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

• Published in: Cell reports (Cambridge) Vol. 43; no. 7; p. 114509
• Main Authors: Apuschkin, Mia, Burm, Hayley B., Schmidt, Jan H., Skov, Louise J., Andersen, Rita C., Bowin, Carl-Fredrik, Støier, Jonatan F., Jensen, Kathrine L., Posselt, Leonie P., Dmytriyeva, Oksana, Sørensen, Andreas T., Egerod, Kristoffer L., Holst, Birgitte, Rickhag, Mattias, Schwartz, Thue W., Gether, Ulrik
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 23.07.2024; Elsevier
• Subjects: Animals; array analysis; CP: Metabolism; CP: Neuroscience; Dat-eGFP mice; dopamine; Dopaminergic Neurons - metabolism; Drinking; Eating; fatty acids; FFAR4; fluorescence-activated cell sorting; G protein-coupled receptors; gpr120; heterogeneity; Male; Mesencephalon - metabolism; metabolism; Mice; Mice, Inbred C57BL; Receptors, G-Protein-Coupled - genetics; Receptors, G-Protein-Coupled - metabolism; G protein-coupled receptors; gpr120; fatty acids; Dat-eGFP mice; CP: Neuroscience; CP: Metabolism; FFAR4; array analysis; fluorescence-activated cell sorting; metabolism; dopamine; heterogeneity
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2024.114509

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. [Display omitted] •An unbiased GPCR atlas shows 179 distinct GPCRs present on DANs•38 GPCRs are responsible for the vast majority of all GPCR transcripts detected in DANs•41 GPCRs are expressed on midbrain DANs but not on midbrain non-DANs•FFAR4 is found on a subset of DANs and is involved in regulation of food and water intake Apuschkin et al. map the population-wide GPCR expression profile of dopamine neurons (DANs) to provide a framework for deciphering metabotropic DAN regulation. The authors highlight expression of the free fatty acid receptor 4 (FFAR4) on a subset of DANs and showcase this receptor as a food and water intake modulator.