Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis
Olivia Sveidahl Johansen, Tao Ma, Jakob Bondo Hansen, Lasse K. Markussen, Renate Schreiber, Laia Reverte-Salisa, Hua Dong, Dan Ploug Christensen, Wenfei Sun, Thorsten Gnad, Iuliia Karavaeva, Thomas S. Nielsen, Sander Kooijman, Cheryl Cero, Oksana Dmytriyeva, Yachen Shen, Maria Razzoli, Shannon O’Brien, Eline N. Kuipers, Carsten H. Nielsen, William R. Orchard, Nienke Willemsen, Naja Zenius Jespersen, Morten Lundh, Elahu G. Sustarsic, Cecilie Mørch Hallgren, Mikkel Frost, Seth McGonigle, Marie S. Isidor, Christa Broholm, Oluf Pedersen, Jacob B. Hansen, Niels Grarup, Torben Hansen, Andreas Kjær, James G. Granneman, Mohan Babu, Davide Calebiro, Søren Nielsen, Mikael Rydén, Raymond E. Soccio, Patrick C.N. Rensen, Jonas T. Treebak, Thue W. Schwartz, Brice Emanuelli, Alessandro Bartolomucci, Alexander Pfeifer, Rudolf Zechner, Camilla Schéele, Susanne Mandrup, Zachary Gerhart‐Hines
Abstract
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.