TNF-alpha downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents

Obesity is assocd. with chronic low-grade inflammation. Thus, at metabolically relevant sites, including adipose tissue and muscle, there is abnormal prodn. of proinflammatory cytokines such as TNF-a. Here we demonstrate that eNOS expression was reduced, with a concomitant redn. of mitochondrial biogenesis and function, in white and brown adipose tissue and in the soleus muscle of 3 different animal models of obesity. The genetic deletion of TNF receptor 1 in obese mice restored eNOS expression and mitochondrial biogenesis in fat and muscle; this was assocd. with less body wt. gain than in obese wild-type controls. Furthermore, TNF-a downregulated eNOS expression and mitochondrial biogenesis in cultured white and brown adipocytes and muscle satellite cells of mice. The NO donors DETA-NO and SNAP prevented the redn. of mitochondrial biogenesis obsd. with TNF-a. Our findings demonstrate that TNF-a impairs mitochondrial biogenesis and function in different tissues of obese rodents by downregulating eNOS expression and suggest a novel pathophysiol. process that sustains obesity. [on SciFinder (R)]