Melanocortin 4 receptor

About: Melanocortin 4 receptor is a research topic. Over the lifetime, 798 publications have been published within this topic receiving 46769 citations. The topic is also known as: MC4-R & melanocortin receptor 4.

Antagonism of Central Melanocortin Receptors in Vitro and in Vivo by Agouti-Related Protein

Abstract: Expression of Agouti protein is normally limited to the skin where it affects pigmentation, but ubiquitous expression causes obesity. An expressed sequence tag was identified that encodes Agouti-related protein, whose RNA is normally expressed in the hypothalamus and whose levels were increased eightfold in ob/ob mice. Recombinant Agouti-related protein was a potent, selective antagonist of Mc3r and Mc4r, melanocortin receptor subtypes implicated in weight regulation. Ubiquitous expression of human AGRP complementary DNA in transgenic mice caused obesity without altering pigmentation. Thus, Agouti-related protein is a neuropeptide implicated in the normal control of body weight downstream of leptin signaling.

Role of melanocortinergic neurons in feeding and the agouti obesity syndrome

Abstract: DOMINANT alleles at the agouti locus (A) cause an obesity syndrome in the mouse, as a consequence of ectopic expression of the agouti peptide1–6. This peptide, normally only found in the skin, is a high-affinity antagonist of the melanocyte-stimulating hormone receptor (MC1-R)7, thus explaining the inhibitory effect of agouti on eumelanin pigment synthesis. The agouti peptide is also an antagonist of the hypothalamic melanocortin-4 receptor (MC4-R)7–9. To test the hypothesis that agouti causes obesity by antagonism of hypothalamic melanocortin receptors7, we identified cyclic melanocortin analogues10 that are potent agonists or antagonists of the neural MC3 (refs 11, 12) and MC4 receptors. Intracerebroventricular administration of the agonist, MTII, inhibited feeding in four models of hyperphagia: fasted C57BL/6J, ob/ob, and AY mice, and mice injected with neuropeptide Y. Co-administration of the specific melanocortin antagonist and agouti-mimetic SHU9119 completely blocked this inhibition. Furthermore, administration of SHU9119 significantly enhanced nocturnal feeding, or feeding stimulated by a prior fast. 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.

Clinical spectrum of obesity and mutations in the melanocortin 4 receptor gene.

Abstract: Background Melanocortin 4 receptor (MC4R) deficiency is the commonest monogenic form of obesity. However, the clinical spectrum and mode of inheritance have not been defined, pathophysiological mechanisms leading to obesity are poorly understood, and there is little information regarding genotype–phenotype correlations. Methods We determined the nucleotide sequence of the MC4R gene in 500 probands with severe childhood obesity. Family studies were undertaken to examine cosegregation of identified mutations with obesity. Subjects with MC4R deficiency underwent metabolic and endocrine evaluation; the results were correlated with the signaling properties of mutant receptors. Results Twenty-nine probands (5.8 percent) had mutations in MC4R; 23 were heterozygous, and 6 were homozygous. Mutation carriers had severe obesity, increased lean mass, increased linear growth, hyperphagia, and severe hyperinsulinemia; homozygotes were more severely affected than heterozygotes. Subjects with mutations retaining residual...

Anatomy and regulation of the central melanocortin system.

Abstract: 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.