Attenuated secretion of glucose-dependent insulinotropic polypeptide (GIP) does not alleviate hyperphagic obesity and insulin resistance in ob/ob mice.
Attenuated secretion of glucose-dependent insulinotropic polypeptide (GIP) does not alleviate hyperphagic obesity and insulin resistance in ob/ob mice.
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DOI：
10.1016/j.molmet.2017.01.006
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发表时间：
2017-03
影响因子：
8.1
通讯作者：
Inagaki N
中科院分区：
文献类型：
--
作者：
Shimazu-Kuwahara S;Harada N;Yamane S;Joo E;Sankoda A;Kieffer TJ;Inagaki N
葡萄糖依赖性促胰岛素多肽（GIP）在进餐时释放，促进营养物质的吸收和储存。 GIP 受体敲除小鼠可以免受饮食引起的体重增加的影响，因此 GIP 拮抗剂已被提议作为肥胖的治疗方法。在这项研究中，我们评估了 GIP 在瘦素缺陷 (Lepob/ob) 小鼠因食欲过盛引起的肥胖和代谢异常中的作用。我们将完全 GIP 敲除的 GIP-GFP 敲入纯合小鼠 (GIPgfp/gfp) 与 ob 突变杂合小鼠 (Lepob/+) 杂交，产生 Lepob/+/GIP+/+、Lepob/ob/GIP+/+ 和 Lepob/ob/GIPgfp/gfp 小鼠。每周对雄性动物称重，并进行口服葡萄糖和胰岛素耐量测试，以评估葡萄糖稳态以及 GIP 和胰岛素的循环特征。通过计算机断层扫描（CT）扫描评估身体成分，并进行间接量热法和运动活动分析。与 Lepob/+/GIP+/+ 对照相比，Lepob/ob/GIP+/+ 小鼠的餐后 GIP 水平显着升高，并且在 Lepob/ob/GIPgfp/gfp 小鼠中检测不到。与 8 周龄的对照组相比，Lepob/ob/GIP+/+ 和 Lepob/ob/GIPgfp/gfp 小鼠的胰岛素水平同等升高，但到 21 周时 Lepob/ob/GIPgfp/gfp 的高胰岛素血症略有降低，这与葡萄糖耐受不良的改善有关。 Lepob/ob/GIP+/+ 和 Lepob/ob/GIPgfp/gfp 小鼠均保持同等的胰岛素抵抗。 Lepob/ob/GIP+/+和Lepob/ob/GIPgfp/gfp小鼠的体重增加以及皮下和内脏脂肪体积均显着高于Lepob/+/GIP+/+小鼠，而Lepob/ob/GIP+/+和Lepob/ob/GIPgfp/gfp小鼠之间没有显着差异。与对照 Lepob/+/GIP+/+ 小鼠相比，Lepob/ob/GIP+/+ 和 Lepob/ob/GIPgfp/gfp 小鼠的运动活性和能量消耗均降低，而 Lepob/ob/GIP+/+ 和 Lepob/ob/GIPgfp/gfp 小鼠之间没有观察到显着差异。三组之间的脂肪氧化没有显着差异。与Lepob/ob/GIP+/+小鼠相比，Lepob/ob/GIPgfp/gfp小鼠肝脏脂肪含量显着降低，而对照Lepob/+/GIP+/+小鼠肝脏脂肪含量最低。我们的结果表明，GIP 敲除并不能阻止食欲过盛的瘦素缺乏小鼠的体重过度增加和代谢紊乱。完全缺乏 GIP 并不能阻止 Lepob/ob 小鼠发生高胰岛素血症和胰岛素抵抗。 GIP 缺乏并不能减轻 Lepob/ob 小鼠的体重过度增加和脂肪堆积。内源性 GIP 不参与完全缺乏瘦素的小鼠肥胖的发生。
Glucose-dependent insulinotropic polypeptide (GIP) is released during meals and promotes nutrient uptake and storage. GIP receptor knockout mice are protected from diet induced weight gain and thus GIP antagonists have been proposed as a treatment for obesity. In this study, we assessed the role of GIP in hyperphagia induced obesity and metabolic abnormalities in leptin deficient (Lepob/ob) mice. We crossbred GIP-GFP knock-in homozygous mice (GIPgfp/gfp) that have complete GIP knockout, and mice heterozygous for the ob mutation (Lepob/+) mice to generate Lepob/+/GIP+/+, Lepob/ob/GIP+/+, and Lepob/ob/GIPgfp/gfp mice. Male animals were weighed weekly and both oral glucose and insulin tolerance testing were performed to assess glucose homeostasis and circulating profiles of GIP and insulin. Body composition was evaluated by computerized tomography (CT) scan and analyses of indirect calorimetry and locomotor activity were performed. Postprandial GIP levels were markedly elevated in Lepob/ob/GIP+/+ mice compared to Lepob/+/GIP+/+ controls and were undetectable in Lepob/ob/GIPgfp/gfp mice. Insulin levels were equivalently elevated in both Lepob/ob/GIP+/+ and Lepob/ob/GIPgfp/gfp mice compared to controls at 8 weeks of age but the hyperinsulinemia was marginally reduced in Lepob/ob/GIPgfp/gfp by 21 weeks, in association with amelioration of glucose intolerance. Both Lepob/ob/GIP+/+ and Lepob/ob/GIPgfp/gfp mice remained equivalently insulin resistant. Body weight gain and subcutaneous and visceral fat volume of both Lepob/ob/GIP+/+ and Lepob/ob/GIPgfp/gfp mice were significantly higher than that of Lepob/+/GIP+/+ mice, while no significant differences were seen between Lepob/ob/GIP+/+ and Lepob/ob/GIPgfp/gfp mice. Locomotor activity and energy expenditure were decreased in both Lepob/ob/GIP+/+ and Lepob/ob/GIPgfp/gfp mice compared to control Lepob/+/GIP+/+ mice, while no significant differences were seen between Lepob/ob/GIP+/+ and Lepob/ob/GIPgfp/gfp mice. There was no significant difference in fat oxidation among the three groups. Fat content in liver was significantly lower in Lepob/ob/GIPgfp/gfp compared to Lepob/ob/GIP+/+ mice, while that of control Lepob/+/GIP+/+ mice was the lowest. Our results indicate that GIP knockout does not prevent excess weight gain and metabolic derangement in hyperphagic leptin deficient mice. Complete absence of GIP does not prevent hyperinsulinemia and insulin resistance from developing in Lepob/ob mice. GIP deficiency does not alleviate excess weight gain and fat accumulation in Lepob/ob mice. Endogenous GIP is not involved in the development of obesity in mice with complete absence of leptin.