The regulated release of anorexigenic α-MSH and orexigenic Agouti-related protein (AgRP) from discrete hypothalamic arcuate neurons onto common target sites in the CNS plays a fundamental role in the regulation of energy homeostasis. Both peptides bind with high affinity to the melanocortin-4 receptor (MC4R); existing data showα-MSH is an agonist that couples the receptor to the Gαs signaling pathway1, while AgRP binds competitively to block α-MSH binding2, and block the constitutive activity mediated by the ligand-mimetic amino terminal domain of the receptor3. Here, we show that regulation of firing activity of hypothalamic PVN neurons by α-MSH and AgRP can be mediated independently of Gαs signaling by ligand-induced coupling of MC4R to closure of inwardly rectifying potassium channel, Kir7.1. Further, AgRP is a biased agonist that hyperpolarizes neurons by binding to MC4R and opening Kir7.1, independently of its inhibition of α-MSH binding. Consequently, Kir7.1 signaling appears central to melanocortin-mediated regulation of energy homeostasis within the PVN. Coupling of MC4R to Kir7.1 may explain unusual aspects of the control of energy homeostasis by melanocortin signaling, including the gene dosage effect of MC4R4, and the sustained effects of AgRP on food intake5.
The melanocortin peptides derived from pro-opiomelanocortin (POMC) were originally understood in terms of the biological actions of α-melanocyte-stimulating hormone (α-MSH) on pigmentation and adrenocorticotrophic hormone on adrenocortical glucocorticoid production. However, the discovery of POMC mRNA and melanocortin peptides in the CNS generated activities directed at understanding the direct biological actions of melanocortins in the brain. Ultimately, discovery of unique melanocortin receptors expressed in the CNS, the melanocortin-3 (MC3R) and melanocortin-4 (MC4R) receptors, led to the development of pharmacological tools and genetic models leading to the demonstration that the central melanocortin system plays a critical role in the regulation of energy homeostasis. Indeed, mutations in MC4R are now known to be the most common cause of early onset syndromic obesity, accounting for 2–5% of all cases. This review discusses the history of these discoveries, as well as the latest work attempting to understand the molecular and cellular basis of regulation of feeding and energy homeostasis by the predominant melanocortin peptide in the CNS, α-MSH.
Melanocortin-4 receptor (MC4R) is critical for energy homeostasis, and the paraventricular nucleus of the hypothalamus (PVN) is a key site of MC4R action. Most studies suggest that leptin regulates PVN neurons indirectly, by binding to receptors in the arcuate nucleus or ventromedial hypothalamus and regulating release of products like α-melanocyte-stimulating hormone (α-MSH), neuropeptide Y (NPY), glutamate, and GABA from firstorder neurons onto the MC4R PVN cells. Here, we investigate mechanisms underlying regulation of activity of these neurons under various metabolic states by using hypothalamic slices from a transgenic MC4R-GFP mouse to record directly from MC4R neurons. First, we show that in vivo leptin levels regulate the tonic firing rate of second-order MC4R PVN neurons, with fasting increasing firing frequency in a leptin-dependent manner. We also show that, although leptin inhibits these neurons directly at the postsynaptic membrane, α-MSH and NPY potently stimulate and inhibit the cells, respectively. Thus, in contrast with the conventional model of leptin action, the primary control of MC4R PVN neurons is unlikely to be mediated by leptin action on arcuate NPY/agouti-related protein and proopiomelanocortin neurons. We also show that the activity of MC4R PVN neurons is controlled by the constitutive activity of the MC4R and that expression of the receptor mRNA and α-MSH sensitivity are both stimulated by leptin. Thus, leptin acts multinodally on arcuate nucleus/PVN circuits to regulate energy homeostasis, with prominent mechanisms involving direct control of both membrane conductances and gene expression in the MC4R PVN neuron.melanocortin signaling | electrophysiology | obesity N eurons expressing melanocortin-4 receptor (MC4R) in the paraventricular nucleus of the hypothalamus (PVN) play a crucial role in energy homeostasis. The genetic and pharmacological disruption of MC4R increases energy intake and decreases thermogenesis (1, 2). Thus, these neurons sense peripheral signals of adiposity and maintain energy homeostasis by coordinating energy intake and expenditure (2, 3). The adipocyte hormone leptin relays information on changes in peripheral energy stores to melanocortin and other circuits in the brain to regulate energy homeostasis (4). Neurons in the arcuate nucleus of the hypothalamus (ARC) and other nuclei, including the ventromedial nucleus (VMH), dorsomedial nucleus, and lateral nucleus, express leptin receptors and play an important role in transmitting the leptin signal to PVN neurons (5-7). Despite functional evidence suggesting expression of the leptin receptor in PVN (8), direct action of leptin on PVN neurons has not been thoroughly investigated, perhaps because of the low density of leptin-receptor expression (9, 10).Circulating leptin, by affecting the activity of neuropeptide Y (NPY) and proopiomelanocortin (POMC) neurons in the ARC, regulates synthesis of NPY/agouti-related protein (AgRP) and α-melanocyte-stimulating hormone (α-MSH) as well as their putative release from nerve...
The melanocortin-3 receptor acts as a rheostat on energy homeostasis through presynaptic inhibition of MC4R neuronal activity.
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