Neural Orchestration of Food Intake and Energy Expenditure


Eating is one of the most hard‐wired and ubiquitous behaviours. Yet, we have only begun to map the neural circuits underlying its control. By sensing peripheral metabolic states via hormonal signals such as leptin, insulin, ghrelin and cholecystokinin, circuits composed of specific cell types either drive or suppress food intake. Homeostatic inhibitory neurons of the hypothalamic arcuate nucleus co‐expressing agouti gene‐related protein and neuropeptide Y coordinate hunger through divergent projections, while additional circuitry seems dedicated to hedonic feeding and the motivation to eat. In contrast, the vagus nerve delivers visceral information to broadly projecting neurons of the nucleus tractus solitarius to acutely suppress appetite. One of their downstream targets includes excitatory calcitonin gene‐related peptide‐expressing neurons of the parabrachial nucleus that project to the central amygdala. Distinct circuitry seems to regulate energy expenditure and body weight independent of feeding. Hence, the nervous system differentially stimulates and suppresses eating via a number of separate, neuroanatomically distributed and molecularly distinct circuits.

Key Concepts

  • Peripheral metabolic signals influence neurons either by circulating through the blood and passing from vasculature into the central nervous system or by acting on interoceptive sensory neurons of the vagus nerve.
  • Each peripheral metabolic signal has the potential to have widespread and coordinated effects on different neural populations.
  • Separable neural circuitry is dedicated to appetite stimulation versus appetite suppression.
  • Considering either the neural circuitry of appetite stimulation or suppression, there are a number of circuit‐level mechanisms that likely interact and act in parallel.
  • Some neural circuits appear to affect energy expenditure independent of feeding.

Keywords: eating; feeding; appetite; circuit; AgRP ; POMC ; vagus; NTS; PBN; CeA

Figure 1. Sagittal sections of the rodent brain illustrating the two general mechanisms by which peripheral metabolic signals can have widespread and coordinated effects on neural populations. (a) A peripheral signal can pass from the vasculature into different brain regions expressing its receptor. As an example, the outlined regions represent those with expression of the leptin receptor (Elmquist ., ; Grill and Hayes, ). (b) Peripheral signals can also activate the vagus nerve, which then relays visceral information to broadly projecting neurons of the nucleus tractus solitarius (NTS) (Grill and Hayes ; Alhadeff ., , ). AP, area postrema; ARC, arcuate nucleus; CB, cerebellum; DMH, dorsomedial hypothalamus; DMX, dorsal motor nucleus of the vagus; DRN, dorsl raphe nucleus; LGN, lateral geniculate nucleus; LHA, lateral hypothalamus; NAc, nucleus accumbens; PBN, parabrachial nucleus; PIR, piriform cortex; PVH, paraventricular nucleus of the hypothalamus; VMH, ventromedial hypothalamus; VTA, ventral tegmental area.
Figure 2. Parallel projections of AgRP neurons with distinct circuits to different downstream neural populations. Those circuits that are sufficient to stimulate feeding are coloured in green, whereas those that are not are in black. The arrowheads represent excitation and the flat‐heads inhibition. For simplicity, the one‐to‐one projection pattern of distinct aBNST, anterior bed nucleus of the stria terminalis; AgRP, agouti gene‐related protein; ARC, arcuate nucleus; CeA, central amygdala; LHA, lateral hypothalamus; NPY, neuropeptide Y PAG, periaqueductal grey; PBN, parabrachial nucleus; POMC, pro‐opiomelanocortin; PVH, paraventricular nucleus of the hypothalamus; and PVT, paraventricular thalamic nucleus.
Figure 3. An example of the neural circuitry that acutely suppresses appetite. A peripheral satiety signal, for example, cholecystokinin (CCK), activates the vagus nerve, which then relays visceral information to neural populations of the nucleus tractus solitarius (NTS), including those expressing pro‐opiomelanocortin (POMC), glucagon‐like peptide‐1 (GLP‐1) and norepinephrine (NE). NTS neurons provide excitatory input to neurons of the parabrachial nucleus (PBN), such as those expressing calcitonin gene‐related peptide (CGRP). PBN CGRP neurons in turn provide excitatory input to central amygdala (CeA) neurons expressing protein kinase C‐δ (PKC‐δ). The appetite‐relevant downstream targets of CeA PKC‐δ neurons have yet to be identified. The molecular nature of the NTS input to PBN CGRP neurons is also unknown. Note that POMC, GLP‐1 and NE are not necessarily expressed by the same population of NTS neurons, as POMC expression does not colocalise with that of GLP‐1 or NE (Cone, ). For simplicity, the broad projections of NTS neurons have been excluded. The arrowheads represent excitation and the flat‐head inhibition.


Alhadeff AL , Rupprecht LE and Hayes MR (2012) GLP‐1 neurons in the nucleus of the solitary tract project directly to the ventral tegmental area and nucleus accumbens to control for food intake. Endocrinology 153 (2): 647–658.

Alhadeff AL , Baird JP , Swick JC , Hayes MR and Grill HJ (2014) Glucagon‐like peptide‐1 receptor signaling in the lateral parabrachial nucleus contributes to the control of food intake and motivation to feed. Neuropsychopharmacology 39: 2233–2243.

Aponte Y , Atasoy D and Sternson SM (2011) AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nature Neuroscience 14 (3): 351–355.

Atasoy D , Betley JN , Su HH and Sternson SM (2012) Deconstruction of a neural circuit for hunger. Nature 488 (7410): 172–177.

Balthasar N , Coppari R , McMinn J , et al. (2004) Leptin receptor signaling in POMC neurons is required for normal body weight homeostasis. Neuron 42 (6): 983–991.

Benoit SC , Schwartz MW , Lachey JL , et al. (2000) A novel selective melanocortin‐4 agonist reduces food intake in rats and mice without producing aversive consequences. Journal of Neuroscience 20 (9): 3442–3448.

Betley JN , Cao ZF , Ritola KD and Sternson SM (2013) Parallel, redundant circuit organization for homeostatic control of feeding behavior. Cell 155 (6): 1337–1350.

Broberger C , Johansen J , Johansson C , Schalling M and Hokfelt T (1998) The neuropeptide Y/agouti gene‐related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate‐treated mice. Proceedings of the National Academy of Sciences of the United States of America 95 (25): 15043–15048.

Cai H , Haubensak W , Anthony TE and Anderson DJ (2014) Central amygdala PKC‐δ(+) neurons mediate the influence of multiple anorexigenic signals. Nature Neuroscience 17 (9): 1240–1248.

Cannon CM and Palmiter RD (2003) Peptides that regulate food intake: norepinephrine is not required for reduction of feeding induced by cholecystokinin. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology 284 (6): 1384–1388.

Carter ME , Soden ME , Zweifel LS and Palmiter RD (2013) Genetic identification of a neural circuit that suppresses appetite. Nature 503 (7474): 111–114.

Choudhury AI , Heffron H , Smith MA , et al. (2005) The role of insulin receptor substrate 2 in hypothalamic and beta cell function. Journal of Clinical Investigation 115 (4): 940–950.

Clark JT , Kalra PS , Crowley WR and Kalra SP (1984) Neuropeptide Y and human pancreatic polypeptide stimulate feeding behavior in rats. Endocrinology 115 (1): 427–429.

Cohen P , Zhao C , Cai X , et al. (2001) Selective deletion of leptin receptor in neurons leads to obesity. Journal of Clinical Investigation 108 (8): 1113–1121.

Cone RD (2005) Anatomy and regulation of the central melanocortin system. Nature Neuroscience 8 (5): 571–578.

Cone JJ , McCutcheon JE and Roitman MF (2014) Ghrelin acts as an interface between physiological state and phasic dopamine signaling. Journal of Neuroscience 34 (14): 4905–4913.

Cowley MA , Smart JL , Rubeinstein MG , et al. (2001) Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411 (6836): 480–484.

Deutsch JA and Hardy WT (1977) Cholecystokinin produces bait shyness in rats. Nature 266 (5598): 196.

Dietrich MO , Bober J , Ferreira JG , et al. (2012) AgRP neurons regulate development of dopamine neuronal plasticity and nonfood‐associated behaviors. Nature Neuroscience 15 (8): 1108–1110.

Elmquist JK , Bjørbæk C , Ahima RS , Flier JS and Saper CB (1998) Distributions of leptin receptor mRNA isoforms in the rat brain. Journal of Comparative Neurology 395 (4): 535–547.

Erickson JC , Clegg KE and Palmiter RD (1996) Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y. Nature 381 (6581): 415–421.

Garfield AS and Lowell BB (2013) Was it something I ate? Cell Metabolism 18 (6): 769–770.

Goldstone AP , Prechtl de Hernandez CG , Beaver JD , et al. (2009) Fasting biases brain reward systems towards high‐calorie foods. European Journal of Neuroscience 30 (8): 1625–1635.

Grill HJ and Hayes MR (2012) Hindbrain neurons as an essential hub in the neuroanatomically distributed control of energy balance. Cell Metabolism 16 (3): 296–309.

Guan HM , Yu H , Palyha O , et al. (1997) Distribution of mRNA encoding the growth hormone secretagogue receptor in brain and peripheral tissues. Molecular Brain Research 48 (1): 23–29.

Hahn TM , Breininger JF , Baskin DG and Schwartz MW (1998) Coexpression of Agrp and NPY in fasting‐activated hypothalamic neurons. Nature Neuroscience 1 (4): 271–272.

Jennings JH , Rizzi G , Stamatakis AM , Ung RL and Stuber GD (2013) The inhibitory circuit architecture of the lateral hypothalamus orchestrates feeding. Science 341 (6153): 1517–1521.

Kaye W (2008) Neurobiology of anorexia and bulimia nervosa. Physiology and Behavior 94 (1): 121–135.

Kenny PJ (2011) Reward mechanisms in obesity: new insights and future directions. Neuron 69 (4): 664–679.

Kong D , Tong Q , Ye C , et al. (2012) GABAergic RIP‐Cre neurons in the arcuate nucleus selectively regulate energy expenditure. Cell 151 (3): 645–657.

Krashes MJ , Koda S , Ye C , et al. (2011) Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. Journal of Clinical Investigation 121 (4): 1424–1428.

Krashes MJ , Shah BP , Koda S and Lowell BB (2013) Rapid versus delayed stimulation of feeding by the endogenously released AgRP neuron mediators GABA, NPY, and AgRP. Cell Metabolism 18 (4): 588–595.

Krashes MJ , Shah BP , Madara JC , et al. (2014) An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger. Nature 507 (7491): 238–242.

Land BB , Narayanan NS , Liu RJ , et al. (2014) Medial prefrontal D1 dopamine neurons control food intake. Nature Neuroscience 17 (2): 248–253.

Liu C , Bookout AL , Lee S , et al. (2014) PPARγ in vagal neurons regulates high‐fat diet induced thermogenesis. Cell Metabolism 19 (4): 722–730.

Luquet S , Perez FA , Hnakso TS and Palmiter RD (2005) NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science 310 (5748): 683–685.

McFarlane MR , Brown MS , Goldstein JL and Zhao TJ (2014) Induced ablation of ghrelin cells in adult mice does not decrease food intake, body weight, or response to high‐fat diet. Cell Metabolism 20 (1): 54–60.

Morton GJ , Meek TH and Schwartz MW (2014) Neurobiology of food intake in health and disease. Nature Reviews Neuroscience 15 (6): 367–378.

Nestler EJ , Barrot M , DiLeone RJ , et al. (2002) Neurobiology of depression. Neuron 34 (1): 13–25.

Qian S , Chen H , Weingarth D , et al. (2002) Neither agouti‐related protein nor neuropeptide Y is critically required for the regulation of energy homeostasis in mice. Molecular and Cellular Biology 22 (14): 5027–5035.

Qiu J , Zhang C , Borgquist A , et al. (2014) Insulin excites anorexigenic proopiomelanocortin neurons via activation of canonical transient receptor potential channels. Cell Metabolism 19 (4): 682–693.

Riediger T , Zuend D , Becskei C and Lutz TA (2004) The anorectic hormone amylin contributes to feeding‐related changes of neuronal activity in key structures of the gust‐brain axis. American Journal of Physiology: Regulatory, Integrative and Comparative Physiology 286 (1): R114–R122.

Rossi M , Kim MS , Morgan DGI , et al. (1998) A C‐terminal fragment of agouti‐related protein increases feeding and antagonizes the effect of alpha‐melanocyte stimulating hormone in vivo. Endocrinology 139 (10): 4428–4431.

Saper CB , Chou TC and Elmquist JK (2002) The need to feed: homeostatic and hedonic control of eating. Neuron 36 (2): 199–211.

Schwartz MW , Woods SC , Porte D Jr Seeley RJ and Baskin DG (2000) Central nervous system control of food intake. Nature 404 (6778): 661–671.

Siljee JE , Unmehopa UA , Kalsbeek A , et al. (2013) Melanocortin 4 receptor distribution in the human hypothalamus. European Journal of Endocrinology 168 (3): 361–369.

Sumal KK , Blessing WW , Joh TH , Reis DJ and Pickel VM (1983) Synaptic interaction of vagal afferents and catecholaminergic neurons in the rat nucleus tractus solitarius. Brain Research 277 (1): 31–40.

Volkow ND and Wise RA (2005) How can drug addiction help us understand obesity. Nature Neuroscience 8 (5): 555–560.

West DB , Greenwood MR , Marshall KA and Woods SC (1987) Lithium chloride, cholecystokinin and meal patterns: evidence that cholecystokinin suppress meal size in rats without causing malaise. Appetite 8 (3): 221–227.

Wu Q , Boyle MP and Palmiter RD (2009) Loss of GABAergic signaling by AgRP neurons to the parabrachial nucleus leads to starvation. Cell 137 (7): 1225–1234.

Yang Y , Atasoy D , Su HH and Sternson SM (2011) Hunger states switch a flip‐flop memory circuit via a synaptic AMPK‐dependent positive feedback loop. Cell 146 (6): 992–1003.

Zhan C , Zhou J , Feng Q , et al. (2013) Acute and long‐term suppression of feeding behavior by POMC neurons in the brainstem and hypothalamus, respectively. Journal of Neuroscience 33 (8): 3624–3632.

Zhou QY and Palmiter RD (1995) Dopamine‐deficient mice are severely hypoactive, adipsic, and aphagic. Cell 83 (7): 1197–1209.

Further Reading

Fenno L , Yizhar O and Deisseroth K (2011) The development and application of optogenetics. Annual Review of Neuroscience 34: 389–412.

Krashes MJ and Kravitz AV (2014) Optogenetic and chemogenetic insights into the food addiction hypothesis. Frontiers in Behavioral Neuroscience 9 (57): 1–9.

Schwartz MW and Baskin DG (2013) Leptin and the brain: then and now. Journal of Clinical Investigation 123 (6): 2344–2345.

Trivedi BP (2014) Neuroscience: dissecting appetite. Nature 508 (7496): S64–S65.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Soleiman, Matthew T(Apr 2015) Neural Orchestration of Food Intake and Energy Expenditure. In: eLS. John Wiley & Sons Ltd, Chichester. [doi: 10.1002/9780470015902.a0003378.pub2]