An atlas of GPCRs in dopamine neurons: Identification of the free fatty acid receptor 4 as a regulator of food and water intake
Mia Apuschkin,
Hayley B. Burm,
Jan H. Schmidt,
Louise J. Skov,
Rita C. Andersen,
Carl-Fredrik Bowin,
Jonatan F. Støier,
Kathrine L. Jensen,
Leonie P. Posselt,
Oksana Dmytriyeva,
Andreas T. Sørensen,
Kristoffer L. Egerod,
Birgitte Holst,
Mattias Rickhag,
Thue W. Schwartz,
Ulrik Gether
Affiliations
Mia Apuschkin
Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Hayley B. Burm
Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Jan H. Schmidt
Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Louise J. Skov
Novo Nordic Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen, Denmark
Rita C. Andersen
Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Carl-Fredrik Bowin
Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden
Jonatan F. Støier
Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Kathrine L. Jensen
Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Leonie P. Posselt
Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Oksana Dmytriyeva
Novo Nordic Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen, Denmark
Andreas T. Sørensen
Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark
Kristoffer L. Egerod
Novo Nordic Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen, Denmark
Birgitte Holst
Department of Biomedical Sciences, Laboratory for Molecular Pharmacology and Novo Nordic Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen, Denmark
Mattias Rickhag
Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Danish Research Centre for Magnetic Resonance (DRCMR), Copenhagen University Hospital Amager and Hvidovre, Hvidovre, Denmark
Thue W. Schwartz
Novo Nordic Foundation Center for Basic Metabolic Research, University of Copenhagen, 2200 Copenhagen, Denmark
Ulrik Gether
Molecular Neuropharmacology and Genetics Laboratory, Department of Neuroscience, Faculty of Health and Medical Sciences, University of Copenhagen, 2200 Copenhagen, Denmark; Corresponding author
Summary: Midbrain dopaminergic neurons (DANs) are subject to extensive metabotropic regulation, but the repertoire of G protein-coupled receptors (GPCRs) present in these neurons has not been mapped. Here, we isolate DANs from Dat-eGFP mice to generate a GPCR atlas by unbiased qPCR array expression analysis of 377 GPCRs. Combined with data mining of scRNA-seq databases, we identify multiple receptors in DAN subpopulations with 38 of these receptors representing the majority of transcripts. We identify 41 receptors expressed in midbrain DANs but not in non-DAN midbrain cells, including the free fatty acid receptor 4 (FFAR4). Functional expression of FFAR4 is validated by ex vivo Ca2+ imaging, and in vivo experiments support that FFAR4 negatively regulates food and water intake and bodyweight. In addition to providing a critical framework for understanding metabotropic DAN regulation, our data suggest fatty acid sensing by FFAR4 as a mechanism linking high-energy intake to the dopamine-reward pathway.
