Uysal K T, Wiesbrock S M, Marino M W, Hotamisligil G S
Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
Nature. 1997 Oct 9;389(6651):610-4. doi: 10.1038/39335.
Obesity is highly associated with insulin resistance and is the biggest risk factor for non-insulin-dependent diabetes mellitus. The molecular basis of this common syndrome, however, is poorly understood. It has been suggested that tumour necrosis factor (TNF)-alpha is a candidate mediator of insulin resistance in obesity, as it is overexpressed in the adipose tissues of rodents and humans and it blocks the action of insulin in cultured cells and whole animals. To investigate the role of TNF-alpha in obesity and insulin resistance, we have generated obese mice with a targeted null mutation in the gene encoding TNF-alpha and those encoding the two receptors for TNF-alpha. The absence of TNF-alpha resulted in significantly improved insulin sensitivity in both diet-induced obesity and that resulting for the ob/ob model of obesity. The TNFalpha-deficient obese mice had lower levels of circulating free fatty acids, and were protected from the obesity-related reduction in the insulin receptor signalling in muscle and fat tissues. These results indicate that TNF-alpha is an important mediator of insulin resistance in obesity through its effects on several important sites of insulin action.
肥胖与胰岛素抵抗高度相关，是非胰岛素依赖型糖尿病的最大风险因素。然而，这种常见综合征的分子基础却知之甚少。有人提出肿瘤坏死因子（TNF）-α是肥胖中胰岛素抵抗的候选介质，因为它在啮齿动物和人类的脂肪组织中过度表达，并且在培养细胞和整体动物中会阻断胰岛素的作用。为了研究TNF-α在肥胖和胰岛素抵抗中的作用，我们培育出了在编码TNF-α的基因以及编码TNF-α的两种受体的基因中带有靶向无效突变的肥胖小鼠。在饮食诱导的肥胖以及ob/ob肥胖模型中，TNF-α的缺失均导致胰岛素敏感性显著改善。缺乏TNF-α的肥胖小鼠循环游离脂肪酸水平较低，并且免受肥胖相关的肌肉和脂肪组织中胰岛素受体信号传导减少的影响。这些结果表明，TNF-α通过其对胰岛素作用的几个重要位点的影响，是肥胖中胰岛素抵抗的重要介质。
