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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.

Gut hormone gastric inhibitory polypeptide (GIP) stimulates insulin secretion from pancreatic beta-cells upon ingestion of nutrients. Inhibition of GIP signaling prevents the onset of obesity and consequent insulin resistance induced by high-fat diet. In this study, we investigated the role of GIP in accumulation of triglycerides into adipocytes and in fat oxidation peripherally using insulin receptor substrate (IRS)-1-deficient mice and revealed that IRS-1(-/-)GIPR(-/-) mice exhibited both reduced adiposity and ameliorated insulin resistance. Furthermore, increased gene expression of CD36 and UCP2 in liver, and increased expression and enzyme activity of 3-hydroxyacyl-CoA dehydrogenase in skeletal muscle of IRS-1(-/-)GIPR(-/-) mice might contribute to the lower respiratory quotient and the higher fat oxidation in light phase. These results suggest that GIP plays a crucial role in switching from fat oxidation to fat accumulation under the diminished insulin action as a potential target for secondary prevention of insulin resistance.

Gastric inhibitory polypeptide (GIP) is an incretin that potentiates insulin secretion from pancreatic ␤-cells by binding to GIP receptor (GIPR) and subsequently increasing the level of intracellular adenosine 3Ј,5Ј-cyclic monophosphate (cAMP). We have identified a novel GIPR splice variant in mouse ␤-cells that retains intron 8, resulting in a COOH-terminal truncated form (truncated GIPR). This isoform was coexpressed with full-length GIPR (wild-type GIPR) in normal GIPR-expressing tissues. In an experiment using cells transfected with both GIPRs, truncated GIPR did not lead to cAMP production induced by GIP but inhibited GIP-induced cAMP production through wild-type GIPR (n ϭ 3-4, P Ͻ 0.05). Wild-type GIPR was normally located on the cell surface, but its expression was decreased in the presence of truncated GIPR, suggesting a dominant negative effect of truncated GIPR against wild-type GIPR. The functional relevance of truncated GIPR in vivo was investigated. In high-fat diet-fed obese mice (HFD mice), blood glucose levels were maintained by compensatory increased insulin secretion (n ϭ 8, P Ͻ 0.05), and cAMP production (n ϭ 6, P Ͻ 0.01) and insulin secretion (n ϭ 10, P Ͻ 0.05) induced by GIP were significantly increased in isolated islets, suggesting hypersensitivity of the GIPR. Total GIPR mRNA expression was not increased in the islets of HFD mice, but the expression ratio of truncated GIPR to total GIPR was reduced by 32% compared with that of control mice (n ϭ 6, P Ͻ 0.05). These results indicate that a relative reduction of truncated GIPR expression may be involved in hypersensitivity of GIPR and hyperinsulinemia in diet-induced obese mice.gastric inhibitory polypeptide; gastric inhibitory polypeptide receptor; alternative splicing; dominant negative effect; obesity OBESITY LEADS TO INSULIN RESISTANCE, characterized by fasting hyperinsulinemia and excessive insulin secretion after meal ingestion in the attempt to maintain euglycemia (25). Obesity is an important risk factor in progression to type 2 diabetes mellitus (14) and also in cardiovascular disease (16), and reduction of obesity can normalize hyperinsulinemia and impede the progression of diabetes and arteriosclerosis.Incretins are a group of peptide hormones released from the gastrointestinal tract into the circulation in response to meal ingestion that potentiate glucose-stimulated insulin secretion and include gastric inhibitory polypeptide (GIP), also called glucose-dependent insulinotropic polypeptide (24). GIP is secreted from the K cells of the duodenum and proximal jejunum upon meal ingestion and binds to the GIP receptor (GIPR) on the surface of pancreatic ␤-cells, adipose tissues, and osteoblasts to stimulate insulin secretion (21), fat accumulation (20), and bone formation (30) by increasing the level of intracellular adenosine 3Ј,5Ј-cyclic monophosphate (cAMP).Previously, we found that GIPR-deficient mice exhibit insufficient compensatory insulin secretion upon high-fat loading (21), indicating that GIP plays a critical role in mainta...