60 YEARS OF POMC: Regulation of feeding and energy homeostasis by α-MSH

Abstract

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.

Keywords: MC4R; POMC; food intake; melanocortin; α-MSH.

Figure 1

Yin–Yang model of control of feeding behavior and energy homeostasis. NPY/AgRP and POMC neurons within the arcuate nucleus form a coordinately regulated network due to dense NPY/ AgRP fibers that project to POMC cell bodies. Some of the receptors for a large number of hormones and neuropeptides known to regulate the network are indicated. These fibers project to many of the same nuclei, where dual release of α-MSH and AgRP were proposed to compete for MC4R binding, to coordinately regulate food intake and energy homeostasis. AgRP, agouti-related peptide; GABA, γ-aminobutyric acid; GHS, growth-hormone secretagogue receptor; Lep, leptin; MC3R, melanocortin 3 receptor; NPY, neuropeptide Y; μ-OR, μ-opiate receptor; R, receptor; GLP-1, glucagon-like peptide 1. Modified, with permission, from Cowley MA, Smart JL, Rubinstein M, Cerdan MG, Diano S, Horvath TL, Cone RD & Low MJ (2001) Leptin activates anorexigenic POMC neurons through a neural network in the arcuate nucleus. Nature 411 480–484.

Figure 2

A highly simplified schematic of the central melanocortin system. Receipt of long-term adipostatic signals and acute satiety signals by neurons in arcuate nucleus and brainstem, respectively. Light blue boxes indicate nuclei containing POMC neurons; yellow boxes indicate nuclei containing MC4R neurons that may serve to integrate adipostatic and satiety signals; and pink boxes show some circumventricular organs involved in energy homeostasis. Red arrows designate projections of POMC neurons; blue arrows show projections of agouti-related protein (AgRP neurons). AP, area postrema; ARC, arcuate nucleus; BST, bed nucleus of the stria terminalis; CCK, cholecystokinin; CEA, central nucleus of the amygdala; DMV, dorsal motor nucleus of the vagus; LH, lateral hypothalamic area; LPB, lateral parabrachial nucleus; ME, median eminence; NTS, nucleus tractus solitarius; PVH, paraventricular nucleus of the hypothalamus; RET, reticular formation. For simplicity, only a fraction of the >100 MC4R target sites are shown, and none of the MC3R target nuclei is indicated. Adapted, with permission, from Fan W, Boston BA, Kesterson RA, Hruby VJ & Cone RD (1997) Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385 165–168.

Figure 3

The MC4R signaling complex. α-MSH and AgRP signaling at the MC4R involves a multiprotein signaling complex that appears to be highly regulated. In addition to interactions with well-characterized members of the G protein signaling cascade (α-, β, and γ subunits and β-arrestin), the MC4R appears to interact directly with the transmembrane protein MRAP2, which blocks constitutive activation of the receptor by the amino terminal domain, and enhances sensitivity to α-MSH action. The receptor also appears to interact with inward rectifier channels such as Kir7.1, with α-MSH and AgRP modulating channel activity in a receptor-dependent manner. Attractin and mahogunin are involved in receptor internalization, and attractin may also be involved in AgRP binding. For simplicity, syndecan and defensins are not indicated here.

Figure 4

A new model of MC4R microcircuitry. The Yin–Yang model of α-MSH and AgRP action (Fig. 1) suggested competitive binding of these peptides to individual MC4R sites (orange box), and anatomical data suggest in regions where these peptides undergo volume release, that competition for binding to the MC4R may occur. New subcellular anatomical data suggest that in the PVH, AgRP synaptic contacts predominate at cell bodies, while POMC synaptic contacts predominate at distal dendrites. Along with the fact that AgRP immunoreactive fibers are only observed in a subset of MC4R expressing nuclei containing POMC-immunoreactive fibers, α-MSH may this often act independently of AgRP (right circle). At these sites, α-MSH may be expected to signal through both cAMP, and Kir7.1. The ability of AgRP to act independently of α-MSH as a potent hyperpolarizing agonist, via regulation of Kir7.1, suggests the likely existence of independent AgRP sites of action (left circle). Another MC4R signaling pathway, involving cAMP/PKA-dependent activation of K_ATP channels and α-MSH-induced hyperpolarization, has been demonstrated in MC4R neurons in the dorsal motor nucleus of the vagus in the brainstem (bottom right). Thus, α-MSH and AgRP utilize a diversity of signaling modalities to regulate feeding and energy homeostasis through the MC4R. Modified, with permission, from Ghamari-Langroudi M, Digby GJ, Sebag JA, Millhauser GL, Palomino R, Matthews R, Gillyard T, Panaro BL, Tough IR, Cox HM, et al. (2015) G-protein-independent coupling of MC4R to Kir7.1 in hypothalamic neurons. Nature 520 94–98.