GPR120 is a receptor for long chain fatty acids and is expressed in small intestinal endocrine cells, L cells and adipose tissue. Activation of GPR120 promotes the secretion of incretin GLP-1, which is known to have effects on anti-metabolic syndrome. As such, GPR120 is a potential target of pharmaceuticals for type II diabetes. In this study, we performed ligand-screening for GPR120 on glycero- and sphingo-type lipids and their derivatives using a Transforming Growth Factor α-shedding assay. We found that phytosphingosine (PHS) activates GPR120 in a manner comparable to the natural ligand α-linolenic acid (ALA) and superior to that of the synthetic ligand GW9508. The IC50 value of PHS was 33.4 μM, of ALA was 31.0 μM and of GW9508 was 41.7 μM. Additionally, PHS-induced activation of GPR120 was inhibited by the specific antagonist AH7614. Many of the natural or synthetic ligands found thus far are compounds with carboxyl groups. However, PHS does not possess a carboxyl group, suggesting that its manner of interaction with GPR120 may be significantly different from that of other ligands. Since PHS is rich in the plasma membrane of yeast, our results imply that PHS found in fermented food could have effects on anti-diabetes through activation of GPR120.

9‐Methyl‐sphingadiene has a characteristic structure containing a methyl group and is only found in fungi including mushrooms and mycota such as Aspergillus oryzae. The Japanese daily ingest it through traditional fermented foods, such like miso, soy sauce, and sake. However, the food function of 9‐methyl‐sphingadiene is hardly elucidated. In this study, we first revealed that 9‐methyl‐sphingadiene is a novel ligand for peroxisome proliferator‐activated receptor γ (PPARγ) and GPR120, and induces differentiation in 3T3‐L1 cells. Synthetic ligands of PPARγ are widely used to treat type 2 diabetes, and are known to accelerate adipogenesis. GPR120 plays an important role in the browning of adipocytes and their differentiation into beige cells. An increase in beige cells and brown adipocytes is known to suppress obesity. Thus, ligands for PPARγ and/or GPR120 are thought to have important function in controlling diabetes and obesity. Our result indicates that fungal sphingoid bases in fermented foods have anti‐diabetic role. Practical applications One major characteristic of Japanese meal is to use various food fermented with the non‐pathogenic fungus Aspergillus oryzae, Koji. The Koji contains unique sphingoid base, 9‐methyl‐sphingadiene. In this study, we investigated a food function of the 9‐methyl‐sphingadiene, and found that 9‐methyl‐sphingadiene is a novel ligand for PPARγ and GPR120. Since the ligands of PPARγ and GPR120 are involved in anti‐obesity and anti‐diabetes, our result indicates that daily intake of Koji might prevent the development of obesity and diabetes. This study do not only reveals one of the health benefit of Japanese food containing Koji, but also the possibility in the application of 9‐methyl‐sphingadiene as functional food.

Post-fermented teas, produced by microbial fermentation, are attracting attention due to health benefits that reducing the risk of hyperlipidemia and atherosclerosis. Although several novel polyphenols have been identified from post-fermented...

Free fatty acid receptor 4 (FFAR4)/GPR120 comprises a receptor for medium-and long-chain fatty acids. We previously identified phytosphingosine (PHS) as a novel ligand of FFAR4. Although many natural FFAR4 ligands have carboxyl groups, PHS does not, thus suggesting that binding to FFAR4 is driven by a completely different mechanism than other natural ligands such as a-linolenic acid (ALA). To test this hypothesis, we performed docking simulation analysis using a FFAR4 homology model based on a protein model derived from the crystal structure of activated turkey beta-1 adrenoceptor. The docking simulation revealed that the probable hydrogen bonds to FFAR4 differ between various ligands. In particular, binding was predicted between R264 of the FFAR4 and the oxygen of the carboxylate group in ALA, as well as between E249 of the FFAR4 and the oxygen of the hydroxy group at the C4-position in PHS. Alanine substitution at E249 (E249A) dramatically reduced PHS-induced FFAR4 activation but demonstrated a weaker effect on ALA-induced FFAR4 activation. Kinetic analysis and K m values clearly demonstrated that the E249A substitution resulted in reduced affinity for PHS but not for ALA. Additionally, we observed that sphingosine, lacking a hydroxyl group at C4-position, could not activate FFAR4. Our data show that E249 of the FFAR4 receptor is crucial for binding to the hydroxy group at the C4position in PHS, and this is a completely different molecular mechanism of binding from ALA. Because GPR120 agonists have attracted attention as treatments for type 2 diabetes, our findings may provide new insights into their development.Free fatty acid receptor 4 (FFAR4)/GPR120 comprises a receptor for medium-and long-chain fatty acids that is expressed in small intestinal endocrine cells, L cells and adipose tissue. Activation of FFAR4 promotes the secretion of glucagon-like peptide-1 (GLP-1) [1], which is known as an intestinal hormone incretin. GLP-1 was reported to suppress appetite and increase insulin secretion, exhibiting anti-diabetic effects [2][3][4]. Dipeptidyl peptidase-4, which degrades GLP-1, is known to extend the half-life of GLP-1 in