Chronic Reduction of GIP Secretion Alleviates Obesity and Insulin Resistance Under High-Fat Diet Conditions
Chronic Reduction of GIP Secretion Alleviates Obesity and Insulin Resistance Under High-Fat Diet Conditions
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DOI：
10.2337/db13-1563
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发表时间：
2014-07-01
期刊：
影响因子：
7.7
通讯作者：
Inagaki, Nobuya
中科院分区：
文献类型：
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作者：
Nasteska, Daniela;Harada, Norio;Inagaki, Nobuya
胃抑制多肽 (GIP) 对 β 细胞具有强大的促胰岛素作用，对骨形成和脂肪积累具有合成代谢作用。我们在新型 GIP-GFP 敲入 (KI) 小鼠中探讨了体内 GIP 水平降低对葡萄糖稳态、骨形成和脂肪积累的影响。我们生成了具有截短的 prepro-GIP 基因的 GIP-GFP KI 小鼠。在体内和体外对对照脂肪饮食和高脂肪饮食（HFD）小鼠的杂合和纯合状态下的表型进行评估。杂合的 GIP-GFP KI 小鼠（GIP 减少的小鼠 [GIP(gfp/+)]）表现出 GIP 分泌减少；在纯合状态下（缺乏 GIP 的小鼠 [GIP(gfp/gfp)]），检测不到 GIP 分泌。当喂食标准食物时，GIP(gfp/+) 和 GIP(gfp/gfp) 小鼠表现出轻度葡萄糖不耐受，胰岛素水平下降； GIP(gfp/gfp) 小鼠骨体积减少，GIP(gfp/+) 小鼠骨体积保持不变。在 HFD 下，野生型、GIP(gfp/+) 和 GIP(gfp/gfp) 小鼠的口服葡萄糖耐量试验期间的葡萄糖水平相似，而胰岛素分泌仍然较低。 GIP(gfp/+) 和 GIP(gfp/gfp) 小鼠显示出肥胖减少和胰岛素抵抗减少，同时脂肪氧化和能量消耗增加。 GIP 减少的小鼠证明，GIP 的部分减少不会广泛改变葡萄糖耐量，但它可以减轻肥胖并减轻 HFD 条件下的胰岛素抵抗程度，这表明其具有潜在的治疗价值。
Gastric inhibitory polypeptide (GIP) exhibits potent insulinotropic effects on beta-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) in vivo and in vitro. Heterozygous GIP-GFP KI mice (GIP-reduced mice [GIP(gfp/+)]) exhibited reduced GIP secretion; in the homozygous state (GIP-lacking mice [GIP(gfp/gfp)]), GIP secretion was undetectable. When fed standard chow, GIP(gfp/+) and GIP(gfp/gfp) mice showed mild glucose intolerance with decreased insulin levels; bone volume was decreased in GIP(gfp/gfp) mice and preserved in GIP(gfp/+) mice. Under an HFD, glucose levels during an oral glucose tolerance test were similar in wild-type, GIP(gfp/+), 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.