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

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

doi:10.1016/j.cell.2021.04.037

Abstract

SummaryThermogenic 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.

Highlights

Exposure to environmental cold stimulates thermogenic catabolism of lipids and carbohydrates in brown adipose tissue (BAT) (Cannon and Nedergaard, 2004; Rosen and Spiegelman, 2014)
The constitutively active receptor GPR3 is the most coldinduced Gs-coupled G protein-coupled receptors (GPCRs) in thermogenic adipose tissue Given that GPCRs are under-represented in global pools of transcripts (Fredriksson and Schioth, 2005), we employed a targeted
GPR3 is characterized by high intrinsic receptor activity that signals in the absence of an exogenous ligand (Eggerickx et al, 1995)

Summary

Introduction

Exposure to environmental cold stimulates thermogenic catabolism of lipids and carbohydrates in brown adipose tissue (BAT) (Cannon and Nedergaard, 2004; Rosen and Spiegelman, 2014). Of the four primary Ga subtypes (Gs, Gi, Gq, and G12/13), BAT activation is predominantly ascribed to the Gs-coupled family, which signals through increased cyclic AMP (cAMP) This class is exemplified by the b-adrenergic receptors (ADRB1, ADRB2, and ADRB3), which represent the canonical means of sympathetic, ligand-mediated thermogenic control (Collins, 2012). Several additional Gs-coupled receptors have been shown to activate adipose thermogenesis including receptors for secretin (Li et al, 2018), glucagon (Beaudry et al, 2019a), glucose-dependent insulinotropic polypeptide (Beaudry et al, 2019b), adrenocorticotropic hormone (Schnabl et al, 2019), and adenosine (Gnad et al, 2014)

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