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

• DOI: 10.1016/j.cell.2021.04.037
• Publication Date: 2021-05-27T15:36:31Z
• Authors: Olivia Sveidahl J...; Tao Ma; Jakob Bondo Hansen; Lasse Kruse Marku...; Renate Schreiber; Laia Reverte-Salisa; Hua Dong; Dan Ploug Christe...; Wenfei Sun; Thorsten Gnad; Iuliia Karavaeva; Thomas Svava Nielsen; Sander Kooijman; Cheryl Cero; Oksana Dmytriyeva; Yachen Shen; Maria Razzoli; Shannon L. O’Brien; Eline N. Kuipers; Carsten Haagen Ni...; William Orchard; Nienke Willemsen; Naja Zenius Jespe...; Morten Lundh; Elahu Gosney Sust...; Cecilie Mørch Hal...; Mikkel Frost; Seth McGonigle; Marie Sophie Isidor; Christa Broholm; Oluf Pedersen; Jacob Bo Hansen; Niels Grarup; Torben Hansen; Andreas Kjær; James G. Granneman; M. Madan Babu; Davide Calebiro; Søren Nielsen; Mikael Rydén; Raymond Soccio; Patrick C.N. Rensen; Jonas Thue Treebak; Thue Walter Schwartz; Brice Emanuelli; Alessandro Bartol...; Alexander Pfeifer; Rudolf Zechner; Camilla Scheele; Susanne Mandrup; Zachary Gerhart-H...
• Keywords: 0301 basic medicine; Sympathetic Nervous System; Transcription, Genetic; Inbred C57BL; Receptors, G-Protein-Coupled; Mice; GPCR; Adipose Tissue, Brown; Receptors; energy expenditure; Chlorocebus aethiops; Adipocytes; Dietary Fat; Cells, Cultured; adrenergic receptor; GPR3; ddc:610; 0303 health sciences; Adipocyte; Cultured; 600; Thermogenesis; thermogenesis; Cold Temperature; Phenotype; Adipose Tissue; COS Cells; transcription; Human; Signal Transduction; Cells; Lipolysis; 610; Chlorocebus aethiop; Article; thermogenesi; G-Protein-Coupled; 03 medical and health sciences; Genetic; COS Cell; constitutively active; Animals; Humans; G protein-coupled receptor; Constitutive Androstane Receptor; lipolysi; Animal; Brown; brown adipose tissue; Dietary Fats; Mice, Inbred C57BL; lipolysis

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.<br/>ISSN:0092-8674<br/>Cell, 184 (13)<br/>ISSN:1097-4172<br/>