Intracrine FFA4 signaling controls lipolysis at lipid droplets
G-protein-coupled receptors (GPCRs) can signal from intracellular compartments but the occurrence and relevance of this phenomenon for metabolite-sensing GPCRs is largely unknown. Here, we investigate free fatty acid receptor 4 (FFA4), a metabolite-sensing GPCR activated by medium-chain and long-chain fatty acids. Using live-cell imaging, bioluminescence resonance energy transfer, super-resolution microscopy and cell fractionation, we show that FFA4 localizes to intracellular membranes, particularly endoplasmic reticulum subdomains surrounding lipid droplets, in both immortalized adipocytes and mouse adipose tissue. Upon lipolysis, locally released fatty acids appear to rapidly activate this intracellular FFA4 pool, leading to G<sub>i</sub><sub>/o</sub> protein signaling and preferential reduction of cyclic adenosine monophosphate levels near lipid droplets. These mechanisms are required for efficient FFA4-mediated lipolysis regulation, as shown using tethered mini-Gα<sub>i/o</sub> proteins to locally inhibit G<sub>i/o</sub> signaling. These findings reveal an unexpected 'intracrine' GPCR signaling modality involved in the local regulation of cell metabolism, with biological and pharmacological implications.
Authors
- Jennie Roberts (ORCID: https://orcid.org/0000-0001-7372-8498)
- Joao Correia (ORCID: https://orcid.org/0000-0002-4376-978X)
- Élodie Blondel-Tepaz
- Davide Calebiro
- Adam Boufersaoui (ORCID: https://orcid.org/0000-0001-8277-121X)
- Natasja Barki (ORCID: https://orcid.org/0000-0003-4869-4307)
- Thue Walter Schwartz (ORCID: https://orcid.org/0000-0002-0261-6904)
- Jeremy A. Pike (ORCID: https://orcid.org/0000-0003-4163-0335)
- Daniel A. Tennant (ORCID: https://orcid.org/0000-0003-0499-2732)
- Shannon O’Brien
- Graeme Milligan (ORCID: https://orcid.org/0000-0002-6946-3519)
- Tamara Miljuš (ORCID: https://orcid.org/0000-0003-0462-7866)
- Brian D. Hudson (ORCID: https://orcid.org/0000-0001-7059-0091)
- Zachary Gerhart‐Hines (ORCID: https://orcid.org/0000-0003-2981-4991)
- Emma Tripp (ORCID: https://orcid.org/0000-0003-1425-5541)
- Michel Bouvier (ORCID: https://orcid.org/0000-0003-1128-0100)
- Gabrielle Smith
Institutions
- University of Copenhagen (DK)
- Novo Nordisk Foundation (DK)
- National Institute for Health and Care Research (GB)
- Institute for Research in Immunology and Cancer (CA)
- NIHR Surgical Reconstruction and Microbiology Research Centre (GB)
- NIHR Birmingham Biomedical Research Centre (GB)
- Université de Montréal (CA)
- University of Glasgow (GB)
- University of Birmingham (GB)
Publication Details
- Journal
- Nature Chemical Biology
- Published
- 2025-08-05
- DOI
- https://doi.org/10.1038/s41589-025-01982-5
- Citations
- 2
- Primary Topic
- Lipid metabolism and biosynthesis
- Type
- article
- Field-Weighted Citation Impact
- 2.22
Funders
- Wellcome
- Wellcome Trust
- Cancer Research UK
- National Institute for Health and Care Research
- Directorate for Biological Sciences
- Canadian Institutes of Health Research
- Medical Research Council
- Biotechnology and Biological Sciences Research Council