Long-Chain Free Fatty Acid Receptor GPR120 Mediates Oil-Induced GIP Secretion Through CCK in Male Mice

: Free fatty acid receptors GPR120 and GPR40 are involved in the secretion of gut hormones. GPR120 and GPR40 are expressed in enteroendocrine K cells, and their activation induces the secretion of the incretin glucose-dependent insulinotropic polypeptide (GIP). However, the role of these receptors in fat-induced GIP secretion in vivo and the associated mechanisms are unclear. In this study, we investigated corn oil-induced GIP secretion in GPR120-knockout (GPR120-/-) and GPR40-knockout (GPR40-/-) mice. Oil-induced GIP secretion was reduced by 50% and 80% in GPR120-/- and GPR40-/- mice, respectively, compared with wild-type mice. This was not associated with a significant difference in K-cell number or GIP content in K cells, nor messenger RNA levels of the lipid receptor GPR119, nor bile acid receptors TGR5 and farnesoid X receptor. GPR120-/- and GPR40-/- mice also exhibited substantially decreased levels of cholecystokinin (CCK), a hormone from I cells that promotes bile and pancreatic lipase secretion, and this decrease was associated with impaired gallbladder contraction. Notably, treatment with a CCK analog resulted in recovery of oil-induced GIP secretion in GPR120-/- mice but not in GPR40-/- mice. These results indicate that corn oil-induced GIP secretion from K cells involves both GPR120 and GPR40 signaling pathways, and GPR120-induced GIP secretion is indirectly mediated by CCK.