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<p>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.</p><p></p>

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Intracrine FFA4 signaling controls lipolysis at lipid droplets

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年8月5日

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  • Shannon L. O’Brien,
  • Emma Tripp,
  • Natasja Barki,
  • Elodie Blondel-Tepaz,
  • Gabrielle Smith,
  • Adam Boufersaoui,
  • Jennie Roberts,
  • Jeremy A. Pike,
  • Joao Correia,
  • Tamara Miljus,
  • Michel Bouvier,
  • Daniel A. Tennant,
  • Brian D. Hudson,
  • Zachary Gerhart-Hines,
  • Graeme Milligan,
  • Thue W. Schwartz,
  • Davide Calebiro

摘要

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.