The orphan receptor Gpr83 regulates systemic energy metabolism via ghrelin-dependent and ghrelin-independent mechanisms

Abstract

The G protein-coupled receptor 83 (Gpr83) is widely expressed in brain regions regulating energy metabolism. Here we report that hypothalamic expression of Gpr83 is regulated in response to nutrient availability and is decreased in obese mice compared with lean mice. In the arcuate nucleus, Gpr83 colocalizes with the ghrelin receptor (Ghsr1a) and the agouti-related protein. In vitro analyses show heterodimerization of Gpr83 with Ghsr1a diminishes activation of Ghsr1a by acyl-ghrelin. The orexigenic and adipogenic effect of ghrelin is accordingly potentiated in Gpr83-deficient mice. Interestingly, Gpr83 knock-out mice have normal body weight and glucose tolerance when fed a regular chow diet, but are protected from obesity and glucose intolerance when challenged with a high-fat diet, despite hyperphagia and increased hypothalamic expression of agouti-related protein, Npy, Hcrt and Ghsr1a. Together, our data suggest that Gpr83 modulates ghrelin action but also indicate that Gpr83 regulates systemic metabolism through other ghrelin-independent pathways.

Oligomerization of GPCRs involved in endocrine regulation

“…in the thymus and hypothalamus (Harrigan et al 1989, 1991, Brezillon et al 2001. Most importantly, GPR83 has been previously found to be involved in the control of circulating adiponectin levels (De Moerlooze et al 2000), and Gpr83 expression is decreased in obese mice when compared with lean mice (Muller et al 2013b). Moreover, GPR83 constitutes homodimers but also has the capacity for heteromerization, as has been demonstrated by heteromerization with the ghrelin receptor (Muller et al 2013a).…”

“…The GPR83 was recently identified as a new determinant involved in body weight regulation (Muller et al 2013b). So far this orphan receptor is expressed e.g.…”

“…Interaction of MC3R with GHSR leads to the upregulation of α-MSH-stimulated signaling and the downregulation of basal-and ghrelin-induced GHSR signaling (Rediger et al 2011). Both the GHSR and the MC3R have been reported to have further diverse GPCR interaction partners (Borroto-Escuela et al 2014) and also interact with orphan GPCRs such as GPR83 (Muller et al 2013b). This, in turn, makes predictions of any physiological/functional impact due to modifications at the MC3R, the MC4R, or further interacting partners difficult.…”

Impact of G protein-coupled receptor heteromers in endocrine systems

“…In vitro analysis using HEK293 cells demonstrated heteromerization of GPR83 and GHSR via BRET (46). Moreover, in vivo exploration of the physiological role of the GPR83/GHSR heteromers using transgenic knock-out approaches showed that GPR83 knockout mice were protected from weight gain when fed on high-fat diets, despite hyperphagia (46) demonstrating an intriguing role for GPR83 and GHSR heteromers in both feeding behaviour and energy metabolism.…”

Genetic Associations with Obstructive Sleep Apnea Traits in Hispanic/Latino Americans

“…Gpr83 down-regulation in mice leads to decreased core body temperature and increases in weight and circulating adiponectin (37). Gpr83 knockout mice display differences in expression of the sleep-and wake-related genes Npy and Hcrt in the hypothalamus (38). GPR83 is also highly expressed in Fox3p regulatory T (Treg) cells, which are important in modulating inflammatory responses, and seem to be important in Treg cell development.…”