Hotamisligil G S
Harvard School of Public Health, Department of Nutrition, Boston, MA 02115, USA.
Exp Clin Endocrinol Diabetes. 1999;107(2):119-25. doi: 10.1055/s-0029-1212086.
There is now substantial evidence linking TNF-alpha to the presentation of insulin resistance in humans, animals and in vitro systems. We explored the relationship between TNF-alpha and insulin resistance using knockout mice deficient for either TNF-alpha or one or both of its receptors, p55 and p75. In studies of TNF-alpha-deficient knockout mice with diet-induced obesity, obese TNF-alpha knockouts responded to an exogenous dose of insulin or glucose much more efficiently than TNF-alpha wild-type animals. This finding suggests that deletion of TNF-alpha leads to increased insulin sensitivity, ie decreased insulin resistance. In studies using genetically obese ob/ob mice, TNF-alpha receptor wild-type and p75 receptor knockout animals developed a pronounced hyperinsulinemia and transient hyperglycaemia, whereas p55 receptor and double-knockout animals did not. Moreover, in glucose and insulin tolerance tests, we found that p75 knockout animals exhibited profiles identical to those of the wild-type animals, but that p55 knockout animals and double mutants showed a mild improvement in insulin sensitivity, relative to the wild type. Since the improvement in sensitivity was slightly greater with double mutants, p55 alone cannot be responsible for TNF-alpha's promotion of insulin resistance in obese mice, despite the likelihood that it is more important than p75. How TNF-alpha-related insulin resistance is mediated is not fully clear, although phosphorylation of serine residues on IRS-1 has previously been shown to be important. When we monitored Glut 4 expression in obese TNF-alpha wild-type and knockout mice, we found no convincing evidence that TNF-alpha mediation of the down-regulation of Glut 4 mRNA expression is responsible for insulin resistance. However, we found an approximately 2-fold increase in insulin-stimulated tyrosine phosphorylation of the insulin receptor in the muscle and adipose tissue of TNF-alpha knockout mice, suggesting that insulin receptor signalling is an important target for TNF-alpha. Other possible mediators of TNF-alpha-induced insulin resistance include circulating free fatty acids (FFAs) and leptin.
目前有大量证据表明，在人类、动物及体外系统中，肿瘤坏死因子-α（TNF-α）与胰岛素抵抗的表现有关。我们利用缺乏TNF-α或其受体p55和p75中的一个或两个的基因敲除小鼠，探究了TNF-α与胰岛素抵抗之间的关系。在对饮食诱导肥胖的TNF-α基因敲除小鼠的研究中，肥胖的TNF-α基因敲除小鼠对外源剂量的胰岛素或葡萄糖的反应比TNF-α野生型动物更有效。这一发现表明，TNF-α的缺失会导致胰岛素敏感性增加，即胰岛素抵抗降低。在使用基因肥胖的ob/ob小鼠的研究中，TNF-α受体野生型和p75受体基因敲除动物出现了明显的高胰岛素血症和短暂的高血糖症，而p55受体基因敲除动物和双基因敲除动物则没有。此外，在葡萄糖和胰岛素耐量试验中，我们发现p75基因敲除动物的表现与野生型动物相同，但p55基因敲除动物和双突变体相对于野生型显示出胰岛素敏感性有轻微改善。由于双突变体的敏感性改善略大，尽管p55可能比p75更重要，但仅p55并不能解释TNF-α在肥胖小鼠中促进胰岛素抵抗的作用。尽管之前已证明胰岛素受体底物-1（IRS-1）上丝氨酸残基的磷酸化很重要，但TNF-α相关的胰岛素抵抗是如何介导的尚不完全清楚。当我们监测肥胖的TNF-α野生型和基因敲除小鼠中葡萄糖转运蛋白4（Glut 4）的表达时，我们没有发现令人信服的证据表明TNF-α介导的Glut 4 mRNA表达下调是胰岛素抵抗的原因。然而我们发现，在TNF-α基因敲除小鼠的肌肉和脂肪组织中，胰岛素刺激的胰岛素受体酪氨酸磷酸化增加了约2倍，这表明胰岛素受体信号传导是TNF-α的一个重要靶点。TNF-α诱导胰岛素抵抗的其他可能介质包括循环游离脂肪酸（FFA）和瘦素。
