Transcriptional Regulatory Factor X6 (Rfx6) Increases Gastric Inhibitory Polypeptide (GIP) Expression in Enteroendocrine K-cells and Is Involved in GIP Hypersecretion in High Fat Diet-induced Obesity

Suzuki, Kunihiro; Harada, Norio; Yamane, Shunsuke; Nakamura, Yasuhiko; Sasaki, Kazuki; Nasteska, Daniela; Joo, Erina; Shibue, Kazuhisa; Harada, Tadao; Hamasaki, Akihiro; Toyoda, Kentaro; Nagashima, Kazuaki; Inagaki, Nobuya

doi:10.1074/jbc.m112.423137

Cited by 83 publications

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“…Previous reports indicate a strong connection between GIP secretion and obesity in HFD-feeding conditions (27). High caloric intake causes hypersecretion of GIP (12,28,29) due to hyperexpression of the GIP gene (15) and a subsequent rise in insulin secretion (30), leading to increased fat deposition in the adipose tissue and expansion of fat depots (31,32). GIP increases the adipose tissue volume directly (33,34) by binding to its receptors located on the adipocytes and indirectly by potentiating b-cell secretion of insulin, which is known to be involved in adipocyte fat deposition (35).…”

Section: Discussionmentioning

confidence: 99%

“…The main genetic trait of GIP-GFP KI mice is alteration (truncation) of the prepro-GIP gene coupled with insertion of the GFP coding sequence (15). In mice kept on standard chow, the assessment of GIP mRNA levels in the small intestine showed reduced levels in GIP gfp/+ mice (P , 0.05), while in GIP gfp/gfp mice, GIP mRNA could not be detected (P , 0.05, P , 0.01) (Fig.…”

Section: Gip Reduction In Gip-gfp Ki Micementioning

confidence: 99%

“…GIP-GFP KI mice were generated as described previously (15). The animals were maintained under conditions of a 12 h light/dark cycle, with free access to water and food, unless indicated otherwise.…”

Section: Animalsmentioning

confidence: 99%

“…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 or absent GIP secretion in heterozygous GIP-reduced mice and homozygous or GIP-lacking mice, respectively.…”

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Chronic Reduction of GIP Secretion Alleviates Obesity and Insulin Resistance Under High-Fat Diet Conditions

et al. 2014

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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

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Section: Discussionmentioning

confidence: 99%

Section: Gip Reduction In Gip-gfp Ki Micementioning

confidence: 99%

Section: Animalsmentioning

confidence: 99%

mentioning

confidence: 99%

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Chronic Reduction of GIP Secretion Alleviates Obesity and Insulin Resistance Under High-Fat Diet Conditions

et al. 2014

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“…In recent years, transgenic technology has allowed the development of mice which express fluorescent protein reporters under the control of enteroendocrine hormone promoters [Reimann et al 2008;Parker et al 2009;Chandra et al 2010;Wang et al 2011;Suzuki et al 2013]. This technique enabled the isolation, purification and systematic characterization of these otherwise elusive cells and led to rapid strides in our understanding of EEC biology.…”

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confidence: 99%