Ffar4
Developmental stage
Expression detected in differentiated mature adipocytes, with levels increasing during late stage adipocyte differentiation (PubMed:17250804, PubMed:29343498). Low expression is detected in preadipocytes, mainly localized in primary cilium (PubMed:31761534). Expression level in bone marrow mesenchymal stem cells is gradually increased during differentiation toward osteoblasts (PubMed:26365922).
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 (PubMed:26873857, PubMed:27852822). 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) (PubMed:26873857, PubMed:27852822). 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 (PubMed:26873857, PubMed:27852822). In response to dietary fats, plays an important role in the regulation of adipocyte proliferation and differentiation (PubMed:17250804, PubMed:22343897, PubMed:27853148, PubMed:29343498, PubMed:31761534). 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 (PubMed:31761534). Induces differentiation of brown and beige adipocytes probably via autocrine and endocrine functions of FGF21 hormone (PubMed:27853148, PubMed:29343498). Contributes to the thermogenic activation of brown adipose tissue and the browning of white adipose tissue (PubMed:27853148, PubMed:29343498). Activates brown adipocytes by initiating intracellular calcium signaling leading to mitochondrial depolarization and fission, and overall increased mitochondrial respiration (PubMed:29343498). Consequently stimulates fatty acid uptake and oxidation in mitochondria together with UCP1-mediated thermogenic respiration, eventually reducing fat mass (PubMed:29343498). Regulates bi-potential differentiation of bone marrow mesenchymal stem cells toward osteoblasts or adipocytes likely by up-regulating distinct integrins (PubMed:26365922). In response to dietary fats regulates hormone secretion and appetite (PubMed:15619630, PubMed:24222669, PubMed:24663807, PubMed:24742677, PubMed:25535828). 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 (PubMed:15619630, PubMed:24742677, PubMed:25535828). Negatively regulates glucose-induced SST secretion in pancreatic delta cells (PubMed:24663807). Mediates LCFAs inhibition of GHRL secretion, an appetite-controlling hormone (PubMed:24222669). In taste buds, contributes to sensing of dietary fatty acids by the gustatory system (PubMed:20573884). During the inflammatory response, promotes anti-inflammatory M2 macrophage differentiation in adipose tissue (PubMed:20813258). 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 (PubMed:20813258). 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 (PubMed:15774482).
Post-translational modifications
Phosphorylated at two clusters of Ser and Thr residues located in the intracellular C-terminus, a prerequisite for FFAR4 internalization via an ARRB2-dependent pathway.
Sequence Similarities
Belongs to the G-protein coupled receptor 1 family.
Tissue Specificity
Highly expressed in brown and white adipose tissue (PubMed:17250804, PubMed:24222669, PubMed:27853148). Expressed in perivascular ciliated preadipocytes (at protein level) (PubMed:31761534). Expressed in the taste buds of the circumvallate and fungiform papillae, mainly in type II cells (at protein level) (PubMed:19071193, PubMed:20573884). Abundant expression is detected in the gastrointestinal tract (PubMed:15619630, PubMed:17250804, PubMed:24222669, PubMed:27853148). Highly expressed in lung and pituitary gland (PubMed:15619630, PubMed:17250804). Expressed in enteroendocrine K cells of the upper small intestine (PubMed:25535828). Expressed in alpha and delta cells of pancreatic islets (PubMed:24663807, PubMed:24742677). Expressed in pro-inflammatory CD11C-positive macrophages (PubMed:20813258). Also expressed in spleen (PubMed:17250804).
Cellular localization
- Cell membrane
- Multi-pass membrane protein
- Endosome membrane
- Multi-pass membrane protein
- Lysosome membrane
- Multi-pass membrane protein
- Cell projection
- Cilium membrane
- Multi-pass membrane protein
- 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).
Alternative names
Gpr120, O3far1, Ffar4, Free fatty acid receptor 4, G-protein coupled receptor 120, G-protein coupled receptor GT01, Omega-3 fatty acid receptor 1