Gene Symbol: Mc4r
Description: melanocortin 4 receptor
Alias: Mc4-r, Pkcp, melanocortin receptor 4
Species: mouse
Products:     Mc4r

Top Publications

  1. Marks D, Ling N, Cone R. Role of the central melanocortin system in cachexia. Cancer Res. 2001;61:1432-8 pubmed
    ..The final tumor mass is not affected in these animals, providing further support for the potential role of MC4-R antagonism in the treatment of cachexia in disease states. ..
  2. Tallam L, Stec D, Willis M, da Silva A, Hall J. Melanocortin-4 receptor-deficient mice are not hypertensive or salt-sensitive despite obesity, hyperinsulinemia, and hyperleptinemia. Hypertension. 2005;46:326-32 pubmed
    The purpose of this study was to test whether the melanocortin-4 receptor (MC4R) is critical in the development of hypertension associated with obesity and its metabolic disorders...
  3. Halatchev I, Ellacott K, Fan W, Cone R. Peptide YY3-36 inhibits food intake in mice through a melanocortin-4 receptor-independent mechanism. Endocrinology. 2004;145:2585-90 pubmed
    ..Thus, unlike cholecystokinin, PYY(3-36)-induced satiety is atypical, because it does not produce detectable activation of brainstem satiety centers and is not dependent on MC4-R signaling. ..
  4. Cheung W, Yu P, Little B, Cone R, Marks D, Mak R. Role of leptin and melanocortin signaling in uremia-associated cachexia. J Clin Invest. 2005;115:1659-65 pubmed
    ..the hypothesis that uremia-associated cachexia is caused by leptin signaling through the hypothalamic melanocortin receptor 4 (MC4-R)...
  5. Rossi J, Balthasar N, Olson D, Scott M, Berglund E, Lee C, et al. Melanocortin-4 receptors expressed by cholinergic neurons regulate energy balance and glucose homeostasis. Cell Metab. 2011;13:195-204 pubmed publisher
    Melanocortin-4 receptor (MC4R) mutations cause dysregulation of energy balance and hyperinsulinemia. We have used mouse models to study the physiological roles of extrahypothalamic MC4Rs...
  6. Ahn J, Dubern B, Lubrano Berthelier C, Clement K, Karsenty G. Cart overexpression is the only identifiable cause of high bone mass in melanocortin 4 receptor deficiency. Endocrinology. 2006;147:3196-202 pubmed
    ..CART expression in the hypothalamus is increased in mice lacking melanocortin 4 receptor (Mc4r(-/-) mice)...
  7. Tallam L, da Silva A, Hall J. Melanocortin-4 receptor mediates chronic cardiovascular and metabolic actions of leptin. Hypertension. 2006;48:58-64 pubmed
    This study tested whether the melanocortin 4-receptor (MC4R) is essential for the chronic cardiovascular and metabolic actions of leptin...
  8. Nogueiras R, Wiedmer P, Perez Tilve D, Veyrat Durebex C, Keogh J, Sutton G, et al. The central melanocortin system directly controls peripheral lipid metabolism. J Clin Invest. 2007;117:3475-88 pubmed
    ..We report that pharmacological inhibition of melanocortin receptors (Mcr) in rats and genetic disruption of Mc4r in mice directly and potently promoted lipid uptake, triglyceride synthesis, and fat accumulation in white adipose ..
  9. Chen A, Metzger J, Trumbauer M, Guan X, Yu H, Frazier E, et al. Role of the melanocortin-4 receptor in metabolic rate and food intake in mice. Transgenic Res. 2000;9:145-54 pubmed
    ..We conclude that MC-4R can mediate control of both metabolic rate and food intake in mice. We infer that a role for MC-3R in mediating the acute effects of MT-II on basal metabolic rate and food intake in wildtype mice seems limited. ..

More Information


  1. Sohn J, Harris L, Berglund E, Liu T, Vong L, Lowell B, et al. Melanocortin 4 receptors reciprocally regulate sympathetic and parasympathetic preganglionic neurons. Cell. 2013;152:612-9 pubmed publisher
    ..Notably, obese patients with MC4R mutations are hyperinsulinemic and resistant to obesity-induced hypertension...
  2. Chen H, Trumbauer M, Chen A, Weingarth D, Adams J, Frazier E, et al. Orexigenic action of peripheral ghrelin is mediated by neuropeptide Y and agouti-related protein. Endocrinology. 2004;145:2607-12 pubmed
    ..Here we describe treatment of Agrp(-/-);Npy(-/-) and Mc3r(-/-);Mc4r(-/-) double knockout mice as well as Npy(-/-) and Agrp(-/-) single knockout mice with either ghrelin or an orally ..
  3. Irani B, Xiang Z, Moore M, Mandel R, Haskell Luevano C. Voluntary exercise delays monogenetic obesity and overcomes reproductive dysfunction of the melanocortin-4 receptor knockout mouse. Biochem Biophys Res Commun. 2005;326:638-44 pubmed
    The melanocortin system is involved in hypothalamic regulation of energy homeostasis. The melanocortin-4 receptor (MC4R) has been linked to both obesity and reproductive dysfunction...
  4. Gautron L, Lee C, Funahashi H, Friedman J, Lee S, Elmquist J. Melanocortin-4 receptor expression in a vago-vagal circuitry involved in postprandial functions. J Comp Neurol. 2010;518:6-24 pubmed publisher
    ..In the current study, we investigated melanocortin-4 receptor (MC4R) expression in the nodose ganglion, where the cell bodies of vagal sensory afferents reside...
  5. Gout J, Sarafian D, Tirard J, Blondet A, Vigier M, Rajas F, et al. Leptin infusion and obesity in mouse cause alterations in the hypothalamic melanocortin system. Obesity (Silver Spring). 2008;16:1763-9 pubmed publisher
    ..Moreover, when the metabolic status is highly degraded (with all characteristics of a type 2 diabetes), other regulatory mechanisms (independent of leptin) can also take place. ..
  6. Perez Tilve D, Hofmann S, Basford J, Nogueiras R, Pfluger P, Patterson J, et al. Melanocortin signaling in the CNS directly regulates circulating cholesterol. Nat Neurosci. 2010;13:877-82 pubmed publisher
    ..Our data suggest that a neural circuit in the brain is directly involved in the control of cholesterol metabolism by the liver. ..
  7. Grosse J, Tarnow P, Römpler H, Schneider B, Sedlmeier R, Huffstadt U, et al. N-ethyl-N-nitrosourea-based generation of mouse models for mutant G protein-coupled receptors. Physiol Genomics. 2006;26:209-17 pubmed
    ..members of the large superfamily of G protein-coupled receptors (GPCR), melanocortin type 3 (Mc3r) and type 4 (Mc4r) receptors, and the orphan chemoattractant receptor GPR33, were used as model targets to prove the feasibility of ..
  8. Hsu R, Taylor J, Newton S, Alvaro J, Haile C, Han G, et al. Blockade of melanocortin transmission inhibits cocaine reward. Eur J Neurosci. 2005;21:2233-42 pubmed
    ..Modulation of cocaine reward is a novel action of the melanocortin-MC4-R system and could be targeted for the development of new medications for cocaine addiction. ..
  9. Itoh M, Suganami T, Nakagawa N, Tanaka M, Yamamoto Y, Kamei Y, et al. Melanocortin 4 receptor-deficient mice as a novel mouse model of nonalcoholic steatohepatitis. Am J Pathol. 2011;179:2454-63 pubmed publisher
    ..Herein we report that melanocortin 4 receptor-deficient mice (MC4R-KO) develop steatohepatitis when fed a high-fat diet, which is associated with obesity, insulin resistance, and ..
  10. Zechner J, Mirshahi U, Satapati S, Berglund E, Rossi J, Scott M, et al. Weight-independent effects of roux-en-Y gastric bypass on glucose homeostasis via melanocortin-4 receptors in mice and humans. Gastroenterology. 2013;144:580-590.e7 pubmed publisher
    ..Melanocortin-4 receptors (MC4R) have weight-independent effects on glucose homeostasis, via autonomic neurons, and also might contribute to weight ..
  11. Butler A, Marks D, Fan W, Kuhn C, Bartolome M, Cone R. Melanocortin-4 receptor is required for acute homeostatic responses to increased dietary fat. Nat Neurosci. 2001;4:605-11 pubmed
    In response to moderately increased dietary fat content, melanocortin-4 receptor-null mutant (MC4R-/-) mice exhibit hyperphagia and accelerated weight gain compared to wild-type mice...
  12. Van der Ploeg L, Martin W, Howard A, Nargund R, Austin C, Guan X, et al. A role for the melanocortin 4 receptor in sexual function. Proc Natl Acad Sci U S A. 2002;99:11381-6 pubmed
    ..a combination of genetic, pharmacological, and anatomical approaches, we show that the melanocortin 4 receptor (MC4R), implicated in the control of food intake and energy expenditure, also modulates erectile function and sexual ..
  13. Srisai D, Gillum M, Panaro B, Zhang X, Kotchabhakdi N, Shulman G, et al. Characterization of the hyperphagic response to dietary fat in the MC4R knockout mouse. Endocrinology. 2011;152:890-902 pubmed publisher
    ..Defective melanocortin signaling causes hyperphagic obesity in humans and the melanocortin-4 receptor knockout mouse (MC4R(-/-)). The human disease most commonly presents, however, as haploinsufficiency of the MC4R...
  14. Marks D, Butler A, Turner R, Brookhart G, Cone R. Differential role of melanocortin receptor subtypes in cachexia. Endocrinology. 2003;144:1513-23 pubmed
    ..These data underscore the importance of central melanocortin signaling in weight homeostasis and demonstrate differential effects of MC3-R and MC4-R blockade on the development of cachexia. ..
  15. Huszar D, Lynch C, Fairchild Huntress V, Dunmore J, Fang Q, Berkemeier L, et al. Targeted disruption of the melanocortin-4 receptor results in obesity in mice. Cell. 1997;88:131-41 pubmed
    ..Our data identify a novel signaling pathway in the mouse for body weight regulation and support a model in which the primary mechanism by which agouti induces obesity is chronic antagonism of the MC4-R. ..
  16. Voss Andreae A, Murphy J, Ellacott K, Stuart R, Nillni E, Cone R, et al. Role of the central melanocortin circuitry in adaptive thermogenesis of brown adipose tissue. Endocrinology. 2007;148:1550-60 pubmed
    The central melanocortin 4 receptor (MC4R) plays a critical role in energy homeostasis, although little is known regarding its role in the regulation of adaptive thermogenesis of brown adipose tissue (BAT)...
  17. Balthasar N, Dalgaard L, Lee C, Yu J, Funahashi H, Williams T, et al. Divergence of melanocortin pathways in the control of food intake and energy expenditure. Cell. 2005;123:493-505 pubmed
    ..To identify the functionally relevant sites of MC4R expression, we generated a loxP-modified, null Mc4r allele (loxTB Mc4r) that can be reactivated by Cre-recombinase...
  18. Mountjoy K, Mortrud M, Low M, Simerly R, Cone R. Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain. Mol Endocrinol. 1994;8:1298-308 pubmed
    ..The high degree of conservation, distinct pharmacology, and unique neuronal distribution of the MC4 receptor suggest specific and complex roles for the melanocortin peptides in neuroendocrine and autonomic control. ..
  19. Gantz I, Miwa H, Konda Y, Shimoto Y, Tashiro T, Watson S, et al. Molecular cloning, expression, and gene localization of a fourth melanocortin receptor. J Biol Chem. 1993;268:15174-9 pubmed
    ..Using the technique of fluorescent in situ hybridization, the gene encoding the melanocortin-4 receptor was localized to chromosome 18 (q21.3). ..
  20. Kiefer L, Veal J, Mountjoy K, Wilkison W. Melanocortin receptor binding determinants in the agouti protein. Biochemistry. 1998;37:991-7 pubmed
    ..Mutation of Phe117 to alanine causes a similar increase in agouti KI app at melanocortin receptor 4. Substitution of agouti residue Asp108 with alanine results in large increases in KI app for all three ..
  21. Samuelsson A, Mullier A, Maicas N, Oosterhuis N, Eun Bae S, Novoselova T, et al. Central role for melanocortin-4 receptors in offspring hypertension arising from maternal obesity. Proc Natl Acad Sci U S A. 2016;113:12298-12303 pubmed
    Melanocortin-4 receptor (Mc4r)-expressing neurons in the autonomic nervous system, particularly in the paraventricular nucleus of the hypothalamus (PVH), play an essential role in blood pressure (BP) control...
  22. Ste Marie L, Miura G, Marsh D, Yagaloff K, Palmiter R. A metabolic defect promotes obesity in mice lacking melanocortin-4 receptors. Proc Natl Acad Sci U S A. 2000;97:12339-44 pubmed
    Melanocortin-4 receptor (Mc4r)-null mice exhibit late-onset obesity...
  23. Agosti F, Lopez Soto E, Cabral A, Castrogiovanni D, Schioth H, Perello M, et al. Melanocortin 4 receptor activation inhibits presynaptic N-type calcium channels in amygdaloid complex neurons. Eur J Neurosci. 2014;40:2755-65 pubmed publisher
    The melanocortin 4 receptor (MC4R) is a G protein-coupled receptor involved in food intake and energy expenditure regulation...
  24. Lede V, Meusel A, Garten A, Popkova Y, Penke M, Franke C, et al. Altered hepatic lipid metabolism in mice lacking both the melanocortin type 4 receptor and low density lipoprotein receptor. PLoS ONE. 2017;12:e0172000 pubmed publisher
    ..Comparative analyses of our data with previous studies allowed for the identification of common changes and genotype-specific components and pathways involved in obesity-associated NAFLD. ..
  25. Overton J, Leibel R. Mahoganoid and mahogany mutations rectify the obesity of the yellow mouse by effects on endosomal traffic of MC4R protein. J Biol Chem. 2011;286:18914-29 pubmed publisher suppressors of ASP action, blocking its antagonizing effects on the melanocortin 1 and 4 receptors (MC1R and MC4R) in the skin and the brain, respectively, via unknown mechanisms...
  26. Marsh D, Hollopeter G, Huszar D, Laufer R, Yagaloff K, Fisher S, et al. Response of melanocortin-4 receptor-deficient mice to anorectic and orexigenic peptides. Nat Genet. 1999;21:119-22 pubmed
    ..of leptin, the leptin receptor, alpha-melanocyte stimulating hormones (alpha-MSH) and the melanocortin-4 receptor (Mc4r) all lead to obesity in mammals...
  27. Arens J, Moar K, Eiden S, Weide K, Schmidt I, Mercer J, et al. Age-dependent hypothalamic expression of neuropeptides in wild-type and melanocortin-4 receptor-deficient mice. Physiol Genomics. 2003;16:38-46 pubmed
    In young (35- to 56-day-old) and middle-aged (9-mo-old) wild-type (+/+) and melanocortin-4 receptor (MC4R)-deficient (+/-, -/-) mice, expressions of neuropeptide Y (NPY), agouti-related protein (AGRP), pro-opiomelanocortin (POMC), and ..
  28. Gao Y, Ottaway N, Schriever S, Legutko B, García Cáceres C, de la Fuente E, et al. Hormones and diet, but not body weight, control hypothalamic microglial activity. Glia. 2014;62:17-25 pubmed publisher
    ..obese ob/ob (leptin deficient), db/db (leptin-receptor mutation), and Type-4 melanocortin receptor knockout (MC4R KO) mice on either a HFD or on standardized chow (SC) diet...
  29. Kawahara Y, Grimberg A, Teegarden S, Mombereau C, Liu S, Bale T, et al. Dysregulated editing of serotonin 2C receptor mRNAs results in energy dissipation and loss of fat mass. J Neurosci. 2008;28:12834-44 pubmed publisher
    ..Melanocortin 4 receptor (MC4R) regulates energy homeostasis (Balthasar et al., 2005; Heisler et al., 2006; Lam et al...
  30. Asai M, Ramachandrappa S, Joachim M, Shen Y, Zhang R, Nuthalapati N, et al. Loss of function of the melanocortin 2 receptor accessory protein 2 is associated with mammalian obesity. Science. 2013;341:275-8 pubmed publisher
    ..Mrap2 interacts directly with melanocortin 4 receptor (Mc4r), a protein previously implicated in mammalian obesity, and it enhances Mc4r-mediated generation of the second ..
  31. Zhu X, Krasnow S, Roth Carter Q, Levasseur P, Braun T, Grossberg A, et al. Hypothalamic signaling in anorexia induced by indispensable amino acid deficiency. Am J Physiol Endocrinol Metab. 2012;303:E1446-58 pubmed publisher
    ..Our observations indicate that the hypothalamic melanocortin system plays a minor role in acute, but not chronic, IAADA and suggest that the restraint on feeding is analogous to that observed after chronic dehydration...
  32. Mavrikaki M, Girardet C, Kern A, Faruzzi Brantley A, Miller C, Macarthur H, et al. Melanocortin-3 receptors in the limbic system mediate feeding-related motivational responses during weight loss. Mol Metab. 2016;5:566-579 pubmed publisher
    ..Mesolimbic MC3Rs mediate enhanced motivational responses during CR. However, they are insufficient to restore normal caloric loading when food is presented during CR and do not affect metabolic conditions altering nutrient partitioning. ..
  33. Krashes M, Lowell B, Garfield A. Melanocortin-4 receptor-regulated energy homeostasis. Nat Neurosci. 2016;19:206-19 pubmed publisher
    ..Drawing on recent advances in neuroscience and genetic technologies, we consider the structure and function of the melanocortin-4 receptor circuitry and its role in energy homeostasis. ..
  34. Rahmouni K, Haynes W, Morgan D, Mark A. Role of melanocortin-4 receptors in mediating renal sympathoactivation to leptin and insulin. J Neurosci. 2003;23:5998-6004 pubmed
    ..In addition, the renal sympathoexcitatory responses to leptin and insulin are dependent on the MC-4R, demonstrating an important role for the MC-4R in the regulation of renal sympathetic nerve outflow by leptin and insulin. ..
  35. De Jonghe B, Hayes M, Zimmer D, Kanoski S, Grill H, Bence K. Food intake reductions and increases in energetic responses by hindbrain leptin and melanotan II are enhanced in mice with POMC-specific PTP1B deficiency. Am J Physiol Endocrinol Metab. 2012;303:E644-51 pubmed publisher
    ..WT animals. In addition, KO mice displayed elevated hindbrain and hypothalamic MC4R mRNA expression...
  36. Garcia Tornadú I, Diaz Torga G, Risso G, Silveyra P, Cataldi N, Ramirez M, et al. Hypothalamic orexin, OX1, alphaMSH, NPY and MCRs expression in dopaminergic D2R knockout mice. Neuropeptides. 2009;43:267-74 pubmed publisher
    ..No differences were found in hypothalamic NPY, MC3R or MC4R concentration...
  37. Gautron L, Lee C, Lee S, Elmquist J. Melanocortin-4 receptor expression in different classes of spinal and vagal primary afferent neurons in the mouse. J Comp Neurol. 2012;520:3933-48 pubmed publisher
    Melanocortin-4 receptor (MC4R) ligands are known to modulate nociception, but the site of action of MC4R signaling on nociception remains to be elucidated...
  38. Chaly A, Srisai D, Gardner E, Sebag J. The Melanocortin Receptor Accessory Protein 2 promotes food intake through inhibition of the Prokineticin Receptor-1. elife. 2016;5: pubmed publisher
    ..MRAP2 mediates its action in part through the potentiation of the MC4R, however, it is clear that MRAP2 is expressed in tissues that do not express MC4R, and that the deletion of MRAP2 ..
  39. Xia T, Cheng Y, Zhang Q, Xiao F, Liu B, Chen S, et al. S6K1 in the central nervous system regulates energy expenditure via MC4R/CRH pathways in response to deprivation of an essential amino acid. Diabetes. 2012;61:2461-71 pubmed
    ..Taken together, our studies provide a new perspective for understanding the regulation of energy expenditure by the CNS and the importance of cross-talk between nutritional control and regulation of endocrine signals. ..
  40. Atalayer D, Robertson K, Haskell Luevano C, Andreasen A, Rowland N. Food demand and meal size in mice with single or combined disruption of melanocortin type 3 and 4 receptors. Am J Physiol Regul Integr Comp Physiol. 2010;298:R1667-74 pubmed publisher
    Mice with homozygous genetic disruption of the melanocortin-4 receptor gene (MC4R-/-) are known to be hyperphagic and become obese, while those with disruption of the melanocortin-3 receptor gene (MC3R-/-) do not become markedly obese...
  41. Dumont L, Wu C, Aschkenasi C, Elmquist J, Lowell B, Mountjoy K. Mouse melanocortin-4 receptor gene 5'-flanking region imparts cell specific expression in vitro. Mol Cell Endocrinol. 2001;184:173-85 pubmed
    ..The mMC4-R gene structure and reporter chimerics provide a fundamental framework for the identification of specific factors regulating MC4-R gene expression. ..
  42. do Carmo J, da Silva A, Rushing J, Pace B, Hall J. Differential control of metabolic and cardiovascular functions by melanocortin-4 receptors in proopiomelanocortin neurons. Am J Physiol Regul Integr Comp Physiol. 2013;305:R359-68 pubmed publisher
    We examined the role of melanocortin-4 receptors (MC4R) in proopiomelanocortin (Pomc) neurons in regulating metabolic and cardiovascular functions...
  43. Guo S, Xie Y, Fan J, Ji F, Wang S, Fei H. α-Melanocyte stimulating hormone attenuates dexamethasone-induced osteoblast damages through activating melanocortin receptor 4-SphK1 signaling. Biochem Biophys Res Commun. 2016;469:281-7 pubmed publisher
    ..b>Melanocortin receptor 4 (MC4R) acts as the receptor of α-MSH in mediating its actions in osteoblasts...
  44. Tsumori T, Oka T, Yokota S, Niu J, Yasui Y. Intrapancreatic ganglia neurons receive projection fibers from melanocortin-4 receptor-expressing neurons in the dorsal motor nucleus of the vagus nerve of the mouse. Brain Res. 2013;1537:132-42 pubmed publisher
    Melanocortin-4 receptor (MC4R)-expressing neurons are widely distributed in the central nervous system and play a crucial role in a variety of physiological functions including energy and glucose/insulin homeostasis...
  45. Tucker K, Godbey S, Thiebaud N, Fadool D. Olfactory ability and object memory in three mouse models of varying body weight, metabolic hormones, and adiposity. Physiol Behav. 2012;107:424-32 pubmed publisher
    ..3-null), and 3) a genetic model of obesity as a result of a gene-targeted deletion of the melanocortin 4 receptor (MC4R-null)...
  46. Zemel M. Agouti/melanocortin interactions with leptin pathways in obesity. Nutr Rev. 1998;56:271-4 pubmed
    ..Both of these actions occur via a Ca(2+)-dependent mechanism, suggesting that modulation of adipocyte Ca2+ transport may be a key target for further investigation. ..
  47. Wankhade U, Good D. Melanocortin 4 receptor is a transcriptional target of nescient helix-loop-helix-2. Mol Cell Endocrinol. 2011;341:39-47 pubmed publisher
    Melanocortin 4 receptor (Mc4r/MC4R) is a G-Protein coupled receptor that is expressed in the hypothalamus and implicated in body weight control. Mutations in MC4R are the most frequent cause of monogenetic forms of human obesity...
  48. Wilson B, Ollmann M, Barsh G. The role of agouti-related protein in regulating body weight. Mol Med Today. 1999;5:250-6 pubmed
    ..two potential downstream mediators, agouti-related protein (Agrp) and its receptor, the melanocortin-4 receptor (Mc4r), have been identified...
  49. Takeda S, Elefteriou F, Levasseur R, Liu X, Zhao L, Parker K, et al. Leptin regulates bone formation via the sympathetic nervous system. Cell. 2002;111:305-17 pubmed
    ..None of these manipulations affects body weight. This study demonstrates a leptin-dependent neuronal regulation of bone formation with potential therapeutic implications for osteoporosis. ..
  50. Ghamari Langroudi M, Srisai D, Cone R. Multinodal regulation of the arcuate/paraventricular nucleus circuit by leptin. Proc Natl Acad Sci U S A. 2011;108:355-60 pubmed publisher
    Melanocortin-4 receptor (MC4R) is critical for energy homeostasis, and the paraventricular nucleus of the hypothalamus (PVN) is a key site of MC4R action...
  51. Elefteriou F, Ahn J, Takeda S, Starbuck M, Yang X, Liu X, et al. Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature. 2005;434:514-20 pubmed
    ..Our study establishes that leptin-regulated neural pathways control both aspects of bone remodelling, and demonstrates that integrity of sympathetic signalling is necessary for the increase in bone resorption caused by gonadal failure. ..
  52. do Carmo J, Tallam L, Roberts J, Brandon E, Biglane J, da Silva A, et al. Impact of obesity on renal structure and function in the presence and absence of hypertension: evidence from melanocortin-4 receptor-deficient mice. Am J Physiol Regul Integr Comp Physiol. 2009;297:R803-12 pubmed publisher
    ..blood pressure salt sensitivity were assessed in 52- to 55-wk-old normotensive melanocortin-4 receptor-deficient (MC4R-/-) mice and lean C57BL/6J wild-type (WT) mice and in 22-wk-old MC4R-/- and WT mice made hypertensive by N(G)-nitro-..
  53. Bera T, Liu X, Yamada M, Gavrilova O, Mezey E, Tessarollo L, et al. A model for obesity and gigantism due to disruption of the Ankrd26 gene. Proc Natl Acad Sci U S A. 2008;105:270-5 pubmed
    ..These results show that alterations in an unidentified gene can lead to obesity and identify a molecular target for the treatment of obesity...
  54. Hao Y, Tian X, Liu T, Liu C, Xiang H, Zhang J. MC4R expression in pedunculopontine nucleus involved in the modulation of midbrain dopamine system. Int J Clin Exp Pathol. 2015;8:2039-43 pubmed
    ..tegmental nucleus (PPTg) in processing aversive stimuli to dopamine systems, and melanocortin-4 receptor (MC4R) are broadly expressed by the neurons in the PPTg, but the exact neurosubstrate underlying the regulation of ..
  55. Butler A, Cone R. Knockout studies defining different roles for melanocortin receptors in energy homeostasis. Ann N Y Acad Sci. 2003;994:240-5 pubmed
    ..Two melanocortin receptors (MC3R, MC4R) are expressed in brain regions receiving projections of POMC fibers, most of which also receive projections from a ..
  56. Trevaskis J, Gawronska Kozak B, Sutton G, McNeil M, Stephens J, Smith S, et al. Role of adiponectin and inflammation in insulin resistance of Mc3r and Mc4r knockout mice. Obesity (Silver Spring). 2007;15:2664-72 pubmed
    ..b>Mc4r deficiency was also associated with high levels of macrophage infiltration of adipose tissue, again exacerbated by ..
  57. Meehan T, Tabeta K, Du X, Woodward L, Firozi K, Beutler B, et al. Point mutations in the melanocortin-4 receptor cause variable obesity in mice. Mamm Genome. 2006;17:1162-71 pubmed
    Mutations in the melanocortin-4 receptor (MC4R) are associated with early-onset obesity in humans. Furthermore, a null Mc4r allele in mice leads to severe obesity due to hyperphagia and decreased energy expenditure...
  58. Arble D, Holland J, Ottaway N, Sorrell J, Pressler J, Morano R, et al. The melanocortin-4 receptor integrates circadian light cues and metabolism. Endocrinology. 2015;156:1685-91 pubmed publisher
    ..between circadian disruption and the control of glucose homeostasis mediated through the melanocortin-4 receptor (Mc4r). Mc4r-deficient mice exhibit exaggerated circadian fluctuations in baseline blood glucose and glucose tolerance...
  59. Ottaway N, Mahbod P, Rivero B, Norman L, Gertler A, D Alessio D, et al. Diet-induced obese mice retain endogenous leptin action. Cell Metab. 2015;21:877-82 pubmed publisher
    ..These findings demonstrate that hyperleptinemic DIO mice retain leptin suppression of feeding comparable to lean mice and counter the view that resistance to endogenous leptin contributes to the persistence of DIO in mice. ..
  60. Arteaga Solis E, Zee T, Emala C, Vinson C, Wess J, Karsenty G. Inhibition of leptin regulation of parasympathetic signaling as a cause of extreme body weight-associated asthma. Cell Metab. 2013;17:35-48 pubmed publisher
    ..These findings may be of use in the management of obesity-associated asthma. ..
  61. Gantz I, Shimoto Y, Konda Y, Miwa H, Dickinson C, Yamada T. Molecular cloning, expression, and characterization of a fifth melanocortin receptor. Biochem Biophys Res Commun. 1994;200:1214-20 pubmed
    ..Northern blot analysis demonstrated the expression of mMC5R mRNA in mouse skeletal muscle, lung, spleen, and brain. ..
  62. Fan W, Boston B, Kesterson R, Hruby V, Cone R. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature. 1997;385:165-8 pubmed
    ..Our data show that melanocortinergic neurons exert a tonic inhibition of feeding behaviour. Chronic disruption of this inhibitory signal is a likely explanation of the agouti obesity syndrome. ..
  63. Albarado D, McClaine J, Stephens J, Mynatt R, Ye J, Bannon A, et al. Impaired coordination of nutrient intake and substrate oxidation in melanocortin-4 receptor knockout mice. Endocrinology. 2004;145:243-52 pubmed
    Mutations in the melanocortin-4 receptor (MC4R) are associated with obesity...
  64. Shaw A, Irani B, Moore M, Haskell Luevano C, Millard W. Ghrelin-induced food intake and growth hormone secretion are altered in melanocortin 3 and 4 receptor knockout mice. Peptides. 2005;26:1720-7 pubmed
    ..signaling in ghrelin-induced food intake by studying melanocortin 3 and 4 receptor knockout (MC3R KO and MC4R KO) mice...
  65. Watson E, Hahm S, Mizuno T, Windsor J, Montgomery C, Scherer P, et al. VGF ablation blocks the development of hyperinsulinemia and hyperglycemia in several mouse models of obesity. Endocrinology. 2005;146:5151-63 pubmed
    ..models of obesity that are also susceptible to adult onset diabetes mellitus, including A(y)/a agouti, ob/ob, and MC4R(-)/MC4R(-) mice...
  66. Sutton G, Trevaskis J, Hulver M, McMillan R, Markward N, Babin M, et al. Diet-genotype interactions in the development of the obese, insulin-resistant phenotype of C57BL/6J mice lacking melanocortin-3 or -4 receptors. Endocrinology. 2006;147:2183-96 pubmed
    ..Little is known about how Mc3r or Mc4r genotype, diet, and obesity affect insulin sensitivity...
  67. de Souza J, Butler A, Cone R. Disproportionate inhibition of feeding in A(y) mice by certain stressors: a cautionary note. Neuroendocrinology. 2000;72:126-32 pubmed
    ..Furthermore, these data demonstrate the need for exercising extreme caution in designing experiments to analyze feeding behavior and metabolism in genetic or pharmacological models involving perturbation of the melanocortin system. ..
  68. Pan X, Song Y, Liu C, Xiang H, Lu C. Melanocortin-4 receptor expression in the rostral ventromedial medulla involved in modulation of nociception in transgenic mice. J Huazhong Univ Sci Technolog Med Sci. 2013;33:195-198 pubmed publisher
    ..In the current study, we investigated melanocortin-4 receptor (MC4R) expression in the RVM, where the neurons involved in modulation of nociception reside...
  69. Semple E, Hill J. Sim1 Neurons Are Sufficient for MC4R-Mediated Sexual Function in Male Mice. Endocrinology. 2018;159:439-449 pubmed publisher
    ..Several studies specifically implicate the melanocortin 4 receptor (MC4R) in the central control of sexual function, but the specific neural circuitry involved is unknown...
  70. Shen Y, Fu W, Cheng E, Fu A, Ip N. Melanocortin-4 receptor regulates hippocampal synaptic plasticity through a protein kinase A-dependent mechanism. J Neurosci. 2013;33:464-72 pubmed publisher memory acquisition and retention, the functional role of its cognate receptor, melanocortin-4 receptor (MC4R), in hippocampal-dependent synaptic plasticity has not been explored...
  71. Li X, Lytton J. An essential role for the K+-dependent Na+/Ca2+-exchanger, NCKX4, in melanocortin-4-receptor-dependent satiety. J Biol Chem. 2014;289:25445-59 pubmed publisher
    ..Feeding and satiety are coordinated centrally by melanocortin-4 receptors (MC4R) in neurons of the hypothalamic paraventricular nucleus (PVN)...
  72. Gonçalves G, Li W, Garcia A, Figueiredo M, Bjørbæk C. Hypothalamic agouti-related peptide neurons and the central melanocortin system are crucial mediators of leptin's antidiabetic actions. Cell Rep. 2014;7:1093-103 pubmed publisher
    ..Furthermore, normalization of blood glucose by leptin is blunted in Lep(ob/ob)/MC4R-null mice, but not in Lep(ob/ob) mice lacking neuropeptide Y (NPY) or gamma-aminobutyric acid (GABA) in AgRP ..
  73. Cui H, Mason B, Lee C, Nishi A, Elmquist J, Lutter M. Melanocortin 4 receptor signaling in dopamine 1 receptor neurons is required for procedural memory learning. Physiol Behav. 2012;106:201-10 pubmed publisher
    ..While the melanocortin 4 receptor (MC4R) has previously been shown to regulate food intake and energy expenditure, little is known about its role in food ..
  74. Fellmann L, Nascimento A, Tibirica E, Bousquet P. Murine models for pharmacological studies of the metabolic syndrome. Pharmacol Ther. 2013;137:331-40 pubmed publisher
    ..Zucker, ZDF, Wistar Ottawa Karlsburg W, and Otsuka Long-Evans Tokushima Fatty rats, ob/ob, db/db, agouti yellow and Mc4R KO mice. The second part of this review is dedicated to metabolic syndrome models obtained by high fat feeding.
  75. Panaro B, Tough I, Engelstoft M, Matthews R, Digby G, Møller C, et al. The melanocortin-4 receptor is expressed in enteroendocrine L cells and regulates the release of peptide YY and glucagon-like peptide 1 in vivo. Cell Metab. 2014;20:1018-29 pubmed publisher
    The melanocortin-4 receptor (MC4R) is expressed in the brainstem and vagal afferent nerves and regulates a number of aspects of gastrointestinal function...
  76. Song Y, Liu T, Feng L, Zhang T, Xiang H. Melanocortin-4 receptor expression in the cuneiform nucleus is involved in modulation of opioidergic signaling. J Huazhong Univ Sci Technolog Med Sci. 2015;35:662-665 pubmed publisher
    ..Using a melanocortin-4 receptor (MC4R)-green fluorescent protein (GFP) reporter knockin mouse, we showed that a large number of MC4R-GFP-positive neurons ..
  77. Tanabe K, Gamo K, Aoki S, Wada K, Kiyama H. Melanocortin receptor 4 is induced in nerve-injured motor and sensory neurons of mouse. J Neurochem. 2007;101:1145-52 pubmed
    We previously identified melanocortin receptor 4 (MC4R) in a search for genes associated with hypoglossal nerve regeneration...
  78. Ni X, Butler A, Cone R, Humphreys M. Central receptors mediating the cardiovascular actions of melanocyte stimulating hormones. J Hypertens. 2006;24:2239-46 pubmed
    ..of synthetic alpha or gamma-MSH intravenously or intracerebroventricularly to anesthetized wild-type (Mc3r+/+, Mc4r+/+) mice and mice with targeted disruption of the gamma-MSH receptor (Mc3r-/-) or the melanocortin 4 receptor (Mc4r-..
  79. Ringholm A, Klovins J, Fredriksson R, Poliakova N, Larson E, Kukkonen J, et al. Presence of melanocortin (MC4) receptor in spiny dogfish suggests an ancient vertebrate origin of central melanocortin system. Eur J Biochem. 2003;270:213-21 pubmed
    ..Conservation of gene structure, pharmacological properties and tissue distribution suggests that this receptor may have similar roles in sharks as in mammals and that these were established more than 450 million years ago...
  80. Karlsson Lindahl L, Schmidt L, Haage D, Hansson C, Taube M, Egecioglu E, et al. Heparanase affects food intake and regulates energy balance in mice. PLoS ONE. 2012;7:e34313 pubmed publisher
    Mutation of the melanocortin-receptor 4 (MC4R) is the most frequent cause of severe obesity in humans. Binding of agouti-related peptide (AgRP) to MC4R involves the co-receptor syndecan-3, a heparan sulfate proteoglycan...
  81. Cui H, Sohn J, Gautron L, Funahashi H, Williams K, Elmquist J, et al. Neuroanatomy of melanocortin-4 receptor pathway in the lateral hypothalamic area. J Comp Neurol. 2012;520:4168-83 pubmed publisher
    The central melanocortin system regulates body energy homeostasis including the melanocortin-4 receptor (MC4R)...