Obesity and diabetes in TNF-α receptor-deficient mice
Obesity and diabetes in TNF-α receptor-deficient mice
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DOI：
10.1172/jci2849
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发表时间：
1998-07-15
影响因子：
15.9
通讯作者：
LeBoeuf, RC
中科院分区：
文献类型：
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作者：
Schreyer, SA;Chua, SC;LeBoeuf, RC
TNF-α可能在介导与肥胖相关的胰岛素抵抗中发挥作用。这一概念是基于对肥胖啮齿动物和人类的研究以及细胞培养模型。TNF通过两种称为p55和p75的受体来增强细胞反应。我们的目的是使用缺乏一种或两种TNF受体的小鼠来测试TNF在葡萄糖稳态中的参与。给缺乏p55（p55（-/-））、p75（-/-））或两种受体（p55（-/-）p75（-/-））的C57 BL/6小鼠喂食高脂饮食以诱导肥胖。在喂食高脂饮食的12至16周之间，在p55（-/-）p75（-/-）雄性小鼠中观察到明显的空腹高胰岛素血症。胰岛素水平是野生型小鼠的四倍。相比之下，p55（-/-）和p75（-/-）小鼠与野生型小鼠相比，分别表现出相似或降低的胰岛素水平。此外，高脂饮食喂养的p75（-/-）小鼠的体重和瘦素水平最低，胰岛素敏感性提高。肥胖（db/db）小鼠，这是不响应瘦素，用于研究p55在严重肥胖症的作用。与表达p55的对照db/db相比，雄性p55（-/-）db/db小鼠在20周龄时表现出高3倍的胰岛素水平和低2倍的葡萄糖水平。基于空腹血浆葡萄糖和胰岛素水平以及葡萄糖和胰岛素耐量试验，所有db/db小鼠都保持严重的胰岛素抵抗。我们的数据不支持TNF通过其受体起作用是肥胖相关胰岛素抵抗的主要因素的观点。事实上，数据表明，这两种TNF受体协同工作，以防止糖尿病。
TNF-alpha may play a role in mediating insulin resistance associated with obesity. This concept is based on studies of obese rodents and humans, and cell culture models. TNF elicits cellular responses via two receptors called p55 and p75, Our purpose was to test the involvement of TNF in glucose homeostasis using mice lacking one or both TNF receptors. C57BL/6 mice lacking p55 (p55(-/-)), p75, (p75(-/-)), or both receptors (p55(-/-)p75(-/-)) were fed a high-fat diet to induce obesity, Marked fasting hyperinsulinemia was seen for p55(-/-)p75(-/-) males between 12 and 16 wk of feeding the high-fat diet. Insulin levels were four times greater than wild-type mice. In contrast, p55(-/-) and p75(-/-) mice exhibited insulin levels that were similar or reduced, respectively, as compared with wild-type mice. In addition, high-fat diet-fed p75(-/-) mice had the lowest body weights and leptin levels, and improved insulin sensitivity. Obese (db/db) mice, which are not responsive to leptin, were used to study the role of p55 in severe obesity. Male p55(-/-)db/db mice exhibited threefold higher insulin levels and twofold lower glucose levels at 20 wk of age than control db/db expressing p55, All db/db mice remained severely insulin resistant based on fasting plasma glucose and insulin levels, and glucose and insulin tolerance tests. Our data do not support the concept that TNF, acting via its receptors, is a major contributor to obesity-associated insulin resistance. In fact, data suggest that the two TNF receptors work in concert to protect against diabetes.