An atlas of GPCRs in dopamine neurons: Identification of the free fatty acid receptor 4 as a regulator of food and water intake

• DOI: 10.1016/j.celrep.2024.114509
• Publication Date: 2024-07-13T16:20:02Z
• Authors: 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
• Keywords: Male; QH301-705.5; Drinking; fatty acids; Receptors, G-Protein-Coupled; Mice; Eating; FFAR4; G protein-coupled receptors; Mesencephalon; Dat-eGFP mice; gpr120; Animals; Biology (General); array analysis; Neuroscience [CP]; Dopaminergic Neurons; CP: Metabolism; Mice, Inbred C57BL; Metabolism [CP]; CP: Neuroscience; dopamine; heterogeneity; metabolism; fluorescence-activated cell sorting

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.