Authors: Sveidahl Johansen, Olivia; Ma, Tao; Hansen, Jakob Bondo; Markussen, Lasse Kruse; Schreiber, Renate; Reverte-Salisa, Laia; Dong, Hua; Christensen, Dan Ploug; Sun, Wenfei; Gnad, Thorsten; Karavaeva, Iuliia; Nielsen, Thomas Svava; Kooijman, Sander; Cero, Cheryl; Dmytriyeva, Oksana; Shen, Yachen; Razzoli, Maria; O’Brien, Shannon L.; Kuipers, Eline N.; Nielsen, Carsten Haagen; Orchard, William; Willemsen, Nienke; Jespersen, Naja Zenius; Lundh, Morten; Sustarsic, Elahu Gosney; Hallgren, Cecilie Mørch; Frost, Mikkel; McGonigle, Seth; Isidor, Marie Sophie; Broholm, Christa; Pedersen, Oluf; Hansen, Jacob Bo; Grarup, Niels; Hansen, Torben; Kjær, Andreas; Granneman, James G.; Babu, M. Madan; Calebiro, Davide; Nielsen, Søren; Rydén, Mikael; Soccio, Raymond; Rensen, Patrick C. N.; Treebak, Jonas Thue; Schwartz, Thue Walter; Emanuelli, Brice; Bartolomucci, Alessandro; Pfeifer, Alexander; Zechner, Rudolf; Scheele, Camilla; Mandrup, Susanne; Gerhart-Hines, Zachary
Issue: Cell. 2021 Jun 24;184(13):3502-3518.e33.
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.