Adipose thermogenesis is a conserved response to environmental cold or dietary excess and is classically triggered by ligand-dependent receptor activation. Johansen et al. report that cold regulation of Gs-coupled receptor expression represents a parallel point of control. Gpr3 turns out to be the most cold-induced Gs-coupled receptor in both brown and beige thermogenic adipose tissues. GPR3 has high basal Gs-coupled activity in the absence of an exogenous ligand. Mimicking the cold induction of Gpr3 triggered cAMP production, activated the thermogenic response, and counteracted metabolic disease in mice. A disease-associated genetic variant in GPR3 in patient-derived adipocytes revealed that GPR3 also acts as a regulator of human thermogenic adipose tissue. Targeting GPR3 could thus enable therapeutic stimulation of thermogenic adipose tissue in metabolic disease.
Cell 184, 3502 (2021).