Gastric inhibitory polypeptide (GIP) exhibits potent insulinotropic effects on b-cells and anabolic effects on bone formation and fat accumulation. We explored the impact of reduced GIP levels in vivo on glucose homeostasis, bone formation, and fat accumulation in a novel GIP-GFP knock-in (KI) mouse. We generated GIP-GFP KI mice with a truncated prepro-GIP gene. The phenotype was assessed in heterozygous and homozygous states in mice on a control fat diet and a high-fat diet (HFD) , and GIP gfp/gfp mice, while insulin secretion remained lower. GIP gfp/+ and GIP gfp/gfp mice showed reduced obesity and reduced insulin resistance, accompanied by higher fat oxidation and energy expenditure. GIP-reduced mice demonstrate that partial reduction of GIP does not extensively alter glucose tolerance, but it alleviates obesity and lessens the degree of insulin resistance under HFD conditions, suggesting a potential therapeutic value.Gastric inhibitory polypeptide (GIP) is a 42-amino acid polypeptide produced by enteroendocrine K cells, which are located mainly in the upper parts of the small intestine. Its main secretagogues are glucose and, even more intensely, fats that reach the intestinal lumen soon after food intake (1). Following secretion, the hormone exerts its effects through specific, G-protein-coupled receptors located mainly in the stomach, pancreas, central nervous system, bone, and adipose tissue (2,3). Apart from its role in the inhibition of gastric acid secretion (4), GIP exhibits potent glucose-dependent insulinotropic action (5,6), and, therefore, it is classified as an incretin (3). In addition to its insulinotropic effect, in the absence of which glucose intolerance develops (7), GIP stimulates islet growth (8) and proliferation of b-cells (9), and reduces b-cell apoptosis (10,11). Studies of GIP receptor (GIPR) knock-out (GIPRKO) mice (7) describe GIP as an obesitypromoting factor in high-fat diet (HFD) conditions, and show that deletion of GIPR signaling causes resistance to obesity (12) but leads to osteoporosis (13), revealing an important role of GIP in bone metabolism. However, in these studies, as well as in a model of GIPR antagonism (14), the reported changes were focused on disrupted or blocked GIPR signaling. The condition of reduced GIP secretion and how it affects the pancreatic and extrapancreatic effects of GIP remain unclear.The aim of the current study is to explore the potential of reduced GIP levels in vivo, and to define the impact on glucose homeostasis, bone formation, and fat accumulation in a novel GIP-green fluorescent protein (GFP) knock-in (KI) mouse model characterized by truncation of the prepro-GIP gene and insertion of a GFP sequence (15). The model was developed for the purpose of visualization and identification of K cells and exhibits reduced

Gastric inhibitory polypeptide (GIP) is an incretin secreted from enteroendocrine K cells in response to meal ingestion. Recently free fatty acid receptor G protein-coupled receptor (GPR) 120 was identified as a lipid sensor involved in glucagon-like peptide-1 secretion. However, Gpr 120 gene expression and its role in K cells remain unclear, partly due to difficulties in separation of K cells from other intestinal epithelial cells. In this study, we purified K cells using GIP-green fluorescent protein (GFP) knock-in mice, in which K cells can be visualized by GFP fluorescence. GFP-positive cells (K cells) were observed in the small intestine but not in the stomach and colon. K cell number and GIP content in K cells were significantly higher in the upper small intestine than those in the lower small intestine. We also examined the expression levels of several free fatty acid receptors in K cells. Among free fatty acid receptors, GPR120 was highly expressed in the K cells of the upper small intestine compared with the lower small intestine. To clarify the role of GPR120 on K cells in vivo, we used GPR120-deficient mice (GPR120(-/-)). GPR120(-/-) exhibited significantly lower GIP secretion (75% reduction, P < .01) after lard oil ingestion compared with that in wild-type mice. Consistently, pharmacological inhibition of GPR120 with grifolic acid methyl ether in wild-type mice significantly attenuated lard oil-induced GIP secretion. In conclusion, GPR120 is expressed abundantly in K cells of the upper small intestine and plays a critical role in lipid-induced GIP secretion.

Background: Gastric inhibitory polypeptide (GIP) secreted from enteroendocrine K-cells potentiates insulin secretion and induces energy accumulation into adipose tissue. Results: Transcriptional Rfx6 is expressed in K-cells and increases GIP expression. Rfx6 expression is up-regulated in K-cells of obese mice. Conclusion: Rfx6 plays critical roles in GIP expression and hypersecretion in obesity. Significance: Gene analysis of K-cells isolated from GIP-GFP knock-in mice enabled identification of Rfx6.

Gastric inhibitory polypeptide receptor (GIPR) directly induces energy accumulation in adipose tissue in vitro. However, the importance of the direct effect of GIPR signaling on adipose tissue in vivo remains unclear. In the current study, we generated adipose tissue-specific GIPR knockout (GIPR) mice and investigated the direct actions of GIP in adipose tissue. Under high-fat diet (HFD)-fed conditions, GIPR mice had significantly lower body weight and lean body mass compared with those in floxed GIPR (GIPR) mice, although the fat volume was not significantly different between the two groups. Interestingly, insulin resistance, liver weight, and hepatic steatosis were reduced in HFD-fed GIPR mice. Plasma levels of interleukin-6 (IL-6), a proinflammatory cytokine that induces insulin resistance, were reduced in HFD-fed GIPR mice compared with those in HFD-fed GIPR mice. Suppressor of cytokine signaling 3 (SOCS3) signaling is located downstream of the IL-6 receptor and is associated with insulin resistance and hepatic steatosis. Expression levels of SOCS3 mRNA were significantly lower in adipose and liver tissues of HFD-fed GIPR mice compared with those of HFD-fed GIPR mice. Thus, GIPR signaling in adipose tissue plays a critical role in HFD-induced insulin resistance and hepatic steatosis in vivo, which may involve IL-6 signaling.

Gastric inhibitory polypeptide (GIP) is an incretin released from enteroendocrine K cells in response to nutrient intake, especially fat. GIP is one of the contributing factors inducing fat accumulation that results in obesity. A recent study shows that fatty acid-binding protein 5 (FABP5) is expressed in murine K cells and is involved in fat-induced GIP secretion. We investigated the mechanism of fat-induced GIP secretion and the impact of FABP5-related GIP response on diet-induced obesity (DIO). Single oral administration of glucose and fat resulted in a 40% reduction of GIP response to fat but not to glucose in whole body FABP5-knockout (FABP5(-/-)) mice, with no change in K cell count or GIP content in K cells. In an ex vivo experiment using isolated upper small intestine, oleic acid induced only a slight increase in GIP release, which was markedly enhanced by coadministration of bile and oleic acid together with attenuated GIP response in the FABP5(-/-) sample. FABP5(-/-) mice exhibited a 24% reduction in body weight gain and body fat mass under a high-fat diet compared with wild-type (FABP5(+/+)) mice; the difference was not observed between GIP-GFP homozygous knock-in (GIP(gfp/gfp))-FABP5(+/+) mice and GIP(gfp/gfp)-FABP5(-/-) mice, in which GIP is genetically deleted. These results demonstrate that bile efficiently amplifies fat-induced GIP secretion and that FABP5 contributes to the development of DIO in a GIP-dependent manner.