The central melanocortin system is perhaps the best-characterized neuronal pathway involved in the regulation of energy homeostasis. This collection of circuits is unique in having the capability of sensing signals from a staggering array of hormones, nutrients and afferent neural inputs. It is likely to be involved in integrating long-term adipostatic signals from leptin and insulin, primarily received by the hypothalamus, with acute signals regulating hunger and satiety, primarily received by the brainstem. The system is also unique from a regulatory point of view in that it is composed of fibers expressing both agonists and antagonists of melanocortin receptors. Given that the central melanocortin system is an active target for development of drugs for the treatment of obesity, diabetes and cachexia, it is important to understand the system in its full complexity, including the likelihood that the system also regulates the cardiovascular and reproductive systems.
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Haskell-Luevano, C. et al. Characterization of the neuroanatomical distribution of agouti-related protein (AGRP) immunoreactivity in the rhesus monkey and the rat. Endocrinology 140, 1408–1415 (1999).
Huszar, D. et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell 88, 131–141 (1997).
Yen, T.T., Gill, A.M., Frigeri, L.G., Barsh, G.S. & Wolff, G.L. Obesity, diabetes, and neoplasia in yellow Avy/− mice: ectopic expression of the agouti gene. FASEB J. 8, 479–488 (1994).
Butler, A.A. et al. A unique metabolic syndrome causes obesity in the melanocortin-3 receptor-deficient mouse. Endocrinology 141, 3518–3521 (2000).
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).
Ollmann, M.M. et al. Antagonism of central melanocortin receptors in vitro and in vivo by agouti-related protein. Science 278, 135–137 (1997).
Krude, H. et al. Severe early-onset obesity, adrenal insufficiency and red hair pigmentation caused by POMC mutations in humans. Nat. Genet. 19, 155–157 (1998).
Vaisse, C., Clement, K., Guy-Grand, B. & Froguel, P. A frameshift mutation in human MC4R is associated with a dominant form of obesity. Nat. Genet. 20, 113–114 (1998).
Yeo, G.S.H. et al. A frameshift mutation in MC4R associated with dominantly inherited human obesity. Nat. Genet. 20, 111–112 (1998).
Farooqi, I.S. et al. Dominant and recessive inheritance of morbid obesity associated with melanocortin 4 receptor deficiency. J. Clin. Invest. 106, 271–279 (2000).
Vaisse, C. et al. Melanocortin-4 receptor mutations are a frequent and heterogeneous cause of morbid obesity. J. Clin. Invest. 106, 253–262 (2000).
Farooqi, I.S. et al. Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene. N. Engl. J. Med. 348, 1160–1163 (2003).
Branson, R. et al. Binge eating as a major phenotype of melanocortin 4 receptor gene mutations. N. Engl. J. Med. 348, 1096–1103 (2003).
Butler, A.A. et al. Melanocortin-4 receptor is required for acute homeostatic responses to increased dietary fat. Nat. Neurosci. 4, 605–611 (2001).
Fan, W. et al. The central melanocortin system can directly regulate serum insulin levels. Endocrinology 141, 3072–3079 (2000).
Watson, S.J., Akil, H., Richard, C.W. & Barchas, J.D. Evidence for two separate opiate peptide neuronal systems and the coexistence of β-lipotropin, β-endorphin, and ACTH immunoreactivities in the same hypothalamic neurons. Nature 275, 226–228 (1978).
Jacobowitz, D.M. & O'Donohue, T.L. α-Melanocyte-stimulating hormone: immunohistochemical identification and mapping in neurons of rat brain. Proc. Natl. Acad. Sci. USA 75, 6300–6304 (1978).
Nilaver, G. et al. Adrenocorticotropin and beta-lipotropin in the hypothalamus. Localization in the same arcuate neurons by sequential immunocytochemical procedures. J. Cell Biol. 81, 50–58 (1979).
Joseph, S.A. & Michael, G.J. Efferent ACTH-IR opiocortin projections from nucleus tractus solitarius: a hypothalamic deafferentation study. Peptides 9, 193–201 (1988).
Pilcher, W.H. & Joseph, S.A. Differential sensitivity of hypothalamic and medullary opiocortin and tyrosine hydroxylase neurons to the neurotoxic effects of monosodium glutamate (MSG). Peptides 7, 783–789 (1986).
Hentges, S.T. et al. GABA release from POMC neurons. J. Neurosci. 24, 1578–1583 (2004).
Collin, M. et al., Plasma membrane and vesicular glutamate transporter mRNAs/proteins in hypothalamic neurons that regulate body weight. Eur. J. Neurosci. 18, 1265–1278 (2003).
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).
Hakansson, M.L., Hulting, A.L. & Meister, B. Expression of leptin receptor mRNA in the hypothalamic arcuate nucleus—relationship with NPY neurones. Neuroreport 7, 3087–3092 (1996).
Elmquist, J.K., Ahima, R.S., Maratos-Flier, E., Flier, J.S. & Saper, C.B. Leptin activates neurons in ventrobasal hypothalamus and brainstem. Endocrinology 138, 839–842 (1997).
Stephens, T. et al. The role of neuropeptide Y in the antiobesity action of the obesity gene product. Nature 377, 530–532 (1995).
Erickson, J., Hollopeter, G. & Palmiter, J.D. Attenuation of the obesity syndrome of ob/ob mice by the loss of neuropeptide Y. Science 274, 1704–1707 (1996).
Mizuno, T.M. & Mobbs, C.V. Hypothalamic agouti-related protein messenger ribonucleic acid is inhibited by leptin and stimulated by fasting. Endocrinology 140, 814–817 (1999).
Mizuno, T.M. et al. Hypothalamic pro-opiomelanocortin mRNA is reduced by fasting and corrected in ob/ob and db/db mice, but is stimulated by leptin. Diabetes 47, 294–297 (1998).
Schwartz, M.W. et al. Leptin increases hypothalamic pro-opiomelanocortin mRNA expression in the rostral arcuate nucleus. Diabetes 46, 2119–2123 (1997).
Niswender, K.D., Baskin, D.G. & Schwartz, M.W. Insulin and its evolving partnership with leptin in the hypothalamic control of energy homeostasis. Trends Endocrinol. Metab. 15, 362–369 (2004).
Spanswick, D., Smith, M.A., Mirshamsi, S., Routh, V.H. & Ashford, M.L. Insulin activates ATP-sensitive K+ channels in hypothalamic neurons of lean, but not obese rats. Nat. Neurosci. 3, 757–758 (2000).
Bruning, J.C. et al. Role of brain insulin receptor in control of body weight and reproduction. Science 289, 2122–2125 (2000).
Obici, S., Zhang, B.B., Karkanias, G. & Rossetti, L. Hypothalamic insulin signaling is required for inhibition of glucose production. Nat. Med. 8, 1376–1382 (2002).
Blum, M., Roberts, J.L. & Wardlaw, S.L. Androgen regulation of proopiomelanocortin gene expression and peptide content in the basal hypothalamus. Endocrinology 124, 2283–2288 (1989).
Kelly, M.J., Qiu, J. & Ronnekleiv, O.K. Estrogen modulation of G-protein-coupled receptor activation of potassium channels in the central nervous system. Ann. NY Acad. Sci. 1007, 6–16 (2003).
Cowley, M.A. et al. Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411, 480–484 (2001).
Cowley, M.A. et al. The distribution and mechanism of action of ghrelin in the CNS demonstrates a novel hypothalamic circuit regulating energy homeostasis. Neuron 37, 649–661 (2003).
Heisler, L.K. et al. Activation of central melanocortin pathways by fenfluramine. Science 297, 609–611 (2002).
Roseberry, A.G., Liu, H., Jackson, A.C., Cai, X. & Friedman, J.M. Neuropeptide Y-mediated inhibition of proopiomelanocortin neurons in the arcuate nucleus shows enhanced desensitization in ob/ob mice. Neuron 41, 711–722 (2004).
Ibrahim, N. et al. Hypothalamic proopiomelanocortin neurons are glucose responsive and express K(ATP) channels. Endocrinology 144, 1331–1340 (2003).
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).
Kojima, M. et al. Ghrelin is a growth-hormone-releasing acylated peptide from stomach. Nature 402, 656–660 (1999).
Kojima, M., Hosoda, H., Matsuo, H. & Kangawa, K. Ghrelin: discovery of the natural endogenous ligand for the growth hormone secretagogue receptor. Trends Endocrinol. Metab. 12, 118–122 (2001).
Ariyasu, H. et al. Stomach is a major source of circulating ghrelin, and feeding state determines plasma ghrelin-like immunoreactivity levels in humans. J. Clin. Endocrinol. Metab. 86, 4753–4758 (2001).
Tschop, M. et al. Post-prandial decrease of circulating human ghrelin levels. J. Endocrinol. Invest. 24, RC19–RC21 (2001).
Cummings, D.E. et al. A preprandial rise in plasma ghrelin levels suggest a role in meal initiation in humans. Diabetes 50, 1714–1719 (2001).
Tschop, M., Smiley, D.L. & Heiman, M.L. Ghrelin induces adiposity in rodents. Nature 407, 908–913 (2000).
Willesen, M., 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).
Hewson, A.K. & Dickson, S.L. Systemic administration of ghrelin induces Fos and Egr-1 proteins in the hypothalamic arcuate nucleus of fasted and fed rats. J. Neuroendocrinol. 12, 1047–1049 (2000).
Kamegai, J. et al. Central effect of ghrelin, an endogenous growth hormone secretagogue, on hypothalamic peptide gene expression. Endocrinology 141, 4797–4800 (2000).
Nakazato, M. et al. A role for ghrelin in the central regulation of feeding. Nature 409, 194–198 (2001).
Shintani, M. et al. Ghrelin, an endogenous growth hormone secretagogue, is a novel orexigenic peptide that antagonizes leptin action through the activation of hypothalamic neuropeptide Y/Y1 receptor pathway. Diabetes 50, 227–232 (2001).
Tschop, M., Statnick, M.A., Suter, T.M. & Heiman, M.L. GH-releasing peptide-2 increases fat mass in mice lacking NPY: indication for a crucial mediating role of hypothalamic agouti-related protein. Endocrinology 143, 558–568 (2002).
Wang, L., Saint-Pierre, D.H. & Tache, Y. Peripheral ghrelin selectively increases Fos expression in neuropeptide Y–synthesizing neurons in mouse hypothalamic arcuate nucleus. Neurosci. Lett. 325, 47–51 (2002).
Tamura, H. et al. Ghrelin stimulates GH but not food intake in arcuate nucleus ablated rats. Endocrinology 143, 3268–3275 (2002).
Date, Y. et al. The role of the gastric afferent vagal nerve in ghrelin-induced feeding and growth hormone secretion in rats. Gastroenterology 123, 1120–1128 (2002).
Adrian, T.E. et al. Human distribution and release of a putative new gut hormone, peptide YY. Gastroenterology 89, 1070–1077 (1985).
Grandt, D. et al. Two molecular forms of peptide YY (PYY) are abundant in human blood: characterization of a radioimmunoassay recognizing PYY 1–36 and PYY 3–36. Regul. Pept. 51, 151–159 (1994).
Halatchev, I.G., Ellacott, K.L., Fan, W. & Cone, R.D. Peptide YY3–36 inhibits food intake in mice through a melanocortin-4 receptor-independent mechanism. Endocrinology 145, 2585–2590 (2004).
Batterham, R.L. et al. Gut hormone PYY(3–36) physiologically inhibits food intake. Nature 418, 650–654 (2002).
Challis, B.G. et al. Mice lacking pro-opiomelanocortin are sensitive to high-fat feeding but respond normally to the acute anorectic effects of peptide-YY(3–36). Proc. Natl. Acad. Sci. USA 101, 4695–4700 (2004).
Halatchev, I.G. & Cone, R.D. Peripheral administration of PYY3–36 produces conditioned taste aversion in mice. Cell Metab. 1, 159–168 (2005).
Mayer, J. Regulation of energy intake and body weight: the glucostatic theory and the lipostatic hypothesis. Ann. NY Acad. Sci. 63, 15–43 (1955).
Obici, S. et al. Central administration of oleic acid inhibits glucose production and food intake. Diabetes 51, 271–275 (2002).
Morgan, K., Obici, S. & Rossetti, L. Hypothalamic responses to long-chain fatty acids are nutritionally regulated. J. Biol. Chem. 279, 31139–31148 (2004).
Obici, S., Feng, Z., Arduini, A., Conti, R. & Rossetti, L. Inhibition of hypothalamic carnitine palmitoyltransferase-1 decreases food intake and glucose production. Nat. Med. 9, 756–761 (2003).
Andersson, U. et al. AMP-activated protein kinase plays a role in the control of food intake. J. Biol. Chem. 279, 12005–12008 (2004).
Minokoshi, Y. et al. AMP-kinase regulates food intake by responding to hormonal and nutrient signals in the hypothalamus. Nature 428, 569–574 (2004).
Andersson, U. et al. Exercise in rats does not alter hypothalamic AMP-activated protein kinase activity. Biochem. Biophys. Res. Commun. 329, 719–725 (2005).
Horvath, T.L., Diano, S. & van den Pol, A.N. Synaptic interaction between hypocretin (orexin) and neuropeptide Y cells in the rodent and primate hypothalamus: a novel circuit implicated in metabolic and endocrine regulations. J. Neurosci. 19, 1072–1087 (1999).
Schwartz, G.J. The role of gastrointestinal vagal afferents in the control of food intake: current prospects. Nutrition 16, 866–873 (2000).
Altschuler, S.M., Bao, X.M., Bieger, D., Hopkins, D.A. & Miselis, R.R. Viscerotopic representation of the upper alimentary tract in the rat: sensory ganglia and nuclei of the solitary and spinal trigeminal tracts. J. Comp. Neurol. 283, 248–268 (1989).
Saper, C.B. Central autonomic system. in The Rat Nervous System (ed. Paxinos, G.) 107–135 (Academic Press, San Diego, 1995).
Raybould, H.E., Gayton, R.J. & Dockray, G.J. CNS effects of circulating CCK8: involvement of brainstem neurones responding to gastric distension. Brain Res. 342, 187–190 (1985).
Zhang, X., Fogel, R. & Renehan, W.E. Relationships between the morphology and function of gastric- and intestine-sensitive neurons in the nucleus of the solitary tract. J. Comp. Neurol. 363, 37–52 (1995).
Rinaman, L., Verbalis, J.G., Stricker, E.M. & Hoffman, G.E. Distribution and neurochemical phenotypes of caudal medullary neurons activated to express cFos following peripheral administration of cholecystokinin. J. Comp. Neurol. 338, 475–490 (1993).
Joseph, S.A., Pilcher, W.H. & Bennet-Clarke, C. Immunocytochemical localization of ACTH parikarya in nucleus tractus solitarius: evidence for a second opiocortin neuronal system. Neurosci. Lett. 38, 221–225 (1983).
Palkovits, M., Mezey, E. & Eskay, R.L. Pro-opiomelanocortin-derived peptides (ACTH/β-endorphin/α-MSH) in brainstem baroreceptor areas of the rat. Brain Res. 436, 323–328 (1987).
Mountjoy, K. et al. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol. Endocrinol. 8, 1298–1308 (1994).
Kishi, T. et al. Expression of melanocortin 4 receptor mRNA in the central nervous system of the rat. J. Comp. Neurol. 457, 213–235 (2003).
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).
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).
Gibbs, J., Falasco, J.D. & McHugh, P.R. Cholecystokinin-decreased food intake in rhesus monkeys. Am. J. Physiol. 230, 15–18 (1976).
Crawley, J.N. & Beinfeld, M.C. Rapid development of tolerance to the behavioural actions of cholecystokinin. Nature 302, 703–706 (1983).
Smith, G.P., Jerome, C., Cushin, B.J., Eterno, R. & Simansky, K.J. Abdominal vagotomy blocks the satiety effect of cholecystokinin in the rat. Science 213, 1036–1037 (1981).
Dourish, C.T., Ruckert, A.C., Tattersall, F.D. & Iversen, S.D. Evidence that decreased feeding induced by systemic injection of cholecystokinin is mediated by CCK-A receptors. Eur. J. Pharmacol. 173, 233–234 (1989).
Riedy, C.A., Chavez, M., Figlewicz, D.P. & Woods, S.C. Central insulin enhances sensitivity to cholecystokinin. Physiol. Behav. 58, 755–760 (1995).
Matson, C.A., Wiater, M.F., Kuijper, J.L. & Weigle, D.S. Synergy between leptin and cholecystokinin (CCK) to control daily caloric intake. Peptides 18, 1275–1278 (1997).
Matson, C.A., Reid, D.F., Cannon, T.A. & Ritter, R.C. Cholecystokinin and leptin act synergistically to reduce body weight. Am. J. Physiol. 278, R882–R890 (2000).
Cannon, C.M. & Palmiter, R.D. Peptides that regulate food intake: norepinephrine is not required for reduction of feeding induced by cholecystokinin. Am. J. Physiol. Regul. Integr. Comp. Physiol. 284, R1384–R1388 (2003).
Fan, W. et al. Cholecystokinin-mediated suppression of feeding involves the brainstem melanocortin system. Nat. Neurosci. 7, 335–336 (2004).
Appleyard, S.M., et al. Proopiomelanocortin neurons in nucleus tractus solitarius are activated by visceral afferents: regulation by cholecystokinin and opioids. J. Neurosci. (in the press).
Li, S.J. et al. Melanocortin antagonists define two distinct pathways of cardiovascular control by α- and γ-melanocyte-stimulating hormones. J. Neurosci. 16, 5182–5188 (1996).
Adan, R.A. Effects of the melanocortins in the central nervous system. in The Melanocortin Receptors (ed. Cone, R.D.) 109–141 (Humana Press, Totowa, New Jersey, USA, 2000).
Humphreys, M.H. γ-MSH, sodium metabolism, and salt-sensitive hypertension. Am. J. Physiol. Regul. Integr. Comp. Physiol. 268, R417–R430 (2004).
Ni, X-P. et al. Prevention of reflex natriuresis after acute unilateral nephrectomy by melanocortin receptor antagonists. Am. J. Physiol. 274, R931–R938 (1998).
Ni, X.P., Pearce, D., Butler, A.A., Cone, R.D. & Humphreys, M.H. Genetic disruption of gamma-melanocyte-stimulating hormone signaling leads to salt-sensitive hypertension in the mouse. J. Clin. Invest. 111, 1251–1258 (2003).
Martin, W.J. & MacIntyre, D.E. Melanocortin receptors and erectile function. Eur. Urol. 45, 706–713 (2004).
Rosen, R.C., Diamond, L.E., Earle, D.C., Shadiack, A.M. & Molinoff, P.B. Evaluation of the safety, pharmacokinetics and pharmacodynamic effects of subcutaneously administered PT-141, a melanocortin receptor agonist, in healthy male subjects and in patients with an inadequate response to Viagra. Int. J. Impot. Res. 16, 135–142 (2004).
The author would like to thank the many students, postdoctoral fellows and collaborators who participated in the work from his laboratory discussed in this review. The author would also like to thank L. Vaskalis for creating the illustrations. This work was funded by the National Institute of Diabetes and Digestive and Kidney Diseases.
Oregon Health and Science University (OHSU) and R.D.C. hold stock in Orexigen and Neurocrine Biosciences. These companies have licensed technology from OHSU of which Dr. Cone is an inventor. These technologies are used in some of the research reviewed in this article. This potential conflict was reviewed and a management plan approved by the OHSU Conflict of Interest in Research Committee.
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Cone, R. Anatomy and regulation of the central melanocortin system. Nat Neurosci 8, 571–578 (2005). https://doi.org/10.1038/nn1455
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