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

J Clin Invest. 2006 Oct;116(10):2791-8. doi: 10.1172/JCI28570. Epub 2006 Sep 14.


Obesity is associated with chronic low-grade inflammation. Thus, at metabolically relevant sites, including adipose tissue and muscle, there is abnormal production of proinflammatory cytokines such as TNF-alpha. Here we demonstrate that eNOS expression was reduced, with a concomitant reduction 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 associated with less body weight gain than in obese wild-type controls. Furthermore, TNF-alpha 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 reduction of mitochondrial biogenesis observed with TNF-alpha. Our findings demonstrate that TNF-alpha impairs mitochondrial biogenesis and function in different tissues of obese rodents by downregulating eNOS expression and suggest a novel pathophysiological process that sustains obesity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Adipose Tissue / metabolism*
  • Animals
  • Cells, Cultured
  • Cytochromes c / metabolism
  • DNA-Binding Proteins / genetics
  • Down-Regulation / drug effects
  • Down-Regulation / genetics
  • Electron Transport Complex IV / metabolism
  • Female
  • High Mobility Group Proteins / genetics
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Obese
  • Mitochondria / genetics
  • Mitochondria / metabolism*
  • Muscle, Skeletal / metabolism*
  • Nitric Oxide Donors / pharmacology
  • Nitric Oxide Synthase Type III / genetics
  • Nitric Oxide Synthase Type III / metabolism*
  • Nuclear Respiratory Factor 1 / genetics
  • Obesity / genetics
  • Obesity / metabolism*
  • Oxygen Consumption / drug effects
  • Rats
  • Rats, Zucker
  • Receptors, Tumor Necrosis Factor / genetics
  • Tumor Necrosis Factor-alpha / pharmacology
  • Tumor Necrosis Factor-alpha / physiology*


  • DNA-Binding Proteins
  • High Mobility Group Proteins
  • Nitric Oxide Donors
  • Nrf1 protein, mouse
  • Nuclear Respiratory Factor 1
  • Receptors, Tumor Necrosis Factor
  • Tfam protein, mouse
  • Tumor Necrosis Factor-alpha
  • Adenosine Triphosphate
  • Cytochromes c
  • Nitric Oxide Synthase Type III
  • Electron Transport Complex IV