Protein: Free fatty acid receptor 4 (G-protein coupled receptor 120) (G-protein coupled receptor GT01) (Omega-3 fatty acid receptor 1) (Q7TMA4)
Organism: Mus musculus (Mouse)
Function: G-protein-coupled receptor for long-chain fatty acids (LCFAs) with a major role in adipogenesis, energy metabolism and inflammation. Signals via G-protein and beta-arrestin pathways. LCFAs sensing initiates activation of phosphoinositidase C-linked G proteins GNAQ and GNA11 (G(q)/G(11)), inducing a variety of cellular responses via second messenger pathways such as intracellular calcium mobilization, modulation of cyclic adenosine monophosphate (cAMP) production, and mitogen-activated protein kinases (MAPKs). After LCFAs binding, associates with beta-arrestin ARRB2 that acts as an adapter protein coupling the receptor to specific downstream signaling pathways, as well as mediating receptor endocytosis. In response to dietary fats, plays an important role in the regulation of adipocyte proliferation and differentiation. Acts as a receptor for omega-3 polyunsaturated fatty acids (PUFAs) at primary cilium of perivascular preadipocytes, initiating an adipogenic program via cAMP and CTCF-dependent chromatin remodeling that ultimately results in transcriptional activation of adipogenic genes and cell cycle entry. Induces differentiation of brown and beige adipocytes probably via autocrine and endocrine functions of FGF21 hormone. Contributes to the thermogenic activation of brown adipose tissue and the browning of white adipose tissue. Activates brown adipocytes by initiating intracellular calcium signaling leading to mitochondrial depolarization and fission, and overall increased mitochondrial respiration. Consequently stimulates fatty acid uptake and oxidation in mitochondria together with UCP1-mediated thermogenic respiration, eventually reducing fat mass. Regulates bi-potential differentiation of bone marrow mesenchymal stem cells toward osteoblasts or adipocytes likely by up-regulating distinct integrins. In response to dietary fats regulates hormone secretion and appetite. Stimulates GIP and GLP1 secretion from enteroendocrine cells as well as GCG secretion in pancreatic alpha cells, thereby playing a role in the regulation of blood glucose levels. Negatively regulates glucose-induced SST secretion in pancreatic delta cells. Mediates LCFAs inhibition of GHRL secretion, an appetite-controlling hormone. In taste buds, contributes to sensing of dietary fatty acids by the gustatory system. During the inflammatory response, promotes anti-inflammatory M2 macrophage differentiation in adipose tissue. Mediates the anti-inflammatory effects of omega-3 PUFAs via inhibition of NLRP3 inflammasome activation (By similarity). In this pathway, interacts with adapter protein ARRB2 and inhibits the priming step triggered by Toll-like receptors (TLRs) at the level of TAK1 and TAB1. Further inhibits the activation step when ARRB2 directly associates with NLRP3, leading to inhibition of pro-inflammatory cytokine release (By similarity). Mediates LCFAs anti-apoptotic effects.
Subcellular location: Cell membrane {ECO:0000269|PubMed:20813258, ECO:0000269|PubMed:26873857, ECO:0000269|PubMed:27852822}; Multi-pass membrane protein {ECO:0000255}. Endosome membrane {ECO:0000250|UniProtKB:Q5NUL3}; Multi-pass membrane protein {ECO:0000255}. Lysosome membrane {ECO:0000250|UniProtKB:Q5NUL3}; Multi-pass membrane protein {ECO:0000255}. Cell projection, cilium membrane {ECO:0000269|PubMed:31761534}; Multi-pass membrane protein {ECO:0000255}. Note=Sorted to late endosome/lysosome compartments upon internalization (By similarity). Specifically localizes to the primary cilium of undifferentiated adipocytes. Ciliary trafficking is TULP3-dependent. As the cilium is lost during adipogenesis, moves to the plasma membrane (PubMed:31761534). {ECO:0000250|UniProtKB:Q5NUL3, ECO:0000269|PubMed:31761534}.
Interaction partners:
- Free fatty acid receptor 1
- Beta-arrestin-2
- Guanine nucleotide-binding protein G
- Pro-glucagon
- Free fatty acid receptor 2
- Free fatty acid receptor 3
- G-protein coupled receptor 84
- Glucose-dependent insulinotropic receptor
- Insulin-2
- Insulin-1
Sequence:
MSPECAQTTGPGPSHTLDQVNRTHFPFFSDVKGDHRLVLSVVETTVLGLIFVVSLLGNVCALVLVARRRRRGATASLVLNLFCADLLFTSAIPLVLVVRWTEAWLLGPVVCHLLFYVMTMSGSVTILTLAAVSLERMVCIVRLRRGLSGPGRRTQAALLAFIWGYSALAALPLCILFRVVPQRLPGGDQEIPICTLDWPNRIGEISWDVFFVTLNFLVPGLVIVISYSKILQITKASRKRLTLSLAYSESHQIRVSQQDYRLFRTLFLLMVSFFIMWSPIIITILLILIQNFRQDLVIWPSLFFWVVAFTFANSALNPILYNMSLFRNEWRKIFCCFFFPEKGAIFTDTSVRRNDLSVISS