axis or
δ and κ opioid receptors, in addition to CB1, elicit ‘liking’ hypothalamic–brainstem–striatal axis.78–80
of sweetness as assessed in a taste reactivity paradigm.64,65 The brainstem includes several nuclei involved in the
Notably, opioids and endocannabionoids can also regulation of energy balance. The nucleus of the soli-
increase the ‘wanting’ for food mainly via the μ recep- tary tract (NTS), the area postrema (AP) and the dorsal
tor,66 and CB1, respectively.64 This increased ‘wanting’ motor nucleus of the vagus nerve, which make up the
of food is partly the result of μ opioid and CB1 recep- dorsal vagal complex (DVC) are key structures that
tor agonism of the whole dopamine mesocorticolimbic integrate homeostatic signals from peripheral media-
circuit.63 The action of the opioids and endocannabinoids tors to inform the forebrain about energy balance.81–83
that enhance the motivation for food has been observed Additionally, the brainstem includes nuclei such as the
in the NAc and the VTA, where agonism of μ opioid or pontine para­brachial nucleus (PBN) the raphe pallidus
CB1 receptors stimulate dopamine neurons projecting (RPa), peri­aqueductal gray (PAG), pontine reticular
to the striatum.67,68 nuclei, and lateral paragigantocellular nucleus, which
The opioid and endocannanbinoid systems are also have all been associated with SNS-mediated BAT
key circuits in the reward-motivated behaviors asso- thermo­genesis.31 These nuclei are part of circuits linking
ciated with the development of obesity. For example, the hypothalamus to the intermediolateral cell column
loss of μ, δ opioid and CB1 receptor function prevent of the spinal cord (the intermediolateral nucleus; IML)
obesity mostly by reducing the hedonic value of food.69–71 from where the preganglionic neurons of the SNS
Furthermore, enhanced μ opioid receptor signalling in outflow to BAT originate (Figure 1).31 The PBN is an
the brain is associated with maternal obesity and high-fat important relay that links the DVC to the forebrain
feeding before or during pregnancy.72 appetite network.80,84

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Reward circuits results from an enhanced energy intake96 and a reduced

Brainstem
NAc, PVT, PAG, PBN, DVC energy expenditure.99 The view that MC4R controls
amygdala, BNST PVH both energy intake and expenditure is also supported
by pharmacological and physiological studies in which
MC4R NPY1-R
or
GABAAR MC4R agonists can reduce food intake and stimulate
NPY5-R energy expenditure via SNS-mediated thermogenesis of
LH
BAT.89,100,101 In contrast to Mc4r-deficient mice, Mc3r–/–
mutants exhibit a form of obesity that appears compa-
rable to human visceral obesity.102 However, the role of
MC3R in energy homeostasis has yet to be fully deter-
mined. Other investigators have suggested that the MC3R
POMC AgRP/NPY/GABA synchronizes eating with food cues,85 as Mc3r knockout
(anorexigenic) (orexigenic) mice do not increase in wakefulness that is associated
with scheduled food administration.103 Additionally,
LepRb GHS-R
Mc3r –/– mice do not have increased adipose tissue
ARC lipo­lysis, liver triglyceride storage and h­ypothalamo–­
CNS control pituitary–adrenal gland axis activation that usually
occurs in response to fasting.104 Finally, POMC products
Peripheral control also include β‑endorphin, the production of which can be
Leptin Ghrelin
enhanced via a CB1-mediated action that paradoxically
(anorexigenic) (orexigenic) links the stimulation of POMC neurons to an increase in
food intake.105
Nature
Figure 3 | Hypothalamic control of food intake. The ARC Reviews
comprises | Endocrinology
POMC and AgRP/ POMC neuron activity is negatively modulated by
NPY/GABA neurons, which have important roles in the control of food intake. Those AgRP cells whose projections follow largely those of the
neurons project to the PVH, which together with the ARC are important in the control POMC neurons.106,107 AgRP has been described as an
of food intake. Neurons in the ARC also connect with other hypothalamic nuclei, for
endo­genous inverse agonist of MC4R, and as a biased
instance the LH, and extrahypothalamic nuclei found in the reward circuits or in the
brainstem. The homeostatic hormones leptin and ghrelin act on the ARC via their agonist that can produce MC4R-medited effects, an
respective receptors. Abbreviations: ARC, arcuate nucleus; AgRP, agouti-related action that is independent of its inhibition of α-MSH
peptide; BNST, bed nucleus of the stria terminalis; CNS, central nervous system; binding.108,109 AgRP, as an anabolic peptide, opposes
DVC, dorsal vagal complex; GABA, γ-aminobutyric acid; GABAAR, GABAA receptor; MC4R-mediated catabolic action.75,110 Similar to syn-
GHS-R, growth hormone secretagogue receptor type 1; LH, lateral hypothalamus; thetic melanocortin receptor antagonists, AgRP leads
LepRb, long form of the leptin receptor; MC4R, melanocortin receptor 4; NAc, to increased food intake and limits energy expendi-
nucleus accumbens; NPY, neuropeptide Y; NPY1-R, neuropeptide Y receptor type 1; ture.111,112 AgRP is overexpressed during fasting and in
NPY5-R, neuropeptide Y receptor type 5; PAG, periaqueductal gray; PBN, parabrachial
obese animals,113,114 and postnatal disruption of AgRP-
nucleus; POMC, pro-opiomelanocortin; PVH, paraventricular hypothalamus; PVT,
paraventricular thalamic nucleus; SF1, steroidogenic factor 1; SN, substantia nigra; expressing neurons leads to hypophagia.115,116 AgRP
SNS, sympathetic nervous system; VTA, ventral tegmental area. neurons might also exert their anabolic effects inde-
pendently of the MC4R at extra-hypothalamic sites,
for example, via GABA-mediated inhibition of PBN
The melanocortin system neurons.117 In addition to producing GABA, the AgRP-
The brain melanocortin system consists of ARC neurons expressing neurons also express NPY,118 the anabolic
producing POMC or AgRP, and cells expressing MC3R action of which is seemingly mediated by the NPY1-R
and MC4R.85–89 POMC neurons also express cocaine and NPY5-R receptors.119
and amphetamine-related transcript (CART) 90 and The sites of the melanocortin action on food intake
project to several structures of the brain appetite-control and energy expenditure remain partly understood. PVH
network (Figure 3).91 injection of MC4R agonists reduces food intake,120 while
POMC neuron activation is catabolic89 and deficiency in increasing energy expenditure through stimulation of
these neurons produces obesity in rodents and humans.92,93 BAT thermogenesis. 121,122 Selective PVH restoration
POMC expression in the ARC can be reduced in some of Mc4r expression in Mc4r knock-out mice eliminates
obese rodents and in response to fasting.94 The catabolic some of the obesity associated with Mc4r disruption by
effect of POMC neurons is produced by the release of returning the heightened food intake associated with
melanocyte-stimulating hormones (MSHs), which are the MC4R loss to normal levels.123 How messages that
fragments freed from cleavage of POMC and which form are signalled via MC4R to the PVH reach the rostral
with ACTH the melanocortins.89 α‑MSH and β‑MSH are forebrain appetite network remains poorly understood.
catabolic melanocortins.89 Within the brain, MSHs bind A hypothalamic–thalamic–striatal axis involving the
to MC3R and MC4R, whose functional metabolic role has ARC, LH, para­ventricular thalamic nucleus (PVT), stri-
been validated in obesity-exhibiting Mc3r 95 and Mc4r 96 atum, and prefrontal cortex has been proposed to relay
knockout mice. Mc4r disruption leads to severe obesity.96 MC4R-related homeostatic signals to the rostral fore-
In patients with obesity, the prevalence of pathogenic brain.78,80 Together with the LH, the PVH also sends neu-
Mc4r mutations ranges from 1% to 6%.97,98 In mice, the ronal projections to the PVT,124 which in turn connects
excess of fat storage that occurs in Mc4r-deficient mutants with the striatum to relay the hypothalamic homeostatic

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information.125 PVH-initiated catabolic MC4R signal- neurons connected to BAT. 122 The medial preoptic
ling to the forebrain which modulates appetite might nucleus (MPO) has been proposed as a site of MC4R
also occur via the PBN, a site innervated by PVH MC4R agonism in a circuit that involves the DMH and pos-
neurons.79,126 Finally, one cannot exclude a direct link sibly RPa or other hindbrain neurons projecting to the
between the melanocortin system and reward circuits IML.134 In our own research, DMH chemical lesion alters
because POMC neurons in the ARC send direct projec- the effects of an MPO injection of MT2 on white adipose
tions to the NAc and VTA,107,127 which express MC4R128 tissue (WAT) metabolism,134 which suggests that the
and MC3R129 respectively. Melanocortins might modulate DMH might be involved in the MC4R-mediated control
the cortico­mesolimbic dopamine circuit. For example, in of brown adipocyte thermogenesis, including WAT
rats injection of the MC4R/MC3R agonist melanotan 2 browning. In obesity-promoting conditions, such as
(MT2) in the VTA decreases the consumption of a sucrose that promoted by loss of MC4R function,96 DMH over-
solution, which was used as a behavioural reward,130 an expresses NPY,135 which prevent proliferation of brown
action likely to be mediated via MC3R. Interestingly, one adipocytes in inguinal WAT.136 DMH knockdown of
third of the VTA dopamine neurons express the MC3R NPY has also been reported to stimulate the browning
and deletion of this receptor increases VTA dopamine of inguinal WAT.136
levels while reducing sucrose intake and preference in Another important autonomic circuit involved
female mice.131 Moreover, MC4R is expressed in the in the control of the energy balance is driven by the
ventral striatum in a subset of medium spiny neurons SF1 neurons in the VMH. 137 SF1 neurons, uniquely
also expressing DRD1, from which melano­cortins can expressed in the VMH, project to the PAG and rostro-
also control food intake and the locomotor activity.132 ventrolateral medulla,138 two caudal brainstem nuclei
Consequently, re­storation of MC4R in DRD1-expressing that drive the SNS outflow to BAT.139,140 SF1 is required
neurons attenuates the severe obesity observed in MC4R for correct development of VMH and regulation of
knock-out mice by decreasing food intake.132 normal body weight; its knockdown leads to reduced
energy expenditure and obesity.141 VMH-specific SF1
SNS control of BAT thermogenesis knock out mice have reduced energy expenditure asso-
In a cold-induced BAT thermogenic response, informa- ciated with reduced expression of UCP1 in BAT.137 SF1
tion about temperature (for example, from the skin) is neurons seem to be negatively modulated by the CB1 as
relayed to the POA, which processes part of the cold its deletion in SF1 neurons reduces adiposity in mice.142
stimulus information.31 This neuronal response is con- SF1 is a direct transcriptional target of FOXO1143 and
veyed via an efferent pathway that connects to the spinal mice with a selective deletion of Foxo1 in SF1-expressing
SNS preganglionic cells that innervate BAT (Figure 1).31 neurons have reduced adiposity and increased energy
Specifically, the thermoregulatory response is initiated by expenditure. 143 Moreover, a subset of SF1 neurons
the stimulation of GABA neurons found in the median expresses brain-derived neurotrophic factor, whose
preoptic nucleus, which in turn inhibits GABA neurons selective deletion in the VMH and adjacent DMH
located in the adjacent medial POA to ultimately relieve results in obesity. 144 The VMH also expresses DEP
inhibition on the DMH glutamatergic neurons project- domain-­containing mammalian-target-of-rapamycin
ing to the brainstem.31 These neurons stimulate SNS (mTOR)-interacting protein (Deptor) and the expres-
premotor neurons in the rostral raphe pallidus (RPa) sion of which in the VMH corresponds to that of SF1
and adjacent areas, which project to the spinal cord and (discussed below).145
synapse with SNS preganglionic neurons emerging from
the IML.31 Additionally, the activity of BAT might also Homeostatic sensing and signalling
be modulated by neurons that contribute to the energy Energy homeostasis is under regulatory mecha-
homeostasis regulatory pathways, which are found in nisms.22,146–148 Changes in energy stores—for example,
hypothalamic nuclei such as the PVH, ARC, LH and by food deprivation, overfeeding or excess physical
VMH nuclei.5 These neurons are sensitive to energy ac­tivity—lead to adaptations in the controls of energy
balance fluctuations and could also act independently intake and expenditure that oppose them. These
of POA–DMH–RPa thermoregulatory circuit as in the changes are signalled by peripheral hormones, such as
case of PVH neurons directly projecting to the IML133 leptin and ghrelin to the reward and autonomic SNS
The melanocortin system controls BAT thermogenesis circuits. For example, leptin, the production of which
via MC4R.101 Two brain circuits, which include POMC varies with the size of the adipocytes in WAT149 can
neurons, have been proposed to control BAT thermo­ initiate its central actions via the hypothalamus and
genesis. One involves POMC neuronal projections to VTA.150,151 Similarly ghrelin, which is also influenced
the PVH, where a high proportion of neurons (>80% by the nutritional status, can also act on the hypo-
in hamsters) that connect to BAT express MC4R.122 The thalamus, VTA and the DVC. 152,153 These regulatory
PVH is a site of the CB1 receptor-mediated stimula- processes seem particularly effective at preventing
tion of BAT thermogenesis by MT2,121 and some PVH the reduction in energy/fat reserves which seem reso-
neurons likely project to the IML133 to control SNS activ- lutely ‘defended’. Such a reduction leads to regulatory
ity in BAT depots. The second circuit involves POMC responses that promote energy intake154,155 and reduce
neuronal projections to the POA, which possibly hosts energy expenditure,156 which unpins the difficulty in an
the second largest hypothalamic proportion of MC4R individual’s ability to combat obesity.157

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Leptin-modulated brain circuits Ghrelin-modulated brain circuits

Leptin is a long-term tonic homeostatic signal,158 and Hormones of the gastrointestinal tract are episodic signals
a catabolic circulating mediator that can limit energy reflective of acute homeostatic changes.158,183 Ghrelin has
depo­s ition by reducing food intake and stimulating emerged as a key homeostatic hormone that ultimately
energy expenditure.149 Leptin secretion parallels the alters food intake and energy expenditure while inform-
fat mass and accesses the brain by crossing the blood– ing the CNS about nutritional status.22 Other gastro-
brain barrier (BBB) via saturable transport or acting intestinal hormones including glucagon-like peptide,
through BBB-devoid circumventricular organs (for oxyntomodulin and peptide tyrosine-tyrosine might
example, median eminence, subfornical organ or area also participate in energy homeostasis via brain-mediated
postrema).150,159 Some investigators have also suggested actions on food intake and energy expenditure.183 Ghrelin
that leptin might reach the cerebrospinal fluid in the is secreted by gastric endocrine cells dispersed within the
third ventricle by penetrating the fenestrated capillaries oxyntic mucosa of the stomach and selectively acts on
of the median eminence to enter and cross the tanycite the growth hormone secretagogue receptor type 1A
barrier located at the floor of the third ventricle.160 In the (GHS-R).184 The post-translational O‑octanoylation by
brain, leptin exerts its effects on food intake and energy ghrelin O‑acyl transferase is required for the activation
expenditure by acting at various levels and influenc- by ghrelin of GHS-R.184 Ghrelin is the only known gastro-
ing the major energy balance regulation circuits.150,151 intestinal hormone that increases food intake and blunts
Leptin binding to its long form receptor LepRb leads to energy expenditure. Deficiency in ghrelin or GHS-R can
ty­rosine-protein kinase JAK2‑mediated phosphorylation prevent high-fat feeding-induced obesity.185,186
of its extended intracellular signalling domain, which GHS-R is widely expressed in the brain and enables
activates STAT3, phosphoinositol‑3-­kinase and mTOR ghrelin to influence appetite and thermogenic networks
signalling pathways.150,161,162 to exert its anabolic effects.187 At low circulating levels,
Leptin functions in the ARC as an early trophic signal ghrelin preferentially accesses the ARC,188 where it binds
to enhance ARC axon outgrowth to the PVH163 and to the GHS-R apparently on AgRP neurons.22 A central
increases activity of the brain melanocortin system.164 role of the AgRP neurons in the action of ghrelin is sup-
AgRP and POMC neurons express LepRb, 165,166 which ported by the demonstration that restoration of GHS-R
is also expressed on GABA neurons devoid of AgRP and expression in these neurons reinstates part of the orexi-
NPY, but which might control POMC neuronal tone.167 genic effects of ghrelin.189 GHS-R is expressed in several
However, leptin can also act at the level of the DMH to brain regions associated with reward networks, including
modulate energy expenditure,168 and exert effects at the the VTA and NAc, upon which ghrelin can directly act to
LH level to modulate the corticomesolimbic dopamine initiate feeding.152 In humans, imaging of the brain has
circuit by stimulating neurotensin neurons,169 which revealed that ghrelin treatment can modulate neuronal
connect with VTA dopaminergic cells that reach to the activity in the amygdala, orbitofrontal cortex, anterior
ventral striatum. Leptin might also directly act on the VTA insula and striatum, in response to food-related cues.190
dopaminergic cells170 and brainstem nuclei that include
the PBN where it modulates food intake without affecting mTOR complexes
the incentive salience for food.171 A role for mTOR as an intermediate translating homeo-
Deficiency in leptin or its receptor leads to obes­ static signal within ARC and VMH neurons has been
ity.149,172 In leptin-deficient humans and animals, leptin-­ presented by a number of investigators.191,192 mTOR is a
replacement therapy can prevent or reverse excess fat serine/threonine kinase that conveys hormonal signals
deposition via reducing food intake and stimulating to influence energy homeostasis,191,192 and is the cata-
energy expenditure.173,174 In leptin-deficient individu- lytic unit of two mTOR complexes namely mTORC1 and
als, leptin replacement can increase forebrain neuronal mTORC2.193 To date, mTORC1 has been the most studied
density and the activity of prefrontal regions of the in association with the regulation of energy balance.191,192
appetite network that is linked to satiety.175,176 However, S6 kinase 1 (S6K1), a downstream effector of mTORC1,
in individuals who are not deficient in this hormone, is involved in energy homeostasis.194 mTORC1 activ-
leptin exhibits only weak anti-obesity action as loss of ity, assessed by phosphorylated S6K1 and S6 ribosomal
leptin sensitivity or leptin resistance develops due to protein, is reduced by fasting and stimulated by leptin, an
sustained leptin overexposure.177,178 Leptin resistance has effect that is blocked by the mTOR inhibitor rapamycin.195
been associated with leptin-induced overexpression of This finding further supports a role for hypothalamic
suppressor-of-cytokine-signaling‑3, which prevents sig- mTORC1 pathway as a critical intracellular target for
nalling via JAK2.162,179,180 Owing to this resistance, using leptin actions on energy balance. Furthermore, the SNS
leptin to treat obesity has been inefficient.177 Notably and haemodynamic effects of leptin require the activity
resistance to leptin selectively develops in the brain and of hypothalamic mTORC1.196 As leptin stimulates SNS-
is not seen in regions that control the hypertensive effects mediated BAT thermo­genesis, mTORC1 is also likely to be
of leptin, which increases SNS activity on the kidney.181 involved in this action. Ghrelin can also exert an anabolic
Furthermore, the DMH might not develop leptin action by inhibiting mTORC1 signalling.197
resistance in its control of SNS-mediated BAT thermo­ A role for mTORC2 in energy balance has also been
genesis.182 In the DMH, LepRb is selectively linked to the reported.198 The neuronal deletion of the rapamycin-
control of energy expenditure.168 insensitive companion of mTOR (known as, Rictor),

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which is a regulator of mTORC2, promotes an increase and mTORC2 in the mediobasal hypothalamus and is
in adipose tissue and enhances energetic efficiency.198 increased in the ARC and VMH in response to energy
mTORC2 is present in POMC and AgRP neurons in the balance challenges such as fasting or obesity.145 Deptor
ARC, and might enhance the POMC tone as evidenced might, therefore, influence energy homeostasis by
by the observation that deletion of Rictor in POMC affecting both mTORC1 and mTORC2.
neurons replicates the anabolic effect of the global
de­letion of Rictor in neurons.198 mTORC2 might regulate Conclusions
energy balance by activating Akt, which directly phos- Considering energy intake and energy expenditure along-
phorylates and prevents the activity of the transcriptional side all the neuronal circuits, systems and mechanisms
factor FOXO1,199 which reduces the expression of POMC involved in energy homeostasis has emerged as a central
and induces the expression of AgRP and NPY.200 concept in the development of obesity. SNS-mediated
The fact that mTORC2 phosphorylates Akt, which in thermogenesis in BAT—and the brain areas involved in
turn activates mTORC1,198 suggests a crosstalk between its control—could also contribute to the maintenance of
mTORC2 and mTORC1 in regulating energy balance. an optimal energy balance. By understanding the inter­
However, this effect has only been suggested and not action between different components of the brain appetite
extensively explored. 191 Notably, both mTORC1 and and thermogenesis networks, we have begun to untangle
mTORC2 contain Deptor, a protein known to modu- the complex links between the cognitive and autonomic
late mTOR activity. 201,202 The expression pattern of circuits regulating energy homeostasis, particularly in an
Deptor, mirrors that of the genes encoding mTORC1 obesogenic environment.

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