2. Academic Validation
  3. Intracrine FFA4 signaling controls lipolysis at lipid droplets

Intracrine FFA4 signaling controls lipolysis at lipid droplets

  • Nat Chem Biol. 2025 Aug 5. doi: 10.1038/s41589-025-01982-5.
Shannon L O'Brien # 1 2,  Emma Tripp # 3 4,  Natasja Barki 5,  Elodie Blondel-Tepaz 6 7,  Gabrielle Smith 3,  Adam Boufersaoui 3,  Jennie Roberts 3,  Jeremy A Pike 4,  Joao Correia 4,  Tamara Miljus 3 4,  Michel Bouvier 6 7,  Daniel A Tennant 3,  Brian D Hudson 5,  Zachary Gerhart-Hines 8,  Graeme Milligan 5,  Thue W Schwartz 8,  Davide Calebiro 9 10 11
Affiliations

Affiliations

  • 1 Department of Metabolism and Systems Science, College of Medicine and Health, University of Birmingham, Birmingham, UK. s.l.obrien@bham.ac.uk.
  • 2 Centre of Membrane Proteins and Receptors (COMPARE), Universities of Nottingham and Birmingham, Birmingham, UK. s.l.obrien@bham.ac.uk.
  • 3 Department of Metabolism and Systems Science, College of Medicine and Health, University of Birmingham, Birmingham, UK.
  • 4 Centre of Membrane Proteins and Receptors (COMPARE), Universities of Nottingham and Birmingham, Birmingham, UK.
  • 5 Centre for Translational Pharmacology, School of Molecular Biosciences, College of Medical, Veterinary and Life Sciences, University of Glasgow, Glasgow, UK.
  • 6 Department of Biochemistry and Molecular Medicine, Université de Montréal, Montreal, Quebec, Canada.
  • 7 Institute for Research in Immunology and Cancer, Université de Montréal, Montreal, Quebec, Canada.
  • 8 Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
  • 9 Department of Metabolism and Systems Science, College of Medicine and Health, University of Birmingham, Birmingham, UK. d.calebiro@bham.ac.uk.
  • 10 Centre of Membrane Proteins and Receptors (COMPARE), Universities of Nottingham and Birmingham, Birmingham, UK. d.calebiro@bham.ac.uk.
  • 11 National Institute for Health and Care Research (NIHR) Birmingham Biomedical Research Centre, Birmingham, UK. d.calebiro@bham.ac.uk.
  • # Contributed equally.
PMID: 40764678 DOI: 10.1038/s41589-025-01982-5
Abstract

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 Gi/o 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-Gαi/o proteins to locally inhibit Gi/o signaling. These findings reveal an unexpected 'intracrine' GPCR signaling modality involved in the local regulation of cell metabolism, with biological and pharmacological implications.

Figures
Products