Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Acts of appetite: neural circuits governing the appetitive, consummatory, and terminating phases of feeding

Nature Metabolism volume 4, pages 836–847 (2022)Cite this article

Subjects

Abstract

The overconsumption of highly caloric and palatable foods has caused a surge in obesity rates in the past half century, thereby posing a healthcare challenge due to the array of comorbidities linked to heightened body fat accrual. Developing treatments to manage body weight requires a grasp of the neurobiological basis of appetite. In this Review, we discuss advances in neuroscience that have identified brain regions and neural circuits that coordinate distinct phases of eating: food procurement, food consumption, and meal termination. While pioneering work identified several hypothalamic nuclei to be involved in feeding, more recent studies have explored how neuronal populations beyond the hypothalamus, such as the mesolimbic pathway and nodes in the hindbrain, interconnect to modulate appetite. We also examine how long-term exposure to a calorically dense diet rewires feeding circuits and alters the response of motivational systems to food. Understanding how the nervous system regulates eating behaviour will bolster the development of medical strategies that will help individuals to maintain a healthy body weight.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Fig. 1: Neural circuitry underlying the three acts of appetite.
Fig. 2: Feeding neurons conform to energy status and food palatability.
Fig. 3: Fine tuning of satiation circuits is required to avoid aversive outcomes.

Similar content being viewed by others

References

  1. Collaborators, G. B. D. O. et al. Health effects of overweight and obesity in 195 countries over 25 years. N. Engl. J. Med. 377, 13–27 (2017).

    Article  Google Scholar 

  2. Sternson, S. M. & Eiselt, A. K. Three pillars for the neural control of appetite. Annu Rev. Physiol. 79, 401–423 (2017). This review served as inspiration for dividing up the discrete phases of feeding into three acts.

    Article  CAS  PubMed  Google Scholar 

  3. Anand, B. K., Dua, S. & Shoenberg, K. Hypothalamic control of food intake in cats and monkeys. J. Physiol. 127, 143–152 (1955).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Aravich, P. F. & Sclafani, A. Paraventricular hypothalamic lesions and medial hypothalamic knife cuts produce similar hyperphagia syndromes. Behav. Neurosci. 97, 970–983 (1983).

    Article  CAS  PubMed  Google Scholar 

  5. Bergen, H. T., Mizuno, T. M., Taylor, J. & Mobbs, C. V. Hyperphagia and weight gain after gold-thioglucose: relation to hypothalamic neuropeptide Y and proopiomelanocortin. Endocrinology 139, 4483–4488 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Gold, R. M., Quackenbush, P. M. & Kapatos, G. Obesity following combination of rostrolateral to VMH cut and contralateral mammillary area lesion. J. Comp. Physiol. Psychol. 79, 210–218 (1972).

  7. Gold, R. M., Jones, A. P. & Sawchenko, P. E. Paraventricular area: critical focus of a longitudinal neurocircuitry mediating food intake. Physiol. Behav. 18, 1111–1119 (1977).

    Article  CAS  PubMed  Google Scholar 

  8. Holzwarth-McBride, M. A., Hurst, E. M. & Knigge, K. M. Monosodium glutamate induced lesions of the arcuate nucleus. I. Endocrine deficiency and ultrastructure of the median eminence. Anat. Rec. 186, 185–205 (1976).

    Article  CAS  PubMed  Google Scholar 

  9. Holzwarth-McBride, M. A., Sladek, J. R. Jr. & Knigge, K. M. Monosodium glutamate induced lesions of the arcurate nucleus. II. Fluorescence histochemistry of catecholamines. Anat. Rec. 186, 197–205 (1976).

    Article  CAS  PubMed  Google Scholar 

  10. Leibowitz, S. F. Reciprocal hunger-regulating circuits involving alpha- and beta-adrenergic receptors located, respectively, in the ventromedial and lateral hypothalamus. Proc. Natl Acad. Sci. USA 67, 1063–1070 (1970).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Leibowitz, S. F., Hammer, N. J. & Chang, K. Hypothalamic paraventricular nucleus lesions produce overeating and obesity in the rat. Physiol. Behav. 27, 1031–1040 (1981).

    Article  CAS  PubMed  Google Scholar 

  12. Teitelbaum, P. & Epstein, A. N. The lateral hypothalamic syndrome: recovery of feeding and drinking after lateral hypothalamic lesions. Psychol. Rev. 69, 74–90 (1962). This study was part of a revoultion of lesion experiments demonstrating the necessity of hypothalamic structures in the regulation of body weight homeostasis.

    Article  CAS  PubMed  Google Scholar 

  13. Boghossian, S., Park, M. & York, D. A. Melanocortin activity in the amygdala controls appetite for dietary fat. Am. J. Physiol. Regul. Integr. Comp. Physiol. 298, R385–R393 (2010).

    Article  CAS  PubMed  Google Scholar 

  14. Booth, D. A. Mechanism of action of norepinephrine in eliciting an eating response on injection into the rat hypothalamus. J. Pharmacol. Exp. Ther. 160, 336–348 (1968).

    CAS  PubMed  Google Scholar 

  15. Grill, H. J., Ginsberg, A. B., Seeley, R. J. & Kaplan, J. M. Brainstem application of melanocortin receptor ligands produces long-lasting effects on feeding and body weight. J. Neurosci. 18, 10128–10135 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Grossman, S. P. Eating or drinking elicited by direct adrenergic or cholinergic stimulation of hypothalamus. Science 132, 301–302 (1960).

    Article  CAS  PubMed  Google Scholar 

  17. Williams, D. L., Kaplan, J. M. & Grill, H. J. The role of the dorsal vagal complex and the vagus nerve in feeding effects of melanocortin-3/4 receptor stimulation. Endocrinology 141, 1332–1337 (2000).

    Article  CAS  PubMed  Google Scholar 

  18. Hoebel, B. G. & Teitelbaum, P. Hypothalamic control of feeding and self-stimulation. Science 135, 375–377 (1962).

    Article  CAS  PubMed  Google Scholar 

  19. Tenen, S. S. & Miller, N. E. Strength of electrical stimulation of lateral hypothalamus, food deprivation, and tolerance for quinine in food. J. Comp. Physiol. Psychol. 58, 55–62 (1964).

    Article  CAS  PubMed  Google Scholar 

  20. Schultz, W. Dopamine neurons and their role in reward mechanisms. Curr. Opin. Neurobiol. 7, 191–197 (1997).

    Article  CAS  PubMed  Google Scholar 

  21. Salamone, J. D., Correa, M., Mingote, S. & Weber, S. M. Nucleus accumbens dopamine and the regulation of effort in food-seeking behavior: implications for studies of natural motivation, psychiatry, and drug abuse. J. Pharmacol. Exp. Ther. 305, 1–8 (2003).

    Article  CAS  PubMed  Google Scholar 

  22. Wise, R. A. The parsing of food reward. Am. J. Physiol. Regul. Integr. Comp. Physiol. 291, R1234–R1235 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. Palmiter, R. D. Is dopamine a physiologically relevant mediator of feeding behavior? Trends Neurosci. 30, 375–381 (2007).

    Article  CAS  PubMed  Google Scholar 

  24. Zhou, Q. Y. & Palmiter, R. D. Dopamine-deficient mice are severely hypoactive, adipsic, and aphagic. Cell 83, 1197–1209 (1995).

    Article  CAS  PubMed  Google Scholar 

  25. Cohen, P. et al. Selective deletion of leptin receptor in neurons leads to obesity. J. Clin. Invest. 108, 1113–1121 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Halaas, J. L. et al. Weight-reducing effects of the plasma protein encoded by the obese gene. Science 269, 543–546 (1995).

    Article  CAS  PubMed  Google Scholar 

  27. Zhang, Y. et al. Positional cloning of the mouse obese gene and its human homologue. Nature 372, 425–432 (1994). This study identified that mutations in the ob gene encoding leptin resulted in profound obsesity and type II diabetes.

    Article  CAS  PubMed  Google Scholar 

  28. Butler, A. A. et al. A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. Endocrinology 141, 3518–3521 (2000).

    Article  CAS  PubMed  Google Scholar 

  29. Fan, W., Boston, B. A., Kesterson, R. A., Hruby, V. J. & Cone, R. D. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385, 165–168 (1997). This is one of three studies that demonstrated the essential role of the melanocortin system on the control of energy balance.

    Article  CAS  PubMed  Google Scholar 

  30. Huszar, D. et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131–141 (1997). This is one of three studies that demonstrated the essential role of the melanocortin system on the control of energy balance.

    Article  CAS  PubMed  Google Scholar 

  31. Ollmann, M. M. et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278, 135–138 (1997). This is one of three studies that demonstrated the essential role of the melanocortin system on the control of energy balance.

    Article  CAS  PubMed  Google Scholar 

  32. Yaswen, L., Diehl, N., Brennan, M. B. & Hochgeschwender, U. Obesity in the mouse model of pro-opiomelanocortin deficiency responds to peripheral melanocortin. Nat. Med. 5, 1066–1070 (1999).

    Article  CAS  PubMed  Google Scholar 

  33. Scrocchi, L. A. et al. Glucose intolerance but normal satiety in mice with a null mutation in the glucagon-like peptide 1 receptor gene. Nat. Med. 2, 1254–1258 (1996).

    Article  CAS  PubMed  Google Scholar 

  34. Scrocchi, L. A., Marshall, B. A., Cook, S. M., Brubaker, P. L. & Drucker, D. J. Identification of glucagon-like peptide 1 (GLP-1) actions essential for glucose homeostasis in mice with disruption of GLP-1 receptor signaling. Diabetes 47, 632–639 (1998).

    Article  CAS  PubMed  Google Scholar 

  35. Hansotia, T. et al. Double incretin receptor knockout (DIRKO) mice reveal an essential role for the enteroinsular axis in transducing the glucoregulatory actions of DPP-IV inhibitors. Diabetes 53, 1326–1335 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Gropp, E. et al. Agouti-related peptide-expressing neurons are mandatory for feeding. Nat. Neurosci. 8, 1289–1291 (2005).

    Article  CAS  PubMed  Google Scholar 

  37. Luquet, S., Perez, F. A., Hnasko, T. S. & Palmiter, R. D. NPY/AgRP neurons are essential for feeding in adult mice but can be ablated in neonates. Science 310, 683–685 (2005).

    Article  CAS  PubMed  Google Scholar 

  38. Wu, Q., Whiddon, B. B. & Palmiter, R. D. Ablation of neurons expressing agouti-related protein, but not melanin concentrating hormone, in leptin-deficient mice restores metabolic functions and fertility. Proc. Natl Acad. Sci. USA 109, 3155–3160 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Xi, D., Gandhi, N., Lai, M. & Kublaoui, B. M. Ablation of Sim1 neurons causes obesity through hyperphagia and reduced energy expenditure. PLoS ONE 7, e36453 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zhan, C. et al. Acute and long-term suppression of feeding behavior by POMC neurons in the brainstem and hypothalamus, respectively. J. Neurosci. 33, 3624–3632 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Kojima, M. et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402, 656–660 (1999).

    Article  CAS  PubMed  Google Scholar 

  42. Muller, T. D. et al. Ghrelin. Mol. Metab. 4, 437–460 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Tschop, M., Smiley, D. L. & Heiman, M. L. Ghrelin induces adiposity in rodents. Nature 407, 908–913 (2000).

    Article  CAS  PubMed  Google Scholar 

  44. Drazen, D. L., Vahl, T. P., D’Alessio, D. A., Seeley, R. J. & Woods, S. C. Effects of a fixed meal pattern on ghrelin secretion: evidence for a learned response independent of nutrient status. Endocrinology 147, 23–30 (2006).

    Article  CAS  PubMed  Google Scholar 

  45. Wren, A. M. et al. The novel hypothalamic peptide ghrelin stimulates food intake and growth hormone secretion. Endocrinology 141, 4325–4328 (2000).

    Article  CAS  PubMed  Google Scholar 

  46. Wren, A. M. et al. Ghrelin enhances appetite and increases food intake in humans. J. Clin. Endocrinol. Metab. 86, 5992 (2001).

    Article  CAS  PubMed  Google Scholar 

  47. Nakazato, M. et al. A role for ghrelin in the central regulation of feeding. Nature 409, 194–198 (2001).

    Article  CAS  PubMed  Google Scholar 

  48. Frederich, R. C. et al. Leptin levels reflect body lipid content in mice: evidence for diet-induced resistance to leptin action. Nat. Med. 1, 1311–1314 (1995).

    Article  CAS  PubMed  Google Scholar 

  49. Ahima, R. S. et al. Role of leptin in the neuroendocrine response to fasting. Nature 382, 250–252 (1996).

    Article  CAS  PubMed  Google Scholar 

  50. Farooqi, I. S. et al. Effects of recombinant leptin therapy in a child with congenital leptin deficiency. N. Engl. J. Med. 341, 879–884 (1999). This study successfully translated rodent findings to a patient with congenital leptin deficiency.

    Article  CAS  PubMed  Google Scholar 

  51. Farr, O. M., Gavrieli, A. & Mantzoros, C. S. Leptin applications in 2015: what have we learned about leptin and obesity? Curr. Opin. Endocrinol. Diabetes Obes. 22, 353–359 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Schaeffer, M. et al. Rapid sensing of circulating ghrelin by hypothalamic appetite-modifying neurons. Proc. Natl Acad. Sci. USA 110, 1512–1517 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Baskin, D. G. et al. Insulin and leptin: dual adiposity signals to the brain for the regulation of food intake and body weight. Brain Res. 848, 114–123 (1999).

    Article  CAS  PubMed  Google Scholar 

  54. Willesen, M. G., Kristensen, P. & Romer, J. Co-localization of growth hormone secretagogue receptor and NPY mRNA in the arcuate nucleus of the rat. Neuroendocrinology 70, 306–316 (1999).

    Article  CAS  PubMed  Google Scholar 

  55. Wilson, B. D. et al. Physiological and anatomical circuitry between Agouti-related protein and leptin signaling. Endocrinology 140, 2387–2397 (1999).

    Article  CAS  PubMed  Google Scholar 

  56. Takahashi, K. A. & Cone, R. D. Fasting induces a large, leptin-dependent increase in the intrinsic action potential frequency of orexigenic arcuate nucleus neuropeptide Y/Agouti-related protein neurons. Endocrinology 146, 1043–1047 (2005). This study demonstrated that internal state of an animal drives activity of appetite-regulating neurons using acute brain slice electrophysiology.

    Article  CAS  PubMed  Google Scholar 

  57. Yang, R. et al. Restoring leptin signaling reduces hyperlipidemia and improves vascular stiffness induced by chronic intermittent hypoxia. Am. J. Physiol. Heart Circ. Physiol. 300, H1467–H1476 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Liu, T. et al. Fasting activation of AgRP neurons requires NMDA receptors and involves spinogenesis and increased excitatory tone. Neuron 73, 511–522 (2012).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  59. Mandelblat-Cerf, Y. et al. Arcuate hypothalamic AgRP and putative POMC neurons show opposite changes in spiking across multiple timescales. eLife 4, e07122 (2015). This is one of three studies that demonstrated that activity of hypothalamic neurons are rapidly and robustly altered via anticipation of food consumption using in vivo electrophysiology.

  60. Mazzone, C. M. et al. High-fat food biases hypothalamic and mesolimbic expression of consummatory drives. Nat. Neurosci. 23, 1253–1266 (2020). This study used longitudinal recordings of hypothalamic neurons and mesolimbic dopamine to demonstrate that palatable food exposure diminishes the capacity of chow diets to alleviate the negative valence associated with hunger and the rewarding properties of food discovery.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Krashes, M. J. et al. An excitatory paraventricular nucleus to AgRP neuron circuit that drives hunger. Nature 507, 238–242 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Clark, J. T., Kalra, P. S., Crowley, W. R. & Kalra, S. P. Neuropeptide Y and human pancreatic polypeptide stimulate feeding behavior in rats. Endocrinology 115, 427–429 (1984).

    Article  CAS  PubMed  Google Scholar 

  63. Rossi, M. et al. A C-terminal fragment of Agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo. Endocrinology 139, 4428–4431 (1998).

    Article  CAS  PubMed  Google Scholar 

  64. Semjonous, N. M. et al. Coordinated changes in energy intake and expenditure following hypothalamic administration of neuropeptides involved in energy balance. Int. J. Obes. 33, 775–785 (2009).

    Article  CAS  Google Scholar 

  65. Stratford, T. R. & Kelley, A. E. GABA in the nucleus accumbens shell participates in the central regulation of feeding behavior. J. Neurosci. 17, 4434–4440 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Krashes, M. J., Shah, B. P., Koda, S. & Lowell, B. B. Rapid versus delayed stimulation of feeding by the endogenously released AgRP neuron mediators GABA, NPY, and AgRP. Cell Metab. 18, 588–595 (2013).

    Article  CAS  PubMed  Google Scholar 

  67. Krashes, M. J. et al. Rapid, reversible activation of AgRP neurons drives feeding behavior in mice. J. Clin. Invest. 121, 1424–1428 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Atasoy, D., Betley, J. N., Su, H. H. & Sternson, S. M. Deconstruction of a neural circuit for hunger. Nature 488, 172–177 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Cavalcanti-de-Albuquerque, J. P., Bober, J., Zimmer, M. R. & Dietrich, M. O. Regulation of substrate utilization and adiposity by Agrp neurons. Nat. Commun. 10, 311 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Joly-Amado, A. et al. Hypothalamic AgRP-neurons control peripheral substrate utilization and nutrient partitioning. EMBO J. 31, 4276–4288 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Burke, L. K. et al. mTORC1 in AGRP neurons integrates exteroceptive and interoceptive food-related cues in the modulation of adaptive energy expenditure in mice. eLife 6, e22848 (2017).

  72. Steculorum, S. M. et al. AgRP neurons control systemic insulin sensitivity via myostatin expression in brown adipose tissue. Cell 165, 125–138 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Alhadeff, A. L. et al. Central leptin signaling transmits positive valence. Brain Res. 1724, 146441 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Reichenbach, A. et al. Metabolic sensing in AgRP neurons integrates homeostatic state with dopamine signalling in the striatum. eLife 11, e72668 (2022).

  75. Aponte, Y., Atasoy, D. & Sternson, S. M. AGRP neurons are sufficient to orchestrate feeding behavior rapidly and without training. Nat. Neurosci. 14, 351–355 (2011). This study was the first to show that acute optogenetic activation of hypothalamic AgRP neurons emulated a fasted state driving food intake.

    Article  CAS  PubMed  Google Scholar 

  76. Burnett, C. J. et al. Hunger-driven motivational state competition. Neuron 92, 187–201 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Burnett, C. J. et al. Need-based prioritization of behavior. eLife 8, e44527 (2019)

  78. Padilla, S. L. et al. Agouti-related peptide neural circuits mediate adaptive behaviors in the starved state. Nat. Neurosci. 19, 734–741 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Alhadeff, A. L. et al. A neural circuit for the suppression of pain by a competing need state. Cell 173, 140–152 e115 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Li, X. Y. et al. AGRP neurons project to the medial preoptic area and modulate maternal nest-building. J. Neurosci. 39, 456–471 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Dietrich, M. O., Zimmer, M. R., Bober, J. & Horvath, T. L. Hypothalamic Agrp neurons drive stereotypic behaviors beyond feeding. Cell 160, 1222–1232 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Goldstein, N. et al. Hypothalamic neurons that regulate feeding can influence sleep/wake states based on homeostatic need. Curr. Biol. 28, 3736–3747 (2018). This study investigated the intersection between feeding circuits and sleep architecture finding reciprocal influences of these two essential behaviors.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Jikomes, N., Ramesh, R. N., Mandelblat-Cerf, Y. & Andermann, M. L. Preemptive stimulation of AgRP neurons in fed mice enables conditioned food seeking under threat. Curr. Biol. 26, 2500–2507 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Chen, Y., Lin, Y. C., Kuo, T. W. & Knight, Z. A. Sensory detection of food rapidly modulates arcuate feeding circuits. Cell 160, 829–841 (2015). This is one of three studies that demonstrated that activity of hypothalamic neurons are rapidly and robustly altered via anticipation of food consumption using in vivo optical-fibre photometry.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  85. Betley, J. N. et al. Neurons for hunger and thirst transmit a negative-valence teaching signal. Nature 521, 180–185 (2015). This is one of three studies that demonstrated that activity of hypothalamic neurons are rapidly and robustly altered via anticipation of food consumption using in vivo single-photon microendoscopy.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Su, Z., Alhadeff, A. L. & Betley, J. N. Nutritive, post-ingestive signals are the primary regulators of AgRP neuron activity. Cell Rep. 21, 2724–2736 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. Horio, N. & Liberles, S. D. Hunger enhances food-odour attraction through a neuropeptide Y spotlight. Nature 592, 262–266 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  88. Garfield, A. S. et al. Dynamic GABAergic afferent modulation of AgRP neurons. Nat. Neurosci. 19, 1628–1635 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Berrios, J. et al. Food cue regulation of AGRP hunger neurons guides learning. Nature 595, 695–700 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Beutler, L. R. et al. Dynamics of gut–brain communication underlying hunger. Neuron 96, 461–475 e465 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Bai, L. et al. Genetic identification of vagal sensory neurons that control feeding. Cell 179, 1129–1143 e1123 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Campos, C. A., Bowen, A. J., Schwartz, M. W. & Palmiter, R. D. Parabrachial CGRP neurons control meal termination. Cell Metab. 23, 811–820 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Chen, Y., Lin, Y. C., Zimmerman, C. A., Essner, R. A. & Knight, Z. A. Hunger neurons drive feeding through a sustained, positive reinforcement signal. eLife 5, e18640 (2016).

  94. Chen, Y. et al. Sustained NPY signaling enables AgRP neurons to drive feeding. eLife 8, e46348 (2019).

  95. Engstrom Ruud, L., Pereira, M. M. A., de Solis, A. J., Fenselau, H. & Bruning, J. C. NPY mediates the rapid feeding and glucose metabolism regulatory functions of AgRP neurons. Nat. Commun. 11, 442 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  96. Tan, K., Knight, Z. A. & Friedman, J. M. Ablation of AgRP neurons impairs adaption to restricted feeding. Mol. Metab. 3, 694–704 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Betley, J. N., Cao, Z. F., Ritola, K. D. & Sternson, S. M. Parallel, redundant circuit organization for homeostatic control of feeding behavior. Cell 155, 1337–1350 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Fu, O. et al. Hypothalamic neuronal circuits regulating hunger-induced taste modification. Nat. Commun. 10, 4560 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  99. Henry, F. E., Sugino, K., Tozer, A., Branco, T. & Sternson, S. M. Cell type-specific transcriptomics of hypothalamic energy-sensing neuron responses to weight-loss. eLife 4, e09800 (2015).

  100. Campbell, J. N. et al. A molecular census of arcuate hypothalamus and median eminence cell types. Nat. Neurosci. 20, 484–496 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Briggs, D. I., Lemus, M. B., Kua, E. & Andrews, Z. B. Diet-induced obesity attenuates fasting-induced hyperphagia. J. Neuroendocrinol. 23, 620–626 (2011).

    Article  CAS  PubMed  Google Scholar 

  102. Ueno, N., Asakawa, A. & Inui, A. Blunted metabolic response to fasting in obese mice. Endocrine 32, 192–196 (2007).

    Article  CAS  PubMed  Google Scholar 

  103. Beutler, L. R. et al. Obesity causes selective and long-lasting desensitization of AgRP neurons to dietary fat. eLife 9, e55909 (2020).

  104. Baver, S. B. et al. Leptin modulates the intrinsic excitability of AgRP/NPY neurons in the arcuate nucleus of the hypothalamus. J. Neurosci. 34, 5486–5496 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Wei, W. et al. Diet composition, not calorie intake, rapidly alters intrinsic excitability of hypothalamic AgRP/NPY neurons in mice. Sci. Rep. 5, 16810 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Zhu, C. et al. Profound and redundant functions of arcuate neurons in obesity development. Nat. Metab. 2, 763–774 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Zhang, X. & van den Pol, A. N. Hypothalamic arcuate nucleus tyrosine hydroxylase neurons play orexigenic role in energy homeostasis. Nat. Neurosci. 19, 1341–1347 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Luo, S. X. et al. Regulation of feeding by somatostatin neurons in the tuberal nucleus. Science 361, 76–81 (2018).

    Article  CAS  PubMed  Google Scholar 

  109. Jais, A. et al. PNOC(ARC) neurons promote hyperphagia and obesity upon high-fat-diet feeding. Neuron 106, 1009–1025 (2020). This study characterized a novel population of hypothalamic neurons activated upon palatable food consumption with the capacity to promote hyperphagia.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. Wiesenfeld, Z., Halpern, B. P. & Tapper, D. N. Licking behavior: evidence of hypoglossal oscillator. Science 196, 1122–1124 (1977).

    Article  CAS  PubMed  Google Scholar 

  111. Mickelsen, L. E. et al. Single-cell transcriptomic analysis of the lateral hypothalamic area reveals molecularly distinct populations of inhibitory and excitatory neurons. Nat. Neurosci. 22, 642–656 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Rossi, M. A. et al. Obesity remodels activity and transcriptional state of a lateral hypothalamic brake on feeding. Science 364, 1271–1274 (2019). This study performed longitudinal two-photon neural recordings to demonstrate how diet disrupts the function of an endogenous feeding suppression system to promote overeating and obesity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Rossi, M. A. et al. Transcriptional and functional divergence in lateral hypothalamic glutamate neurons projecting to the lateral habenula and ventral tegmental area. Neuron 109, 3823–3837 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Rada, P., Tucci, S., Murzi, E. & Hernández, L. Extracellular glutamate increases in the lateral hypothalamus and decreases in the nucleus accumbens during feeding. Brain Res. 768, 338–340 (1997).

    Article  CAS  PubMed  Google Scholar 

  115. Jennings, J. H., Rizzi, G., Stamatakis, A. M., Ung, R. L. & Stuber, G. D. The inhibitory circuit architecture of the lateral hypothalamus orchestrates feeding. Science 341, 1517–1521 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Siemian, J. N., Arenivar, M. A., Sarsfield, S. & Aponte, Y. Hypothalamic control of interoceptive hunger. Curr. Biol. 31, 3797–3809 (2021).

    Article  CAS  PubMed  Google Scholar 

  117. Jennings, JoshuaH. et al. Visualizing hypothalamic network dynamics for appetitive and consummatory behaviors. Cell 160, 516–527 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  118. Leinninger, G. M. et al. Leptin acts via leptin receptor-expressing lateral hypothalamic neurons to modulate the mesolimbic dopamine system and suppress feeding. Cell Metab. 10, 89–98 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. Schiffino, F. L. et al. Activation of a lateral hypothalamic-ventral tegmental circuit gates motivation. PLoS ONE 14, e0219522 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Siemian, J. N. et al. Lateral hypothalamic LEPR neurons drive appetitive but not consummatory behaviors. Cell Rep. 36, 109615 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Mickelsen, L. E. et al. Cellular taxonomy and spatial organization of the murine ventral posterior hypothalamus. eLife 9, e58901 (2020).

  122. Qu, D. et al. A role for melanin-concentrating hormone in the central regulation of feeding behaviour. Nature 380, 243–247 (1996).

    Article  CAS  PubMed  Google Scholar 

  123. Sakurai, T. et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573–585 (1998).

    Article  CAS  PubMed  Google Scholar 

  124. de Lecea, L. et al. The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc. Natl Acad. Sci. USA 95, 322–327 (1998).

    Article  PubMed  PubMed Central  Google Scholar 

  125. Rossi, M. et al. Investigation of the feeding effects of melanin concentrating hormone on food intake — action independent of galanin and the melanocortin receptors. Brain Res. 846, 164–170 (1999).

    Article  CAS  PubMed  Google Scholar 

  126. Della-Zuana, O. et al. Acute and chronic administration of melanin-concentrating hormone enhances food intake and body weight in Wistar and Sprague–Dawley rats. Int. J. Obes. 26, 1289–1295 (2002).

    Article  CAS  Google Scholar 

  127. Gomori, A. et al. Chronic intracerebroventricular infusion of MCH causes obesity in mice. Am. J. Physiol. Endocrinol. Metab. 284, E583–E588 (2003).

    Article  CAS  PubMed  Google Scholar 

  128. Noble, E. E. et al. Hypothalamus–hippocampus circuitry regulates impulsivity via melanin-concentrating hormone. Nat. Commun. 10, 4923 (2019).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  129. Ludwig, D. S. et al. Melanin-concentrating hormone: a functional melanocortin antagonist in the hypothalamus. Am. J. Physiol. Endocrinol. Metab. 274, E627–E633 (1998).

    Article  CAS  Google Scholar 

  130. Edwards, C. M. et al. The effect of the orexins on food intake: comparison with neuropeptide Y, melanin-concentrating hormone and galanin. J. Endocrinol. 160, R7–R12 (1999).

    Article  CAS  PubMed  Google Scholar 

  131. Jeon, J. Y. et al. MCH–/– mice are resistant to aging-associated increases in body weight and insulin resistance. Diabetes 55, 428–434 (2006).

    Article  CAS  PubMed  Google Scholar 

  132. Inutsuka, A. et al. Concurrent and robust regulation of feeding behaviors and metabolism by orexin neurons. Neuropharmacology 85, 451–460 (2014).

    Article  CAS  PubMed  Google Scholar 

  133. Hara, J. et al. Genetic ablation of orexin neurons in mice results in narcolepsy, hypophagia, and obesity. Neuron 30, 345–354 (2001).

    Article  CAS  PubMed  Google Scholar 

  134. González, J. A. et al. Inhibitory interplay between orexin neurons and eating. Curr. Biol. 26, 2486–2491 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  135. Dilsiz, P. et al. MCH neuron activity is sufficient for reward and reinforces feeding. Neuroendocrinology 110, 258–270 (2020).

    Article  CAS  PubMed  Google Scholar 

  136. Delgado, J. M. & Anand, B. K. Increase of food intake induced by electrical stimulation of the lateral hypothalamus. Am. J. Physiol. 172, 162–168, (1953). This study was the first to show that excitation of the lateral hypothalamus via electrical stimulation augmented food intake.

    Article  CAS  PubMed  Google Scholar 

  137. Mogenson, G. J. & Stevenson, J. A. Drinking induced by electrical stimulation of the lateral hypothalamus. Exp. Neurol. 17, 119–127 (1967).

    Article  CAS  PubMed  Google Scholar 

  138. Woodworth, C. H. Attack elicited in rats by electrical stimulation of the lateral hypothalamus. Physiol. Behav. 6, 345–353 (1971).

    Article  CAS  PubMed  Google Scholar 

  139. Valenstein, E. S., Cox, V. C. & Kakolewski, J. W. Modification of motivated behavior elicited by electrical stimulation of the hypothalamus. Science 159, 1119–1121 (1968).

    Article  CAS  PubMed  Google Scholar 

  140. Vaughan, E. & Fisher, A. E. Male sexual behavior induced by intracranial electrical stimulation. Science 137, 758–760 (1962).

    Article  CAS  PubMed  Google Scholar 

  141. Navarro, M. et al. Lateral hypothalamus GABAergic neurons modulate consummatory behaviors regardless of the caloric content or biological relevance of the consumed stimuli. Neuropsychopharmacology 41, 1505–1512 (2016). This study demonstrated that artificial activation of feeding centers can elicit consummatory responses to inedible, non-caloric objects.

    Article  CAS  PubMed  Google Scholar 

  142. Nieh, E. H. et al. Decoding neural circuits that control compulsive sucrose seeking. Cell 160, 528–541 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  143. Margules, D. L. & Olds, J. Identical ‘feeding’ and ‘rewarding’ systems in the lateral hypothalamus of rats. Science 135, 374–375 (1962).

    Article  CAS  PubMed  Google Scholar 

  144. Nieh, EdwardH. et al. Inhibitory input from the lateral hypothalamus to the ventral tegmental area disinhibits dopamine neurons and promotes behavioral activation. Neuron 90, 1286–1298 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  145. O’Connor, EoinC. et al. Accumbal D1R neurons projecting to lateral hypothalamus authorize feeding. Neuron 88, 553–564 (2015).

    Article  PubMed  CAS  Google Scholar 

  146. Thoeni, S., Loureiro, M., O’Connor, E. C. & Lüscher, C. Depression of accumbal to lateral hypothalamic synapses gates overeating. Neuron 107, 158–172.e154 (2020).

    Article  CAS  PubMed  Google Scholar 

  147. Broberger, C., Johansen, J., Johansson, C., Schalling, M. & Hokfelt, T. The neuropeptide Y/agouti gene-related protein (AGRP) brain circuitry in normal, anorectic, and monosodium glutamate-treated mice. Proc. Natl Acad. Sci. USA 95, 15043–15048 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Tolson, K. P. et al. Postnatal Sim1 deficiency causes hyperphagic obesity and reduced Mc4r and oxytocin expression. J. Neurosci. 30, 3803–3812 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Baltasar, A. et al. Laparoscopic sleeve gastrectomy: a multi-purpose bariatric operation. Obes. Surg. 15, 1124–1128 (2005).

    Article  PubMed  Google Scholar 

  150. Michaud, J. L., Rosenquist, T., May, N. R. & Fan, C. M. Development of neuroendocrine lineages requires the bHLH-PAS transcription factor SIM1. Genes Dev. 12, 3264–3275 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Xi, B., Chandak, G. R., Shen, Y., Wang, Q. & Zhou, D. Association between common polymorphism near the MC4R gene and obesity risk: a systematic review and meta-analysis. PLoS ONE 7, e45731 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Li, M. M. et al. The paraventricular hypothalamus regulates satiety and prevents obesity via two genetically distinct circuits. Neuron 102, 653–667 e656 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Shah, B. P. et al. MC4R-expressing glutamatergic neurons in the paraventricular hypothalamus regulate feeding and are synaptically connected to the parabrachial nucleus. Proc. Natl Acad. Sci. USA 111, 13193–13198 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Garfield, A. S. et al. A neural basis for melanocortin-4 receptor-regulated appetite. Nat. Neurosci. 18, 863–871 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Sutton, A. K. et al. Control of food intake and energy expenditure by Nos1 neurons of the paraventricular hypothalamus. J. Neurosci. 34, 15306–15318 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  156. Sutton, A. K. et al. Paraventricular, subparaventricular and periventricular hypothalamic IRS4-expressing neurons are required for normal energy balance. Sci. Rep. 10, 5546 (2020).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  157. An, J. J., Liao, G. Y., Kinney, C. E., Sahibzada, N. & Xu, B. Discrete BDNF neurons in the paraventricular hypothalamus control feeding and energy expenditure. Cell Metab. 22, 175–188 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  158. Kim, J. et al. Rapid, biphasic CRF neuronal responses encode positive and negative valence. Nat. Neurosci. 22, 576–585 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  159. Sweeney, P., Chen, C., Rajapakse, I. & Cone, R. D. Network dynamics of hypothalamic feeding neurons. Proc. Natl Acad. Sci. USA 118, e2011140118 (2021).

  160. Xu, S. et al. Behavioral state coding by molecularly defined paraventricular hypothalamic cell type ensembles. Science 370, eabb2494 (2020).

  161. Stachniak, T. J., Ghosh, A. & Sternson, S. M. Chemogenetic synaptic silencing of neural circuits localizes a hypothalamus→midbrain pathway for feeding behavior. Neuron 82, 797–808 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  162. Gong, R., Xu, S., Hermundstad, A., Yu, Y. & Sternson, S. M. Hindbrain double-negative feedback mediates palatability-guided food and water consumption. Cell 182, 1589–1605 (2020). This study highlights a population of hindbrain neurons that increase consumption by enhancing palatbility and prolonging ingestion duration.

    Article  CAS  PubMed  Google Scholar 

  163. Li, C. et al. Defined paraventricular hypothalamic populations exhibit differential responses to food contingent on caloric state. Cell Metab. 29, 681–694 e685 (2019).

    Article  CAS  PubMed  Google Scholar 

  164. Travers, J. B., Dinardo, L. A. & Karimnamazi, H. Motor and premotor mechanisms of licking. Neurosci. Biobehav. Rev. 21, 631–647 (1997).

    Article  CAS  PubMed  Google Scholar 

  165. Mohammad, H. et al. A neural circuit for excessive feeding driven by environmental context in mice. Nat. Neurosci. 24, 1132–1141 (2021).

    Article  CAS  PubMed  Google Scholar 

  166. Zhang, X. & van den Pol, A. N. Rapid binge-like eating and body weight gain driven by zona incerta GABA neuron activation. Science 356, 853–859 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Herman, A. M. et al. A cholinergic basal forebrain feeding circuit modulates appetite suppression. Nature 538, 253–256 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  168. Pinol, R. A. et al. Brs3 neurons in the mouse dorsomedial hypothalamus regulate body temperature, energy expenditure, and heart rate, but not food intake. Nat. Neurosci. 21, 1530–1540 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  169. Miller, G. D. Appetite regulation: hormones, peptides, and neurotransmitters and their role in obesity. Am. J. Lifestyle Med. 13, 586–601 (2019).

    Article  PubMed  Google Scholar 

  170. Schwartz, G. J., Salorio, C. F., Skoglund, C. & Moran, T. H. Gut vagal afferent lesions increase meal size but do not block gastric preload-induced feeding suppression. Am. J. Physiol. 276, R1623–R1629 (1999).

    CAS  PubMed  Google Scholar 

  171. Ritter, S., Dinh, T. T. & Friedman, M. I. Induction of Fos-like immunoreactivity (Fos-li) and stimulation of feeding by 2,5-anhydro-d-mannitol (2,5-AM) require the vagus nerve. Brain Res. 646, 53–64 (1994).

    Article  CAS  PubMed  Google Scholar 

  172. Fan, W. et al. Cholecystokinin-mediated suppression of feeding involves the brainstem melanocortin system. Nat. Neurosci. 7, 335–336 (2004).

    Article  CAS  PubMed  Google Scholar 

  173. Kreisler, A. D., Davis, E. A. & Rinaman, L. Differential activation of chemically identified neurons in the caudal nucleus of the solitary tract in non-entrained rats after intake of satiating vs. non-satiating meals. Physiol. Behav. 136, 47–54 (2014).

    Article  CAS  PubMed  Google Scholar 

  174. Blouet, C. & Schwartz, GaryJ. Brainstem nutrient sensing in the nucleus of the solitary tract inhibits feeding. Cell Metab. 16, 579–587 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Chen, J. et al. A vagal–NTS neural pathway that stimulates feeding. Curr. Biol. 30, 3986–3998.e3985 (2020).

    Article  CAS  PubMed  Google Scholar 

  176. Browning, K. N. & Travagli, R. A. Central nervous system control of gastrointestinal motility and secretion and modulation of gastrointestinal functions. Compr. Physiol. 4, 1339–1368 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  177. Sutton, A. K. & Krashes, M. J. Integrating hunger with rival motivations. Trends Endocrinol. Metab. 31, 495–507 (2020).

    Article  CAS  PubMed  Google Scholar 

  178. Carter, M. E., Soden, M. E., Zweifel, L. S. & Palmiter, R. D. Genetic identification of a neural circuit that suppresses appetite. Nature 503, 111–114 (2013). This study identified a neural circuit from the parabrachial nucleus to the amygdala that mediates appetite suppression in conditions when it is unfavorable to eat.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  179. Carter, M. E., Han, S. & Palmiter, R. D. Parabrachial calcitonin gene-related peptide neurons mediate conditioned taste aversion. J. Neurosci. 35, 4582–4586 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  180. Campos, C. A., Bowen, A. J., Roman, C. W. & Palmiter, R. D. Encoding of danger by parabrachial CGRP neurons. Nature 555, 617–622 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Chen, J. Y., Campos, C. A., Jarvie, B. C. & Palmiter, R. D. Parabrachial CGRP neurons establish and sustain aversive taste memories. Neuron 100, 891–899 e895 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Reilly, S. The parabrachial nucleus and conditioned taste aversion. Brain Res. Bull. 48, 239–254 (1999).

    Article  CAS  PubMed  Google Scholar 

  183. Phua, S. C. et al. A distinct parabrachial-to-lateral hypothalamus circuit for motivational suppression of feeding by nociception. Sci. Adv. 7, eabe4323 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  184. Han, S., Soleiman, M. T., Soden, M. E., Zweifel, L. S. & Palmiter, R. D. Elucidating an affective pain circuit that creates a threat memory. Cell 162, 363–374 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Sabatini, P. V. et al. GFRAL-expressing neurons suppress food intake via aversive pathways. Proc. Natl Acad. Sci. USA 118, e2021357118 (2021).

  186. Alhadeff, A. L. & Grill, H. J. Hindbrain nucleus tractus solitarius glucagon-like peptide-1 receptor signaling reduces appetitive and motivational aspects of feeding. Am. J. Physiol. Regul. Integr. Comp. Physiol. 307, R465–R470 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  187. Richard, J. E. et al. GLP-1 receptor stimulation of the lateral parabrachial nucleus reduces food intake: neuroanatomical, electrophysiological, and behavioral evidence. Endocrinology 155, 4356–4367 (2014).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  188. Roman, C. W., Derkach, V. A. & Palmiter, R. D. Genetically and functionally defined NTS to PBN brain circuits mediating anorexia. Nat. Commun. 7, 11905 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  189. Roman, C. W., Sloat, S. R. & Palmiter, R. D. A tale of two circuits: CCK(NTS) neuron stimulation controls appetite and induces opposing motivational states by projections to distinct brain regions. Neuroscience 358, 316–324 (2017).

    Article  CAS  PubMed  Google Scholar 

  190. Huang, D., Grady, F. S., Peltekian, L., Laing, J. J. & Geerling, J. C. Efferent projections of CGRP/Calca-expressing parabrachial neurons in mice. J. Comp. Neurol. 529, 2911–2957 (2021).

    Article  CAS  PubMed  Google Scholar 

  191. Kim, J. H. et al. A discrete parasubthalamic nucleus subpopulation plays a critical role in appetite suppression. eLife 11, e75470 (2022).

  192. Cai, H., Haubensak, W., Anthony, T. E. & Anderson, D. J. Central amygdala PKC-delta+ neurons mediate the influence of multiple anorexigenic signals. Nat. Neurosci. 17, 1240–1248 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Cheng, W. et al. Calcitonin receptor neurons in the mouse nucleus tractus solitarius control energy balance via the non-aversive suppression of feeding. Cell Metab. 31, 301–312 e305 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Cheng, W. et al. NTS Prlh overcomes orexigenic stimuli and ameliorates dietary and genetic forms of obesity. Nat. Commun. 12, 5175 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. Luskin, A. T. et al. Extended amygdala-parabrachial circuits alter threat assessment and regulate feeding. Sci. Adv. 7, eabd3666 (2021).

  196. Flak, J. N. et al. Leptin-inhibited PBN neurons enhance responses to hypoglycemia in negative energy balance. Nat. Neurosci. 17, 1744–1750 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Mumphrey, M. B. et al. Eating in mice with gastric bypass surgery causes exaggerated activation of brainstem anorexia circuit. Int J. Obes. 40, 921–928 (2016).

    Article  CAS  Google Scholar 

  198. Evers, S. S., Sandoval, D. A. & Seeley, R. J. The physiology and molecular underpinnings of the effects of bariatric surgery on obesity and diabetes. Annu Rev. Physiol. 79, 313–334 (2017).

    Article  CAS  PubMed  Google Scholar 

  199. Low, A. Y. T. et al. Reverse-translational identification of a cerebellar satiation network. Nature 600, 269–273 (2021).

    Article  CAS  PubMed  Google Scholar 

  200. Alhadeff, A. L., Rupprecht, L. E. & Hayes, M. R. 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, 647–658 (2012).

    Article  CAS  PubMed  Google Scholar 

  201. Angulo, M. A., Butler, M. G. & Cataletto, M. E. Prader–Willi syndrome: a review of clinical, genetic, and endocrine findings. J. Endocrinol. Invest 38, 1249–1263 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Goldstein, N. et al. Hypothalamic detection of macronutrients via multiple gut-brain pathways. Cell Metab. 33, 676–687 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  203. Corbett, D. & Wise, R. A. Intracranial self-stimulation in relation to the ascending dopaminergic systems of the midbrain: a moveable electrode mapping study. Brain Res. 185, 1–15 (1980).

    Article  CAS  PubMed  Google Scholar 

  204. Yeomans, M. R. Taste, palatability and the control of appetite. Proc. Nutr. Soc. 57, 609–615 (1998).

    Article  CAS  PubMed  Google Scholar 

  205. Cabanac, M. Physiological role of pleasure. Science 173, 1103–1107 (1971).

    Article  CAS  PubMed  Google Scholar 

  206. Sorensen, L. B., Moller, P., Flint, A., Martens, M. & Raben, A. Effect of sensory perception of foods on appetite and food intake: a review of studies on humans. Int. J. Obes. Relat. Metab. Disord. 27, 1152–1166 (2003).

    Article  CAS  PubMed  Google Scholar 

  207. Campos, C. A. et al. Cancer-induced anorexia and malaise are mediated by CGRP neurons in the parabrachial nucleus. Nat. Neurosci. 20, 934–942 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  208. Bowen, A. J. et al. Dissociable control of unconditioned responses and associative fear learning by parabrachial CGRP neurons. eLife 9, e59799 (2020).

  209. Astrup, A. et al. Safety, tolerability and sustained weight loss over 2 years with the once-daily human GLP-1 analog, liraglutide. Int J. Obes. 36, 843–854 (2012).

    Article  CAS  Google Scholar 

  210. Muller, T. D., Clemmensen, C., Finan, B., DiMarchi, R. D. & Tschop, M. H. Anti-obesity therapy: from rainbow pills to polyagonists. Pharm. Rev. 70, 712–746 (2018).

    Article  CAS  PubMed  Google Scholar 

  211. Pi-Sunyer, X. et al. A randomized, controlled trial of 3.0 mg of liraglutide in weight management. N. Engl. J. Med. 373, 11–22 (2015).

    Article  PubMed  CAS  Google Scholar 

  212. Wilding, J. P. H. et al. Once-weekly semaglutide in adults with overweight or obesity. N. Engl. J. Med. 384, 989 (2021).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors acknowledge with gratitude S. Sarsfield for comments on the manuscript. Y. A. is supported by the National Institute on Drug Abuse Intramural Research Program (NIDA IRP), US National Institutes of Health (NIH). M. K. is supported by the National Institute of Diabetes and Digestive and Kidney Diseases Intramural Research Program (NIDDK IRP), US National Institutes of Health (NIH).

Author information

Author notes

  1. These authors contributed equally: Ivan C. Alcantara, Ana Pamela, Miranda Tapia.

Authors and Affiliations

  1. Diabetes, Endocrinology, and Obesity Branch, National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), National Institutes of Health, Bethesda, MD, USA

    Ivan C. Alcantara & Michael J. Krashes

  2. Department of Neuroscience, Brown University, Providence, RI, USA

    Ivan C. Alcantara

  3. National Institute on Drug Abuse (NIDA), National Institutes of Health, Baltimore, MD, USA

    Ana Pamela Miranda Tapia, Yeka Aponte & Michael J. Krashes

  4. The Solomon H. Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD, USA

    Yeka Aponte

Authors
  1. Ivan C. Alcantara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ana Pamela Miranda Tapia
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yeka Aponte
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael J. Krashes
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

I.C.A, A.P.M.T, Y.A., and M.J.K. conceived the outline, elaborated on the concepts, and wrote the synopsis of the review. I.C.A. wrote the introduction, prologue and act I sections. A.P.M.T. and Y.A. wrote the act II section. M.J.K. wrote the introduction, act III, and epilogue sections and the boxes and figure legends. All authors read and gave feedback on all sections, and approved the final version of the paper.

Corresponding authors

Correspondence to Yeka Aponte or Michael J. Krashes.

Ethics declarations

Competing interests

The authors declare no competing interests.

Peer review

Peer review information

Nature Metabolism thanks the anonymous reviewers for their contribution to the peer review of this work.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Alcantara, I.C., Tapia, A.P.M., Aponte, Y. et al. Acts of appetite: neural circuits governing the appetitive, consummatory, and terminating phases of feeding. Nat Metab 4, 836–847 (2022). https://doi.org/10.1038/s42255-022-00611-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/s42255-022-00611-y

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing