Blockade of Tumor Necrosis Factor (TNF) Receptor Type 1-Mediated TNF-α Signaling Protected Wistar Rats from Diet-Induced Obesity and Insulin Resistance

• Published in: Endocrinology (Philadelphia) Vol. 149; no. 6; pp. 2943 - 2951
• Main Authors: Liang, Huifang, Yin, Bingjiao, Zhang, Hailong, Zhang, Shu, Zeng, Qingling, Wang, Jing, Jiang, Xiaodan, Yuan, Li, Wang, Cong-Yi, Li, Zhuoya
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.06.2008
• Subjects: Animals; Biological and medical sciences; Fundamental and applied biological sciences. Psychology; Humans; Immunoglobulin Fc Fragments - pharmacology; Insulin - physiology; Insulin Resistance - physiology; L Cells (Cell Line) - physiology; Medical sciences; Metabolic diseases; Mice; Obesity; Obesity - prevention & control; Plasmids; Rats; Rats, Wistar; Signal Transduction; TNF Receptor-Associated Factor 1 - antagonists & inhibitors; TNF Receptor-Associated Factor 1 - genetics; TNF Receptor-Associated Factor 1 - physiology; Tumor Necrosis Factor-alpha - physiology; Vertebrates: endocrinology; Endocrinopathy; Obesity; Rat; Cytokine; Rodentia; Nutrition disorder; Metabolic diseases; Feeding; Target tissue resistance; Signal transduction; Vertebrata; Mammalia; Diet; Tumor necrosis factor; Animal; Insulin resistance; Nutritional status; Tumor necrosis factor α; Biological receptor
• ISSN: 0013-7227; 1945-7170
• DOI: 10.1210/en.2007-0978

TNF-α plays an important role in the pathogenesis of obesity and insulin resistance in which the effect of TNF-α signaling via TNF receptor type 1 (TNFR1) largely remains controversial. To delineate the role of TNFR1-mediated TNF-α 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-α release and its local expression in pancreatic islets and muscle and adipose tissues. In addition, blockage of TNFR1-mediated TNF-α 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-α signaling in the pathogenesis of obesity and insulin resistance. Thus, TNFR1BP-Fc may be a good candidate for the treatment of this disease.