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

Research output: Contribution to journalJournal articleResearchpeer-review

  • Tao Ma
  • Jakob Bondo Hansen
  • Lasse Kruse Markussen
  • Renate Schreiber
  • Laia Reverte-Salisa
  • Hua Dong
  • Dan Ploug Christensen
  • Wenfei Sun
  • Thorsten Gnad
  • Sander Kooijman
  • Cheryl Cero
  • Oksana Dmytriyeva
  • Yachen Shen
  • Maria Razzoli
  • Shannon L O'Brien
  • Eline N Kuipers
  • Carsten Haagen Nielsen
  • William Orchard
  • Nienke Willemsen
  • Naja Zenius Jespersen
  • Morten Lundh
  • Elahu Gosney Sustarsic
  • Cecilie Mørch Hallgren
  • Seth McGonigle
  • Christa Broholm
  • James G Granneman
  • M Madan Babu
  • Davide Calebiro
  • Søren Nielsen
  • Mikael Rydén
  • Raymond Soccio
  • Patrick C N Rensen
  • Alessandro Bartolomucci
  • Alexander Pfeifer
  • Rudolf Zechner
  • Susanne Mandrup
  • Zachary Gerhart-Hines

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.

Original languageEnglish
JournalCell
Volume184
Issue number13
Pages (from-to)3502-3518 +
Number of pages50
ISSN0092-8674
DOIs
Publication statusPublished - 2021

ID: 271986976