Hotamisligil G S, Arner P, Caro J F, Atkinson R L, Spiegelman B M
Dana Farber Cancer Institute, Boston, Massachusetts 02115, USA.
J Clin Invest. 1995 May;95(5):2409-15. doi: 10.1172/JCI117936.
Obesity is frequently associated with insulin resistance and abnormal glucose homeostasis. Recent studies in animal models have indicated that TNF-alpha plays an important role in mediating the insulin resistance of obesity through its overexpression in fat tissue. However, the mechanisms linking obesity to insulin resistance and diabetes in humans remain largely unknown. In this study we examined the expression pattern of TNF-alpha mRNA in adipose tissues from 18 control and 19 obese premenopausal women by Northern blot analysis. TNF-alpha protein concentrations in plasma and in conditioned medium of explanted adipose tissue were measured by ELISA. Furthermore, the effects of weight reduction by dietary treatment of obesity on the adipose expression of TNF-alpha mRNA were also analyzed in nine premenopausal obese women, before and after a controlled weight-reduction program. These studies demonstrated that obese individuals express 2.5-fold more TNF-alpha mRNA in fat tissue relative to the lean controls (P < 0.001). Similar increases were also observed in adipose production of TNF-alpha protein but circulating TNF-alpha levels were extremely low or undetectable. A strong positive correlation was observed between TNF-alpha mRNA expression levels in fat tissue and the level of hyperinsulinemia (P < 0.001), an indirect measure of insulin resistance. Finally, body weight reduction in obese subjects which resulted in improved insulin sensitivity was also associated with a decrease in TNF-alpha mRNA expression (45%, P < 0.001) in fat tissue. These results suggest a role for the abnormal regulation of this cytokine in the pathogenesis of obesity-related insulin resistance.
肥胖常与胰岛素抵抗及葡萄糖稳态异常相关。近期动物模型研究表明，肿瘤坏死因子-α（TNF-α）通过在脂肪组织中过度表达，在介导肥胖的胰岛素抵抗中起重要作用。然而，在人类中，将肥胖与胰岛素抵抗及糖尿病联系起来的机制仍 largely 未知。在本研究中，我们通过 Northern 印迹分析检测了 18 名对照和 19 名肥胖绝经前女性脂肪组织中 TNF-α mRNA 的表达模式。通过 ELISA 测定血浆及离体脂肪组织条件培养基中 TNF-α 蛋白浓度。此外，还对 9 名绝经前肥胖女性在控制体重减轻计划前后，通过饮食治疗肥胖减轻体重对脂肪组织中 TNF-α mRNA 表达的影响进行了分析。这些研究表明，肥胖个体脂肪组织中 TNF-α mRNA 的表达量相对于瘦对照者高出 2.5 倍（P < 0.001）。在 TNF-α 蛋白的脂肪生成中也观察到类似的增加，但循环 TNF-α 水平极低或无法检测到。在脂肪组织中 TNF-α mRNA 表达水平与高胰岛素血症水平（P < 0.001）之间观察到强正相关，高胰岛素血症是胰岛素抵抗的间接指标。最后，肥胖受试者体重减轻导致胰岛素敏感性改善，这也与脂肪组织中 TNF-α mRNA 表达降低（45%，P < 0.001）相关。这些结果表明该细胞因子的异常调节在肥胖相关胰岛素抵抗的发病机制中起作用。
