Intracrine FFA4 signaling controls lipolysis at lipid droplets.

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 G_i/o protein signaling and preferential r

SUBMITTER: O'Brien SL 

PROVIDER: S-EPMC12727528 | biostudies-literature | 2026 Jan

REPOSITORIES: biostudies-literature