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

First Author  Sveidahl Johansen O Year  2021
Journal  Cell Volume  184
Issue  13 Pages  3502-3518.e33
PubMed ID  34048700 Mgi Jnum  J:316009
Mgi Id  MGI:6718720 Doi  10.1016/j.cell.2021.04.037
Citation  Sveidahl Johansen O, et al. (2021) Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis. Cell 184(13):3502-3518.e33
abstractText  Thermogenic adipocytes possess a therapeutically appealing, energy-expending capacity, which is canonically cold-induced by ligand-dependent activation of beta-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.
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