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

Open access
Date
2021-06-24Type
- Journal Article
Citations
Cited 29 times in
Web of Science
Cited 33 times in
Scopus
ETH Bibliography
yes
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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. Show more
Permanent link
https://doi.org/10.3929/ethz-b-000491568Publication status
publishedExternal links
Journal / series
CellVolume
Pages / Article No.
Publisher
Cell PressOrganisational unit
03819 - Wolfrum, Christian / Wolfrum, Christian
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Show all metadata
Citations
Cited 29 times in
Web of Science
Cited 33 times in
Scopus
ETH Bibliography
yes
Altmetrics