TNF- plays an important role in the pathogenesis of obesity and insulin resistance in which the effect of TNF- signaling via TNFR1 largely remains controversial. To delineate the role of TNFR1-mediated TNF- 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 with high fat/high-sucrose (HFS) diet for 16 weeks until obesity and insulin resistance developed. In comparison with increased body weight and fat weight, enlarged adipocytes and hypertriglycerideamia in obese state, the subsequent 4-week 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 hyperinsulinaemia, elevated C-peptide, higher degree of hyperglycaemia after glucose challenge and less hypoglycaemic 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- release and its local expression in pancreatic islets, muscle and adipose tissues. In addition, blockage of TNFR1-mediated TNF- 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- signaling in the pathogenesis of obesity and insulin resistance. Thus, TNFR1BP-Fc may be a good candidate for the treatment of this disease.