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Abstract

Gastric inhibitory polypeptide (GIP) is an incretin released from enteroendocrine K-cells in response to nutrient ingestion. GIP potentiates glucose-stimulated insulin secretion and induces energy accumulation into adipose tissue, resulting in obesity. Plasma GIP levels are reported to be increased in the obese state. However, the molecular mechanisms of GIP secretion and high-fat diet (HFD)-induced GIP hypersecretion remain unclear, primarily due to difficulties in separating K-cells from other intestinal epithelial cells in vivo. In the present study, GIP-GFP knock-in mice that enable us to visualize K-cells by EGFP were established. Microarray analysis of isolated K-cells from these mice revealed that transcriptional factor regulatory factor X 6 (Rfx6) is expressed exclusively in K-cells. In vitro experiments using mouse intestinal cell line STC-1 showed that knockdown of Rfx6 decreased mRNA expression, cellular content, and secretion of GIP. Rfx6 bound to the region in GIP promoter that regulates GIP promoter activity and over-expression of Rfx6 increased GIP mRNA expression. HFD induced obesity and GIP hypersecretion in GIP-GFP heterozygous mice in vivo. Immunohistochemical and flow cytometry analysis showed no significant difference in K-cell number between control-fat diet (CFD)-fed and HFD-fed mice. However, GIP content in upper small intestine and GIP mRNA expression in K-cells were significantly increased in HFD-fed mice compared to those in CFD-fed mice. Furthermore, expression levels of Rfx6 mRNA were increased in K-cells of HFD-fed mice. These results suggest that Rfx6 increases GIP expression and content in K-cells and is involved in GIP hypersecretion in HFD-induced obesity.