Liang Huifang, Yin Bingjiao, Zhang Hailong, Zhang Shu, Zeng Qingling, Wang Jing, Jiang Xiaodan, Yuan Li, Wang Cong-Yi, Li Zhuoya
Department of Immunology, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei 430030, People's Republic of China.
Endocrinology. 2008 Jun;149(6):2943-51. doi: 10.1210/en.2007-0978. Epub 2008 Mar 13.
TNF-alpha plays an important role in the pathogenesis of obesity and insulin resistance in which the effect of TNF-alpha signaling via TNF receptor type 1 (TNFR1) largely remains controversial. To delineate the role of TNFR1-mediated TNF-alpha signaling in the pathogenesis of this disorder, a TNFR1 blocking peptide-Fc fusion protein (TNFR1BP-Fc) was used for the present study. Wistar rats were fed a high-fat/high-sucrose (HFS) diet for 16 wk until obesity and insulin resistance developed. In comparison with increased body weight and fat weight, enlarged adipocytes, and hypertriglyceridemia in the obese state, the subsequent 4-wk treatment with TNFR1BP-Fc resulted in significant weight loss characterized by decreased fat pad weight and adipocyte size and reduced plasma triglycerides. Furthermore, obesity-induced insulin resistance, including hyperinsulinemia, elevated C-peptide, higher degree of hyperglycemia after glucose challenge, and less hypoglycemic response to insulin, was markedly improved, and the compensatory hyperplasia and hypertrophy of pancreatic islets were reduced. Interestingly, treatment with TNFR1BP-Fc markedly suppressed systemic TNF-alpha release and its local expression in pancreatic islets and muscle and adipose tissues. In addition, blockage of TNFR1-mediated TNF-alpha signaling in obese rats significantly enhanced tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1) in the muscle and fat tissues. Our results strongly suggest a pivotal role for TNFR1-mediated TNF-alpha signaling in the pathogenesis of obesity and insulin resistance. Thus, TNFR1BP-Fc may be a good candidate for the treatment of this disease.
肿瘤坏死因子-α（TNF-α）在肥胖症和胰岛素抵抗的发病机制中起重要作用，其中TNF-α通过1型肿瘤坏死因子受体（TNFR1）发出的信号所产生的影响在很大程度上仍存在争议。为了阐明TNFR1介导的TNF-α信号在这种疾病发病机制中的作用，本研究使用了一种TNFR1阻断肽-Fc融合蛋白（TNFR1BP-Fc）。将Wistar大鼠喂食高脂/高糖（HFS）饮食16周，直至出现肥胖症和胰岛素抵抗。与肥胖状态下体重增加、脂肪重量增加、脂肪细胞增大和高甘油三酯血症相比，随后用TNFR1BP-Fc进行4周治疗导致体重显著减轻，其特征为脂肪垫重量和脂肪细胞大小减小以及血浆甘油三酯降低。此外，肥胖诱导的胰岛素抵抗，包括高胰岛素血症、C肽升高、葡萄糖激发后更高程度的高血糖以及对胰岛素的低血糖反应降低，均得到显著改善，并且胰岛的代偿性增生和肥大减少。有趣的是，用TNFR1BP-Fc治疗显著抑制了全身TNF-α的释放及其在胰岛、肌肉和脂肪组织中的局部表达。此外，阻断肥胖大鼠中TNFR1介导的TNF-α信号显著增强了肌肉和脂肪组织中胰岛素受体底物1（IRS-1）的酪氨酸磷酸化。我们的结果强烈表明TNFR1介导的TNF-α信号在肥胖症和胰岛素抵抗的发病机制中起关键作用。因此，TNFR1BP-Fc可能是治疗这种疾病的良好候选药物。
