{"doi":"10.1016/j.cell.2021.04.037","title":"Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis","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.","journal":"Cell","year":2021,"id":148064,"datarank":0.7412463633913957,"base_score":4.941642422609304,"endowment":4.941642422609304,"self_citation_contribution":0.7412463633913957,"citation_network_contribution":0.0,"self_endowment_contribution":0.7412463633913957,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":139,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9486,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2021-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":630108,"name":"Tao Ma","orcid":"0000-0003-2570-9449","position":1,"is_corresponding":false},{"id":630109,"name":"Jakob Bondo Hansen","orcid":"0000-0002-6837-0919","position":2,"is_corresponding":false},{"id":630110,"name":"Lasse K. 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