Melanocortin-4 receptor complexity in energy homeostasis,obesity and drug development strategies

Abstract

The melanocortin-4 receptor (MC4R) has been critically investigated for the past two decades, and novel findings regarding MC4R signalling and its potential exploitation in weight loss therapy have lately been emphasized. An association between MC4R and obesity is well established, with disease-causing mutations affecting 1% to 6% of obese patients. More than 200 MC4R variants have been reported, although conflicting results as to their effects have been found in different cohorts. Most notably, some MC4R gain-of-function variants seem to rescue obesity and related complications via specific pathways such as beta-arrestin (ß-arrestin) recruitment. Broadly speaking, however, dysfunctional MC4R dysregulates satiety and induces hyperphagia. The picture at the mechanistic level is complicated as, in addition to the canonical G stimulatory pathway, the ß-arrestin signalling pathway and ions (particularly calcium) seem to interact with MC4R signalling to contribute to or alleviate obesity pathogenesis. Thus, the overall complexity of the MC4R signalling spectra has broadened considerably, indicating there is great potential for the development of new drugs to manage obesity and its related complications. Alpha-melanocyte-stimulating hormone is the major endogenous MC4R agonist, but structure-based ligand discovery studies have identified possible superior and selective agonists that can improve MC4R function. However, some of these agonists characterized in vitro and in vivo confer adverse effects in patients, as demonstrated in clinical trials. In this review, we provide a comprehensive insight into the genetics, function and regulation of MC4R and its contribution to obesity. We also outline new approaches in drug development and emerging drug candidates to treat obesity.

Keywords: Ca2+; Gs; MC4R; drug design; obesity; ß-arrestin.

FIGURE 1

G‐protein signalling pathway. Schematic showing the canonical stimulatory G‐protein (G_s) pathway for melanocortin 4‐receptor (MC4R) signalling and gene expression. Binding of α‐melanocyte‐stimulating hormone (MSH) to the MC4R causes the activation of the G‐protein, with αßγ‐subunits dissociating into α‐/ßγ‐subunits. The dissociated Gα_s causes the activation of adenylyl cyclase (AC), leading to the conversion of ATP to cyclic adenosine monophosphate (cAMP). cAMP activates inactive protein kinase A (PKA) which is translocated into the nucleus, activating the transcription factor cAMP response element binding protein (CREB) via phosphorylation of CREB, which regulates transcription. GTP, guanosine triphosphate

FIGURE 2

β‐arrestin signalling pathway. Schematic elucidating the mechanism of gain‐of‐function induced by a mutation (yellow diamond) in the melanocortin 4‐receptor (MC4R). The mutation causes an increase in the cell‐surface expression of MC4R, possibly via reduced internalization or rapid recycling, causing increased cyclic adenosine monophosphate (cAMP) production, as well as increased production of protein kinase A (PKA) and cAMP‐regulated guanine nucleotide exchange factors (Epac). AC, adenylyl cyclase; GDP, guanosine diphosphate; GTP, guanosine triphosphate; MSH, melanocyte‐stimulating hormone;

FIGURE 3

Ca²⁺ regulated pathway. The endogenous melanocortin 4‐receptor (MC4R) pathway is regulated by agonist α‐melanocyte‐stimulating hormone (MSH) and antagonist agouti‐related peptide (AgRP). Ca²⁺ ions are also important in the regulation of the MC4R pathway. α‐MSH, along with Ca²⁺, induces satiety and reduces food intake. This is regulated partly by closure of the potassium inward rectifying channel KIR7.1. Conversely, AgRP regulates orexigenic signals, also via the opening of the KIR7.1, in addition to other possible mechanisms