Abstract
The melanocortin 4 receptor (MC4R) is a key player in hypothalamic weight regulation and energy expenditure as part of the leptin–melanocortin pathway. Mutations in this G protein coupled receptor (GPCR) are the most common cause for monogenetic obesity, which appears to be mediated by changes in the anorectic action of MC4R via GS-dependent cyclic adenosine-monophosphate (cAMP) signaling as well as other signaling pathways. To study potential bias in the effects of MC4R mutations between the different signaling pathways, we investigated three major MC4R mutations: a GS loss-of-function (S127L) and a GS gain-of-function mutant (H158R), as well as the most common European single nucleotide polymorphism (V103I). We tested signaling of all four major G protein families plus extracellular regulated kinase (ERK) phosphorylation and β-arrestin2 recruitment, using the two endogenous agonists, α- and β-melanocyte stimulating hormone (MSH), along with a synthetic peptide agonist (NDP-α-MSH). The S127L mutation led to a full loss-of-function in all investigated pathways, whereas V103I and H158R were clearly biased towards the Gq/11 pathway when challenged with the endogenous ligands. These results show that MC4R mutations can cause vastly different changes in the various MC4R signaling pathways and highlight the importance of a comprehensive characterization of receptor mutations.
Highlights
A complex hypothalamic network of orexigenic and anorexigenic signals regulates body weight and energy expenditure
One of the key players in this network is a G protein coupled receptor (GPCR), the melanocortin 4 receptor (MC4R), which is mainly expressed in the paraventricular nucleus (PVN) of the hypothalamus
We characterize the three described MC4R mutations in vitro for all known/so far reported signaling pathways to explore the role of GS and non-GS pathways in weight regulation
Summary
A complex hypothalamic network of orexigenic and anorexigenic signals regulates body weight and energy expenditure. More and more studies provided evidence that the MC4R is able to couple to a variety of signaling pathways, such as extracellular regulated kinase (ERK) activation [7,8,9], and to other G proteins, such as Gi/o, Gq/11 and G12/13 [10,11,12,13]. These pathways might be involved in the anorexigenic effect of the activated MC4R [14]. In addition to MC4R activation by endogenous ligands, the MC4R can be activated by a variety of synthetic peptide ligands, such as (Nle, d-Phe7)-α-MSH (NDP-α-MSH) [19]
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