Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain.

Mountjoy, Kathleen G.; Mortrud, Marty; Low, Malcolm J.; Simerly, Richard B.; Cone, Roger D.

doi:10.1210/mend.8.10.7854347

Cited by 436 publications

(292 citation statements)

References 16 publications

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“…The presence of MC-Rs 1, 2, 3, and 5 on adipocytes (11,12,34) and the inductive effect of MSH on serum FFA levels, are consistent with a direct effect of MSH on lipid metabolism in adipocytes. It is not clear at this point through which MC-R MSH is signaling; it is not likely to signal through MC5-R, because the MC5-R null mutant is not obese (35).…”

Section: Discussionsupporting

confidence: 71%

“…Proopiomelanocortin (POMC) neurons are among the hypothalamic neurons expressing the leptin receptor (10). This leptin binding leads to the secretion of melanocyte stimulating hormone (MSH), which in turn binds to neurons expressing the melanocortin-4 receptor (MC4-R) (11); these neurons then suppress appetite (12)(13)(14). This outline is based on the phenotypes of spontaneous and induced mouse mutants (5,9,13,(15)(16)(17)(18)(19) as well as on the phenotype of homologous mutations in humans (20)(21)(22)(23)(24).…”

mentioning

confidence: 99%

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Integrated control of appetite and fat metabolism by the leptin-proopiomelanocortin pathway

Forbes

Bui

Robinson

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

126

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Leptin deficiency results in a complex obesity phenotype comprising both hyperphagia and lowered metabolism. The hyperphagia results, at least in part, from the absence of induction by leptin of melanocyte stimulating hormone (MSH) secretion in the hypothalamus; the MSH normally then binds to melanocortin-4 receptor expressing neurons and inhibits food intake. The basis for the reduced metabolic rate has been unknown. Here we show that leptin administered to leptin-deficient (ob͞ob) mice results in a large increase in peripheral MSH levels; further, peripheral administration of an MSH analogue results in a reversal of their abnormally low metabolic rate, in an acceleration of weight loss during a fast, in partial restoration of thermoregulation in a cold challenge, and in inducing serum free fatty acid levels. These results support an important peripheral role for MSH in the integration of metabolism with appetite in response to perceived fat stores indicated by leptin levels.R ecent research has outlined a pathway for control of body weight (1-4): leptin, the product of the ob gene in mouse, is produced by adipocytes (5). It circulates to the hypothalamus where it binds to cells expressing the leptin receptor, the product of the db gene in mouse (6-9). Proopiomelanocortin (POMC) neurons are among the hypothalamic neurons expressing the leptin receptor (10). This leptin binding leads to the secretion of melanocyte stimulating hormone (MSH), which in turn binds to neurons expressing the melanocortin-4 receptor (MC4-R) (11); these neurons then suppress appetite (12)(13)(14). This outline is based on the phenotypes of spontaneous and induced mouse mutants (5,9,13,(15)(16)(17)(18)(19) as well as on the phenotype of homologous mutations in humans (20-24). These interpretations are in agreement that leptin is the signal from the fat stores (adipocytes) to the center, and further that MSH regulates appetite. However, there are significant aspects of the mutant phenotypes that suggest both a greater complexity of body weight homeostasis, specifically the integration of appetite and metabolism, and a factor from the central nervous system (CNS) to the periphery mediating this integration.First, pomc͞pomc mutants that completely lack POMC peptides, including MSH, show a phenotype of altered lipid metabolism in addition to hyperphagia. As the fat content of the diet increases, the mice gain weight out of proportion to their food intake (17). This shows a particular inability to use dietary fat for sustaining metabolic rate. And when these pomc͞pomc mutants are treated by peripheral administration of an ␣-MSH analog the mice lose weight and eat less, but the weight loss is much greater than the decrease in appetite (17). Again, this result is consistent with a role for MSH in mobilizing peripheral fat stores.Second, leptin-deficient mice (ob͞ob) show decreased metabolic rate (increased metabolic efficiency; ref. 25), which precedes the onset of obesity. Notably these mutants show: (i) weight gain when pair-fed with normal c...

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Section: Discussionsupporting

confidence: 71%

mentioning

confidence: 99%

Integrated control of appetite and fat metabolism by the leptin-proopiomelanocortin pathway

Forbes

Bui

Robinson

et al. 2001

Proc. Natl. Acad. Sci. U.S.A.

126

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“…Considering that PT-141 also binds with high affinity to the melanocortin type 1 receptor, we cannot rule out a peripheral mechanism of action, especially for the increased return latency after ejaculation. However, PT-141's selective binding to melanocortin type 3 and 4 receptors within the CNS make a central action at hypothalamic and/or limbic structures that control appetitive sexual behavior likely (18,19). An increase in the activation of hypothalamic melanocortin systems induced by estrogen may also explain the peak in female-initiated sexual behaviors that occurs in many species, including humans, during ovulation (20).…”

Section: Discussionmentioning

confidence: 99%

Selective facilitation of sexual solicitation in the female rat by a melanocortin receptor agonist

Pfaus

Shadiack²,

Soest³

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

121

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Disorders of sexual desire affect an estimated 30% of women in North America and Europe, with etiologies based on interpersonal, personal, and physiological factors. There are currently no pharmacological agents approved for use in the treatment of female sexual dysfunction. This is due, in part, to a focus on the effects of experimental drugs on reflexive components of sexual behavior, such as lordosis, in animal models. Here we report that PT-141, a peptide analogue of ␣-melanocyte-stimulating hormone that binds to central melanocortin receptors, selectively stimulates solicitational behaviors in the female rat. This occurs without affecting lordosis, pacing, or other sexual behaviors. PT-141 did not cause generalized motor activation, nor did it affect the perception of sexual reward. A selective pharmacological effect on appetitive sexual behavior in female rats has not been reported previously, and indicates that central melanocortin systems are important in the regulation of female sexual desire. Accordingly, PT-141 may be the first identified pharmacological agent with the capability to treat female sexual desire disorders.

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“…Further work is needed to establish whether additional peripheral hormones regulating energy balance can also influence the HPT axis via the melanocortin system. Although both MC3-and MC4-Rs are abundant in the hypothalamus [47,52], it remains unclear which receptor is the key regulator of energy balance. The obesity phenotype of the MC4-R null mouse strongly supports a role for this receptor in obese states [28].…”

Section: The Melanocortin System and The Hpt Axismentioning

confidence: 99%

Interactions between the melanocortin system and the hypothalamo–pituitary–thyroid axis

et al. 2006

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Localization of the melanocortin-4 receptor (MC4-R) in neuroendocrine and autonomic control circuits in the brain.

Cited by 436 publications

References 16 publications

Integrated control of appetite and fat metabolism by the leptin-proopiomelanocortin pathway

Integrated control of appetite and fat metabolism by the leptin-proopiomelanocortin pathway

Selective facilitation of sexual solicitation in the female rat by a melanocortin receptor agonist

Interactions between the melanocortin system and the hypothalamo–pituitary–thyroid axis

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