Department of Diabetes, Endocrinology and Nutrition, Graduate School of Medicine, Kyoto University, 54 Kawahara-cho, Shogoin, Sakyo-ku, Kyoto, 606-8507, Japan.
Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, British Columbia, V6T 1Z3, Canada.
Mol Metab. 2017 Jan 19;6(3):288-294. doi: 10.1016/j.molmet.2017.01.006. eCollection 2017 Mar.
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 (Lep) mice.
We crossbred GIP-GFP knock-in homozygous mice (GIP) that have complete GIP knockout, and mice heterozygous for the mutation (Lep) mice to generate Lep/GIP, Lep/GIP, and Lep/GIP 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 Lep/GIP mice compared to Lep/GIP controls and were undetectable in Lep/GIP mice. Insulin levels were equivalently elevated in both Lep/GIP and Lep/GIP mice compared to controls at 8 weeks of age but the hyperinsulinemia was marginally reduced in Lep/GIP by 21 weeks, in association with amelioration of glucose intolerance. Both Lep/GIP and Lep/GIP mice remained equivalently insulin resistant. Body weight gain and subcutaneous and visceral fat volume of both Lep/GIP and Lep/GIP mice were significantly higher than that of Lep/GIP mice, while no significant differences were seen between Lep/GIP and Lep/GIP mice. Locomotor activity and energy expenditure were decreased in both Lep/GIP and Lep/GIP mice compared to control Lep/GIP mice, while no significant differences were seen between Lep/GIP and Lep/GIP mice. There was no significant difference in fat oxidation among the three groups. Fat content in liver was significantly lower in Lep/GIP compared to Lep/GIP mice, while that of control Lep/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.
葡萄糖依赖性胰岛素多肽（GIP）在进食时释放，促进营养物质的吸收和储存。GIP 受体敲除小鼠可防止饮食引起的体重增加，因此 GIP 拮抗剂已被提议作为肥胖症的治疗方法。在这项研究中，我们评估了 GIP 在瘦素缺乏（Lep）小鼠引起的过度进食性肥胖和代谢异常中的作用。
我们将完全敲除 GIP 的 GIP-GFP 敲入纯合子小鼠（GIP）与 Lep 杂合子小鼠杂交，以生成 Lep/GIP、Lep/GIP 和 Lep/GIP 小鼠。雄性动物每周称重，并进行口服葡萄糖和胰岛素耐量试验，以评估葡萄糖稳态和循环 GIP 和胰岛素水平。通过计算机断层扫描（CT）扫描评估身体成分，并进行间接热量测定和运动活性分析。
与 Lep/GIP 对照相比，Lep/GIP 小鼠餐后 GIP 水平显着升高，而 Lep/GIP 小鼠则无法检测到 GIP。与对照组相比，8 周龄时，Lep/GIP 和 Lep/GIP 小鼠的胰岛素水平同样升高，但到 21 周时，Lep/GIP 小鼠的高胰岛素血症略有降低，与葡萄糖耐量改善相关。Lep/GIP 和 Lep/GIP 小鼠均保持同等的胰岛素抵抗。Lep/GIP 和 Lep/GIP 小鼠的体重增加以及皮下和内脏脂肪体积均明显高于 Lep/GIP 小鼠，而 Lep/GIP 和 Lep/GIP 小鼠之间无显着差异。与对照 Lep/GIP 小鼠相比，Lep/GIP 和 Lep/GIP 小鼠的运动活性和能量消耗均降低，而 Lep/GIP 和 Lep/GIP 小鼠之间无显着差异。三组之间的脂肪氧化无显着差异。与 Lep/GIP 小鼠相比，Lep/GIP 小鼠的肝脏脂肪含量显着降低，而对照 Lep/GIP 小鼠的肝脏脂肪含量最低。
我们的结果表明，GIP 敲除不能防止过度进食性肥胖和代谢紊乱的瘦素缺乏小鼠。
