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(Rfx6) Increases Gastric Inhibitory Polypeptide

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(Rfx6) Increases Gastric Inhibitory Polypeptide CORE Metadata, citation and similar papers at core.ac.uk Provided by Kyoto University Research Information Repository Transcriptional regulatory factor X6 (Rfx6) increases gastric inhibitory polypeptide (GIP) expression in enteroendocrine K- Title cells and is involved in GIP hypersecretion in high fat diet- induced obesity. Suzuki, Kazuyo; Harada, Norio; Yamane, Shunsuke; Nakamura, Yasuhiko; Sasaki, Kazuki; Nasteska, Daniela; Joo, Author(s) Erina; Shibue, Kimitaka; Harada, Takanari; Hamasaki, Akihiro; Toyoda, Kentaro; Nagashima, Kazuaki; Inagaki, Nobuya Citation The Journal of biological chemistry (2013), 288(3): 1929-1938 Issue Date 2013-01-18 URL http://hdl.handle.net/2433/182055 © 2013 by The American Society for Biochemistry and Right Molecular Biology, Inc. Type Journal Article Textversion author Kyoto University Rfx6 increases GIP mRNA expression in K-cells Transcriptional factor regulatory factor X 6 (Rfx6) increases gastric inhibitory polypeptide (GIP) expression in enteroendocrine K-cells and is involved in GIP hypersecretion in high-fat diet-induced obesity Kazuyo Suzuki, Norio Harada, Shunsuke Yamane, Yasuhiko Nakamura, Kazuki Sasaki, Daniela Nasteska, Erina Joo, Kimitaka Shibue, Takanari Harada, Akihiro Hamasaki, Kentaro Toyoda, Kazuaki Nagashima, and Nobuya Inagaki Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, Kyoto, Japan *Running title: Rfx6 increases GIP mRNA expression in K-cells Corresponding Author. Address: Nobuya Inagaki, Department of Diabetes and Clinical Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto 606-8507, Japan. Tel: +81(Japan)-75-751-3562, Fax: +81(Japan)-75-751-6601 E-mail: [email protected] Key words: GIP; K-cell; Rfx6; Pdx1; obesity Background: Gastric inhibitory polypeptide from these mice revealed that (GIP) secreted from enteroendocrine transcriptional factor regulatory factor X K-cells potentiates insulin secretion and 6 (Rfx6) is expressed exclusively in K-cells. induces energy accumulation into adipose In vitro experiments using mouse intestinal tissue. cell line STC-1 showed that knockdown of Results: Transcriptional factor Rfx6 is Rfx6 decreased mRNA expression, cellular expressed in K-cells and increases GIP content, and secretion of GIP. Rfx6 bound expression. Rfx6 expression is upregulated in to the region in GIP promoter that K-cells of obese mice. regulates GIP promoter activity and Conclusion: Rfx6 plays critical roles in GIP over-expression of Rfx6 increased GIP expression and hypersecretion in obesity. mRNA expression. HFD induced obesity Significance: Gene analysis of K-cells and GIP hypersecretion in GIP-GFP isolated from GIP-GFP knock-in mice heterozygous mice in vivo. enabled identification of Rfx6. Immunohistochemical and flow cytometry analysis showed no significant difference SUMMARY in K-cell number between control-fat diet Gastric inhibitory polypeptide (GIP) is an (CFD)-fed and HFD-fed mice. However, incretin released from enteroendocrine GIP content in upper small intestine and K-cells in response to nutrient ingestion. GIP mRNA expression in K-cells were GIP potentiates glucose-stimulated insulin significantly increased in HFD-fed mice secretion and induces energy compared to those in CFD-fed mice. accumulation into adipose tissue, resulting Furthermore, expression levels of Rfx6 in obesity. Plasma GIP levels are reported mRNA were increased in K-cells of to be increased in the obese state. However, HFD-fed mice. These results suggest that the molecular mechanisms of GIP Rfx6 increases GIP expression and content secretion and high-fat diet (HFD)-induced in K-cells and is involved in GIP GIP hypersecretion remain unclear, hypersecretion in HFD-induced obesity. primarily due to difficulties in separating Obesity leads to insulin resistance K-cells from other intestinal epithelial cells characterized by fasting hyperinsulinemia in vivo. In the present study, GIP-GFP and excessive insulin secretion to maintain knock-in mice that enable us to visualize euglycemia after meal ingestion (1). Obesity K-cells by EGFP were established. is an important risk factor in progression to Microarray analysis of isolated K-cells type 2 diabetes mellitus (2) as well as 1 Rfx6 increases GIP mRNA expression in K-cells cardiovascular disease (3), and reduction of fluorescence. We found that the obesity can normalize hyperinsulinemia and transcriptional factor regulatory factor X 6 impede the progression of diabetes and (Rfx6) is expressed exclusively in K-cells of arteriosclerosis. upper small intestine and is involved in GIP Gastric inhibitory polypeptide, also called mRNA expression in the mouse small glucose-dependent insulinotropic polypeptide intestinal cell line STC-1. Furthermore, (GIP), and glucagon-like peptide-1 (GLP-1) expression of Rfx6 as well as Pdx1 was are the incretins, peptide hormones released found to be increased in K-cells of from the gastrointestinal tract into circulation HFD-induced obese mice. Thus, GIP in response to meal ingestion that potentiate expression is stimulated by both Rfx6 and glucose-stimulated insulin secretion (4, 5). Pdx1, suggesting that these transcriptional GIP is secreted from enteroendocrine K-cells factors play an important role in both GIP located in the duodenum and upper small expression and GIP hypersecretion in intestine; GLP-1 is secreted from HFD-induced obesity. enteroendocrine L-cells located in lower small intestine and colon. GIP binds to the EXPERIMENTAL PROCEDURES GIP receptor (GIPR) on the surface of Animals― We designed targeting vector pancreatic -cells, adipose tissue and constructs as short osteoblasts, and stimulates insulin secretion -EGFP-polyA-loxp-Neo-loxp-long cassettes (6), fat accumulation (7), and bone formation using mouse B6N BAC Clone (ID: (8), respectively, by increasing the level of RP23-31E4 and RP23-383D10). A diphtheria intracellular adenosine 3',5'-monophosphate toxin A expression cassette for negative (cAMP). selection was attached to the 3’ end of the It was reported previously that GIP sequence in the targeting vector. Next, GIPR-deficient mice exhibit insufficient the targeting vector was injected in compensatory insulin secretion upon high-fat embryonic stem cells from C57BL6 mice and loading (9), suggesting that GIP plays a a Neo resistance strain was established. The critical role in maintaining blood glucose ES cells positive for the knock-in gene were levels by hypersecretion of insulin in selected by southern blot analysis. The diet-induced obesity. We also reported that established ES cells were then injected into sensitivity of GIPR to GIP in -cells is the blastocyst in order to obtain chimeric increased in high-fat diet (HFD)-induced mice. Finally, we generated hetero-mutant obese mice (10). In addition, GIPR is mice by mating the chimeric mice with wild expressed in adipose tissue (11), and C57BL6. The mice were housed in an increases glucose and triglyceride uptake in air-controlled (temperature 25°C) room with fat cells (12, 13). Thus, GIP has both direct dark–light cycle of 10 h and 14 h, and indirect effects on the accumulation of respectively. Animal care and procedures energy into adipose tissue. Some studies were approved by the Animal Care report that GIP secretion is increased in Committee of Kyoto University. obesity (7, 14, 15, 16) and that pancreatic and GIP-GFP heterozygous mice (7 weeks of duodenal homeobox 1 (Pdx1) , which is age) were fed control fat chow (CFD; 10% known to be an important transcription factor fat, 20% protein, and 70% carbohydrate by in pancreatic development and pancreatice energy) or high fat chow (HFD; 60% fat, β-cell maturation (17), has a critical role in 20% protein, and 20% carbohydrate by GIP production in K-cells (18, 19). However, energy) (Research Diets Inc., New the mechanisms involved in GIP Brunswick, NJ) for 8 weeks. Food intake, hypersecretion from K-cells in obesity water intake, and body weight were remain unclear due to difficulties in measured. separating these cells from other intestinal Immunohistochemistry― Mouse upper epithelial cells in vivo. small intestine samples were fixed in Bouin’s In the present study, we investigated solution and transferred into 70% ethanol expression of various genes in K-cells by before processing through paraffin. using GIP-GFP knock-in (GIP-GFP) mice in Rehydrated paraffin sections were incubated which K-cells can be visualized by EGFP overnight at 4°C with primary mouse 2 Rfx6 increases GIP mRNA expression in K-cells anti-GFP antibody (sc-9996, 1:100, Santa (352340, BD Falcon cell strainer, Becton Cruz Biotechnology Inc., biotechnology, inc., Dickinson and Company, San Jose, CA). CA) and rabbit anti-GIP antibody (T-4053, GFP-positive cells in the intestinal epithelium 1:100, Peninsula Laboratories, Inc., San were analyzed using BD FACS Aria™ flow Carlos, CA). Intestine samples and STC-1 cytometer (Becton Dickinson and Company). cells (kindly provided by Prof. Hanahan, Sorted cells were collected into vials University of California, San Francisco) were containing medium at a rate of 2000 cells / embedded by Tissue-Tek O.C.T. compound tube. 4583 (Sakura Fine Technical Co. Ltd. Tokyo, Total RNA was extracted with PicoPure Japan) and immediately frozen in liquid RNA isolation kit (Applied Biosystems, Inc, nitrogen. Frozen sections (10 m) on slides Alameda, CA) from sorted cells of GIP-GFP were air-dried and fixed in acetone for 5 min. mice intestinal epithelium and treated with Slides
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