The Chemerin Receptor GPR1 Signals Through a RhoA/ROCK Pathway and Contributes to Glucose Homeostasis in Obese Mice

Abstract

Chemerin is an adipose-derived hormone that regulates adipose tissue development, immunity, metabolism, and glucose homeostasis. To date, all chemerin function has been attributed to activation of the G protein-coupled receptor chemokine-like receptor-1 (CMKLR1). Chemerin is also the only known ligand for a second receptor, G protein- coupled receptor-1 (GPR1). The function of GPR1 is unknown in mammals. This study investigated the in vitro signal transduction mechanisms of CMKLR1 and GPR1, and characterized the in vivo effects of Gpr1 loss on adiposity and glucose homeostasis during obesity and diabetes development in mice. Receptor signaling and tissue expression were assessed using a panel of in vitro luciferase- reporters and quantitative PCR, respectively. Unlike CMKLR1, chemerin activation of GPR1 does not induce mitogen-activated protein kinase (MAPK) signaling, but does exhibit higher potency for arrestin recruitment. In common, chemerin activation of both CMKLR1 and GPR1 enhances serum-response factor (SRF) – mediated target gene expression and enhances cell migration via a ras homolog gene family member A (RhoA)/rho-associated protein kinase (ROCK) and MAPK/extracellular-signal-regulated kinase (ERK) dependent pathway. Gpr1 and Cmklr1 exhibit unique expression profiles, having in common highest levels of each observed in white adipose tissue (WAT). In mice, Gpr1, is expressed in metabolically active tissues: skeletal muscle, adipose tissue, and brain. The highest Gpr1 mRNA levels were detected in the hypothalamus, oxidative soleus muscle and in the non- adipocyte stromal vascular fraction (SVF) of adipose tissue. Consistent with this expression pattern, Gpr1 loss resulted in reduced food consumption and exacerbated glucose tolerance in mice consuming a high-fat diet. The later was likely a consequence of impaired insulin secretion and insulin resistance as evidenced by low fasting and glucose-stimulated insulin levels and reduced insulin receptor expression in skeletal muscle, respectively. These results demonstrate that GPR1 is an active chemerin receptor and identify RhoA/SRF as a novel chemerin-signaling axis. Differential receptor expression suggests that GPR1 may play a distinct role in chemerin function. This study provides evidence for the first mammalian function of GPR1 as a chemerin receptor implicated in the maintenance of glucose homeostasis during obesity and identifies novel targets for modulating chemerin function through the RhoA/SRF pathway.