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.

ObjectiveGlucose-dependent insulinotropic polypeptide (GIP) is released during meals and promotes nutrient uptake and storage. GIP receptor knockout mice are protected from diet induced weight gain and thus GIP antagonists have been proposed as a treatment for obesity. In this study, we assessed the role of GIP in hyperphagia induced obesity and metabolic abnormalities in leptin deficient (Lepob/ob) mice.MethodsWe crossbred GIP-GFP knock-in homozygous mice (GIPgfp/gfp) that have complete GIP knockout, and mice heterozygous for the ob mutation (Lepob/+) mice to generate Lepob/+/GIP+/+, Lepob/ob/GIP+/+, and Lepob/ob/GIPgfp/gfp mice. Male animals were weighed weekly and both oral glucose and insulin tolerance testing were performed to assess glucose homeostasis and circulating profiles of GIP and insulin. Body composition was evaluated by computerized tomography (CT) scan and analyses of indirect calorimetry and locomotor activity were performed.ResultsPostprandial GIP levels were markedly elevated in Lepob/ob/GIP+/+ mice compared to Lepob/+/GIP+/+ controls and were undetectable in Lepob/ob/GIPgfp/gfp mice. Insulin levels were equivalently elevated in both Lepob/ob/GIP+/+ and Lepob/ob/GIPgfp/gfp mice compared to controls at 8 weeks of age but the hyperinsulinemia was marginally reduced in Lepob/ob/GIPgfp/gfp by 21 weeks, in association with amelioration of glucose intolerance. Both Lepob/ob/GIP+/+ and Lepob/ob/GIPgfp/gfp mice remained equivalently insulin resistant. Body weight gain and subcutaneous and visceral fat volume of both Lepob/ob/GIP+/+ and Lepob/ob/GIPgfp/gfp mice were significantly higher than that of Lepob/+/GIP+/+ mice, while no significant differences were seen between Lepob/ob/GIP+/+ and Lepob/ob/GIPgfp/gfp mice. Locomotor activity and energy expenditure were decreased in both Lepob/ob/GIP+/+ and Lepob/ob/GIPgfp/gfp mice compared to control Lepob/+/GIP+/+ mice, while no significant differences were seen between Lepob/ob/GIP+/+ and Lepob/ob/GIPgfp/gfp mice. There was no significant difference in fat oxidation among the three groups. Fat content in liver was significantly lower in Lepob/ob/GIPgfp/gfp compared to Lepob/ob/GIP+/+ mice, while that of control Lepob/+/GIP+/+ mice was the lowest.ConclusionsOur results indicate that GIP knockout does not prevent excess weight gain and metabolic derangement in hyperphagic leptin deficient mice.

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Glucose-dependent insulinotropic polypeptide (GIP) is an incretin secreted from enteroendocine K cells after nutrient ingestion. Fat strongly induces GIP secretion, and GIP hypersecretion is involved in high-fat diet-induced obesity and insulin resistance. Aging also induces GIP hypersecretion, but its effect on body weight gain and insulin sensitivity remains unclear. In the present study, we investigated the effect of GIP on age-related body weight gain and insulin resistance using GIP-knockout homozygous (GIP−/−) and heterozygous (GIP+/−) mice, which have entirely absent and 50% reduced GIP secretion compared to wild-type (WT) mice, respectively. Under 12% fat-containing normal diet feeding condition, body weight was significantly lower in GIP−/− mice compared to that in WT and GIP+/− mice from 38 weeks of age, while there was no significant difference between WT and GIP+/− mice. Visceral and s.c. fat mass were also significantly lower in GIP−/− mice compared to those in WT and GIP+/− mice. During oral glucose tolerance test, blood glucose levels did not differ among the three groups. Insulin levels were significantly lower in GIP−/− mice than those in WT and GIP+/− mice. During insulin tolerance test, GIP−/− mice showed higher insulin sensitivity than that of WT and GIP+/− mice. Adiponectin mRNA levels were increased and leptin mRNA levels tended to be decreased in adipose tissue of GIP−/− mice. These results demonstrate that GIP is involved in age-related obesity and insulin resistance and that inhibition of GIP secretion alleviates age-related fat mass gain and insulin resistance under carbohydrate-based diet feeding condition.