ArticleCell2021
Lipolysis drives expression of the constitutively active receptor GPR3 to induce adipose thermogenesis.
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Article in Cell, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 78 papers, 1 of them a synthesis that pooled it.
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78citing papers in PubMed, 1 pooled it
11.2field-weighted citation impact, top 1% of its field
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Who cites it
78 citing papers in PubMed, 1 synthesis or guideline pooled it, 129 citations in OpenAlex.
- GPR3 in neuro-metabolic-immune-reproductive nexus - a potential therapeutic target for Multi-System diseases.Annals of medicine · 2026Pooled it
- Constitutively active glucagon receptor (GCGR) physiologically regulates body temperature in lizards.Science advances · 2026Article
- Alternative Receptor Signaling for the Selective and Multifaceted Regulation of Human Brown Adipocytes.International journal of molecular sciences · 2026Review
- Discovery of Small Molecule Ligands Targeting Orphan G Protein-Coupled Receptors GPR3, GPR6, and GPR12.Journal of medicinal chemistry · 2026Review
- Junctophilin-2-orchestrated calcium signalosome regulates brown adipocyte thermogenesis and energy metabolism.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Mitochondrial carrier SLC25A34 links clock, diet, and temperature control of interorganellar lipid cycling.bioRxiv : the preprint server for biology · 2026Article
- WAT-to-BAT communication facilitates the sustained activation of BAT thermogenesis during cold exposure.Cell discovery · 2026Article
- GPR3 Ligands Discovered through Combined Virtual and Conformational Biosensor-Based Screening.Journal of the American Chemical Society · 2026Article
- EctoShed: a novel gene delivery platform for functional analysis of adipocyte-shed proteoforms.BMC research notes · 2026Article
- Endothelial ADGRF5(GPR116) governs vascular adaptation required for sustained thermogenic remodeling of brown adipose tissue.Molecular metabolism · 2026Article
- GPR3 is an immediate-early gene-like GPCR regulating CREB-dependent neuronal differentiation.iScience · 2026Article
- Fatty acids promote uncoupled respiration via ATP/ADP carriers in white adipocytes.Nature metabolism · 2026Article
- Constitutive activity among orphan G protein-coupled receptors: Molecular mechanisms and pharmacological perspectives.Molecular pharmacology · 2026Review
- Review
- A general one-step protocol to generate impermeable fluorescent HaloTag substrates for in situ live cell application and super-resolution imaging.Nature communications · 2026Article
- The Role of Kupffer Cells and Liver Macrophages in the Pathogenesis of Metabolic Dysfunction-Associated Steatotic Liver Disease.Biomedicines · 2026Review
- Cold exposure induces the constitutively active thermogenic receptor, GPR3, via ERRα and ERRγ.Molecular metabolism · 2026Article
- Adipose Progenitor Cells in Thermogenesis and Metabolic Regulation.Physiology (Bethesda, Md.) · 2026Review
- Targeting GPR3 as a novel approach for nicotine cessation therapeutic development.Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology · 2025Article
- Article
18 more citing papers are in PubMed but not listed here.
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Authors and funding
51 authors at 14 institutions in 8 countries.
Olivia Sveidahl JohansenNovo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; Embark Biotech ApS, Copenhagen, Denmark; Center for Adipocyte Signaling, University of Southern Denmark, Odense, Denmark.
Tao MaNovo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; Embark Biotech ApS, Copenhagen, Denmark.
Jakob Bondo HansenNovo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; Embark Biotech ApS, Copenhagen, Denmark.
Lasse Kruse MarkussenCenter for Adipocyte Signaling, University of Southern Denmark, Odense, Denmark; Functional Genomics and Metabolism Research Unit, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
Renate SchreiberInstitute of Molecular Biosciences, University of Graz, Graz, Austria.
Laia Reverte-SalisaInstitute of Pharmacology and Toxicology, University Hospital, University of Bonn, Bonn, Germany.
Hua DongInstitute of Food, Nutrition and Health, ETH Zurich, Zurich, Switzerland.
Dan Ploug ChristensenEmbark Biotech ApS, Copenhagen, Denmark.
Wenfei SunInstitute of Food, Nutrition and Health, ETH Zurich, Zurich, Switzerland.
Thorsten GnadInstitute of Pharmacology and Toxicology, University Hospital, University of Bonn, Bonn, Germany.
Iuliia KaravaevaNovo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
Thomas Svava NielsenNovo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
Sander KooijmanDepartment of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.
Cheryl CeroDepartment of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA.
Oksana DmytriyevaNovo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
Yachen ShenInstitute for Diabetes, Obesity, and Metabolism, Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Maria RazzoliDepartment of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA.
Shannon L O'BrienInstitute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK; Centre of Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, Birmingham, UK; Institute of Pharmacology and Toxicology and Bio-Imaging Center, University of Würzburg, Würzburg, Germany.
Eline N KuipersDepartment of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.
Carsten Haagen NielsenDepartment of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet, Copenhagen, Denmark.
William OrchardMRC Laboratory of Molecular Biology, Cambridge, UK.
Nienke WillemsenNovo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
Naja Zenius JespersenNovo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; Centre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark.
Morten LundhNovo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
Elahu Gosney SustarsicNovo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
Cecilie Mørch HallgrenNovo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
Mikkel FrostNovo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
Seth McGonigleDepartment of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA.
Marie Sophie IsidorNovo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
Christa BroholmNovo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
Oluf PedersenNovo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
Jacob Bo HansenSection for Cell Biology and Physiology, Department of Biology, University of Copenhagen, Copenhagen, Denmark.
Niels GrarupNovo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
Torben HansenNovo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
Andreas KjærDepartment of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark; Department of Clinical Physiology, Nuclear Medicine & PET and Cluster for Molecular Imaging, Rigshospitalet, Copenhagen, Denmark.
James G GrannemanCenter for Molecular Medicine and Genetics, Wayne State University School of Medicine, Detroit, MI, USA.
M Madan BabuMRC Laboratory of Molecular Biology, Cambridge, UK; Department of Structural Biology and Center for Data Driven Discovery, St. Jude Children's Research Hospital, Memphis, TN, USA.
Davide CalebiroInstitute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK; Centre of Membrane Proteins and Receptors (COMPARE), Universities of Birmingham and Nottingham, Birmingham, UK; Institute of Pharmacology and Toxicology and Bio-Imaging Center, University of Würzburg, Würzburg, Germany.
Søren NielsenCentre of Inflammation and Metabolism and Centre for Physical Activity Research, Rigshospitalet, University Hospital of Copenhagen, Copenhagen, Denmark.
Mikael RydénDepartment of Medicine (H7), Karolinska Institute, Karolinska University Hospital, Stockholm, Sweden.
Raymond SoccioInstitute for Diabetes, Obesity, and Metabolism, Department of Medicine, Division of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.
Patrick C N RensenDepartment of Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden, the Netherlands; Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, the Netherlands.
Jonas Thue TreebakNovo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
Thue Walter SchwartzNovo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; Embark Biotech ApS, Copenhagen, Denmark.
Brice EmanuelliNovo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
Alessandro BartolomucciDepartment of Integrative Biology and Physiology, University of Minnesota, Minneapolis, MN, USA.
Alexander PfeiferInstitute of Pharmacology and Toxicology, University Hospital, University of Bonn, Bonn, Germany.
Rudolf ZechnerInstitute of Molecular Biosciences, University of Graz, Graz, Austria; BioTechMed-Graz, Graz, Austria.
Camilla ScheeleNovo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
Susanne MandrupCenter for Adipocyte Signaling, University of Southern Denmark, Odense, Denmark; Functional Genomics and Metabolism Research Unit, Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark.
Zachary Gerhart-HinesNovo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark; Embark Biotech ApS, Copenhagen, Denmark; Center for Adipocyte Signaling, University of Southern Denmark, Odense, Denmark. Electronic address: zpg@sund.ku.dk.
University of Copenhagen · DKUniversity of Minnesota · USLeiden University Medical Center · NLUniversity of Bonn · DEETH Zurich · CHUniversity of Graz · ATUniversity of Pennsylvania · USUniversity of Southern Denmark · DKUniversity of Würzburg · DEKarolinska University Hospital · SEMRC Laboratory of Molecular Biology · GBRigshospitalet · DKSt. Jude Children's Research Hospital · USWayne State University · US
Funding
Regional Pilot And Feasibility Study Grants ProgramP30DK020572 · NIDDK · UNIVERSITY OF MICHIGAN AT ANN ARBOR · PI DAVID P OLSON · 2013 to 2026
$24.3MNeural mechanisms for VGF regulation of energy balanceR01DK117504 · NIDDK · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI BARTOLOMUCCI, ALESSANDRO, BUETTNER, CHRISTOPH · 2018 to 2021
$2.7MMolecular dissection of TLQP-21 peptide functions in obesityR01DK102496 · NIDDK · UNIVERSITY OF MINNESOTA · PI BARTOLOMUCCI, ALESSANDRO · 2014 to 2018
$1.7MMolecular control of BAT functions by adrenergic/purinergic signalingR56DK118150 · NIDDK · UNIVERSITY OF MINNESOTA · PI BARTOLOMUCCI, ALESSANDRO · 2019 to 2019
$385kMedical Research Council MC_U105185859NIDDK NIH HHS P30 DK020572NIDDK NIH HHS R01 DK102496NIDDK NIH HHS R01 DK117504NIDDK NIH HHS R56 DK118150Wellcome TrustWellcome Trust 212313/Z/18/Z
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.
Indexed as
LipolysisThermogenesisAdipocytesAdipose Tissue, BrownAnimalsCells, CulturedChlorocebus aethiopsCold TemperatureConstitutive Androstane ReceptorCOS CellsDietary FatsHumansMiceMice, Inbred C57BLPhenotypeReceptors, G-Protein-CoupledConstitutive Androstane ReceptorDietary FatsGPR3 protein, humanGPR3 protein, mouseReceptors, G-Protein-Coupledadrenergic receptorbrown adipose tissueconstitutively activeenergy expenditureGPCRGPR3G protein-coupled receptorlipolysisthermogenesistranscription
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.