The melanocortin pathway and control of appetite-progress and therapeutic implications

Abstract

The initial discovery that ob/ob mice become obese because of a recessive mutation of the leptin gene has been crucial to discover the melanocortin pathway to control appetite. In the melanocortin pathway, the fed state is signaled by abundance of circulating hormones such as leptin and insulin, which bind to receptors expressed at the surface of pro-opiomelanocortin (POMC) neurons to promote processing of POMC to the mature hormone α-melanocyte-stimulating hormone (α-MSH). The α-MSH released by POMC neurons then signals to decrease energy intake by binding to melanocortin-4 receptor (MC4R) expressed by MC4R neurons to the paraventricular nucleus (PVN). Conversely, in the 'starved state' activity of agouti-related neuropeptide (AgRP) and of neuropeptide Y (NPY)-expressing neurons is increased by decreased levels of circulating leptin and insulin and by the orexigenic hormone ghrelin to promote food intake. This initial understanding of the melanocortin pathway has recently been implemented by the description of the complex neuronal circuit that controls the activity of POMC, AgRP/NPY and MC4R neurons and downstream signaling by these neurons. This review summarizes the progress done on the melanocortin pathway and describes how obesity alters this pathway to disrupt energy homeostasis. We also describe progress on how leptin and insulin receptors signal in POMC neurons, how MC4R signals and how altered expression and traffic of MC4R change the acute signaling and desensitization properties of the receptor. We also describe how the discovery of the melanocortin pathway has led to the use of melanocortin agonists to treat obesity derived from genetic disorders.

Keywords: AgRP; MC4R; appetite; hypothalamus; leptin; melanocortin.

Fig. 1. POMC neurons in the melanocortin system.

In the fed state, the signal to stop eating and to increase energy expenditure is conveyed by leptin and insulin released in the bloodstream by adipocytes and by the β-cells of the pancreas,respectively. These hormones cross the blood-brain barrier to reach the arcuate nucleus (ARC) of the hypothalamus and promote firing (indicated by glow around the cell perimeter) of distinct populations of POMC neurons expressing the LepR and insulin receptor. Other populations of POMC neurons in the arcuate nucleus and in the nucleus of the solitary tract (NTS) express the serotonin receptor 5-HT_2CR. POMC neurons project to the paraventricular nucleus (PVN) to increase activity of MC4R neurons to decrease food intake and to increase energy expenditure. In the fasted state, POMC neurons in the arcuate nucleus are inhibited by decreased circulating leptin and insulin and by increased activation of AgRP/NPY neurons, which send inhibitory signals to reduce firing of POMC neurons and of MC4R neurons. References are in the main text.

Fig. 2. POMC neurons express leptin, insulin and serotonin receptors.

A) In the fed state, leptin bound to LepR expressed by POMC neurons in the arcuate nucleus and release of α-MSH hormone by multiple pathways initiated by activation of JAK2, a process that involves LepR-dependent activation of ROCK1. In one pathway initiated by JAK2, the kinase phosphorylates STAT3 to function as transcription factor. STAT3 promotes expression of the polypeptide POMC and processing of the pro-hormone to α-MSH. Binding of leptin to LepR induces another JAK2-dependent pathway where SH2-Bβ and IRS1 are recruited to activate the PI3K pathway. PI3K generates PIP₃ from PIP₂ at the plasma membrane. PIP₃ recruits and activates of PKC including the atypical PKCλ. PI3K signaling leads to opening of TrpC5 to allow inward flux of Na⁺ and neuronal firing. PI3K pathway also promotes phosphorylation and translocation of FOXO1 from the nucleus to the cytosol to promote transcription of POMC, increased processing of POMC to α-MSH, and suppression of food intake B). Stat3 induces expression of factors involved in feed-back inhibitory pathways, such as that of Socs-3, which binds to LepR to inhibit receptor signaling. Stat 3 also induces expression of protein phosphatases such as TCPTP to terminate LepR to inhibit receptor signaling. C) In other populations of POMC neurons, the insulin receptor signals through PI3 kinase pathway to induce flux of Na⁺ into the cell through TrpC5 and neuronal firing. D) A population of POMC neurons expresses the GPCR 5-HT_2CR. Binding of serotonin to HT_2CR induces Gq-dependent activation of PLC, generation of increased intracellular IP₃ and Ca²⁺, and opening of TrpC5 to allow Na⁺ into the cell and neuronal firing. Heterogeneity of POMC neurons expressing insulin, leptin and serotonin receptor is indicated by drawing cells expressing these receptors with different colors. References are in the main text.

Fig. 3. AgRP/NPY neurons drive food intake.

Fasting and circulating hormones released by the stomach induce activity of AgRP/NPY neurons localized to the arcuate nucleus (ARC) of the hypothalamus. To promote feeding, subpopulations of AgRP/NPY neurons send projections to: the paraventricular nucleus of hypothalamus (PVN), to synapse with MC4R neurons; and to neurons in the lateral hypothalamus (LH), bed nucleus of the stria terminalis (BNST) and the para-ventricular nucleus of the thalamus (PVT). Other projections to neurons in LH, medial amygdala (MeA), LH, and parabrachial nuclei control insulin sensitivity in brown adipose tissue (BAT) and suppress inflammatory pain in hunger condition. “Behavior” refers to behavior induced by the nutritional status of the organism such as modulation of aggression, fear and exploration to find food. adapted behavior such as modulation of aggression, fear and exploration to find food References are in the main text.

Fig. 4. Localization and function of MC4R and MC3R in the central nervous system.

Amy, amygdala; DMH, dorsomedial nucleus of the hypothalamus; DMV, dorsal motor nucleus of the vagus IML, intermediolateral nucleus of the spinal cord; LH, lateral hypothalamus; NA, nucleus accumbens; PVN, paraventricular nucleus of hypothalamus; VMH, ventromedial nucleus of the hypothalamus; VTA, Ventral Tegmental Area. References are in the main text.

Fig. 5. MC4R signaling.

Binding of α-MSH to MC4R promotes receptor signal through Gs with activation of adenylate cyclase (AC) and increased generation of intracellular cAMP, followed by activation of PKA, EPAC, ERK1/2, CREB, and increased transcription of c-Fos as well as decreased AMPK activity. AgRP antagonizes these effects. The Gs signal induced by MC4R likely takes place in in the dorsomedial hypothalamus (DMH) to control energy expenditure. AgRP can also act a biased agonist to promote MC4R signal by Gi. MC4R can couple constitutively to both Gs and Gi, and AgRP blocks such signal, acting as an inverse agonist. MC4R in a complex with α-MSH also couples to Gq and induces activation of phospholipase C and increased intracellular cytosolic calcium. The Gq signal likely takes place in the paraventricular nucleus (PVN) of the hypothalamus to control food intake. MC4R in a complex with α-MSH opens the Kir7.1 channel to induce depolarization of MC4R neurons in a G-protein independent manner. AgRP acts as a biased agonist by opening the Kir7.1 channel to induce hyperpolarization of MC4R neurons. References are in the main text.