Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis.

Thermogenic adipocytes possess a therapeutically appealing, energy-expending capacity, which is canonically cold-induced by ligand-dependent activation of β-adrenergic G protein-coupled receptors (GPCRs). Here, we uncover an alternate paradigm of GPCR-mediated adipose thermogenesis through the constitutively active receptor, GPR3. We show that the N terminus of GPR3 confers intrinsic signaling activity, resulting in continuous Gs-coupling and cAMP production without an exogenous ligand. Thus, transcriptional induction of Gpr3 represents the regulatory parallel to ligand-binding of conventional GPCRs. Consequently, increasing Gpr3 expression in thermogenic adipocytes is alone sufficient to drive energy expenditure and counteract metabolic disease in mice. Gpr3 transcription is cold-stimulated by a lipolytic signal, and dietary fat potentiates GPR3-dependent thermogenesis to amplify the response to caloric excess. Moreover, we find GPR3 to be an essential, adrenergic-independent regulator of human brown adipocytes. Taken together, our findings reveal a noncanonical mechanism of GPCR control and thermogenic activation through the lipolysis-induced expression of constitutively active GPR3. [Display omitted] • Gpr3 is a cold-induced Gs-coupled receptor in brown and beige adipose tissue • A noncanonical lipolytic signal triggers Gpr3 transcription during cold exposure • GPR3 is a nonadrenergic activator of mouse and human thermogenic adipocytes • GPR3 drives thermogenesis without a ligand via its intrinsic Gs-coupling activity Cold-induced lipolysis drives the expression of a constitutively active GPCR that regulates thermogenesis in mouse and human adipocytes independent of sympathetic or adrenergic inputs. [ABSTRACT FROM AUTHOR]