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

Alessandra Valerio, Annalisa Cardile, Valeria Cozzi, Renata Bracale, Laura Tedesco, Addolorata Pisconti, Letizia Palomba, Orazio Cantoni, Emilio Clementi, Salvador Moncada, Michele O. Carruba, Enzo Nisoli

    Research output: Contribution to journalArticlepeer-review


    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-α. 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-α 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-α. Our findings demonstrate that TNF-α impairs mitochondrial biogenesis and function in different tissues of obese rodents by downregulating eNOS expression and suggest a novel pathophysiological process that sustains obesity.
    Original languageEnglish
    Pages (from-to)2791-2798
    Number of pages7
    JournalJournal of Clinical Investigation
    Issue number10
    Publication statusPublished - 2 Oct 2006


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


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