Abstract
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
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Research Support, Non-U.S. Gov't
MeSH terms
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Adenosine Triphosphate / metabolism
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Adipose Tissue / metabolism*
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Animals
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Cells, Cultured
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Cytochromes c / metabolism
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DNA-Binding Proteins / genetics
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Down-Regulation / drug effects
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Down-Regulation / genetics
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Electron Transport Complex IV / metabolism
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Female
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High Mobility Group Proteins / genetics
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Mice, Obese
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Mitochondria / genetics
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Mitochondria / metabolism*
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Muscle, Skeletal / metabolism*
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Nitric Oxide Donors / pharmacology
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Nitric Oxide Synthase Type III / genetics
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Nitric Oxide Synthase Type III / metabolism*
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Nuclear Respiratory Factor 1 / genetics
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Obesity / genetics
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Obesity / metabolism*
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Oxygen Consumption / drug effects
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Rats
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Rats, Zucker
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Receptors, Tumor Necrosis Factor / genetics
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Tumor Necrosis Factor-alpha / pharmacology
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Tumor Necrosis Factor-alpha / physiology*
Substances
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DNA-Binding Proteins
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High Mobility Group Proteins
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Nitric Oxide Donors
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Nrf1 protein, mouse
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Nuclear Respiratory Factor 1
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Receptors, Tumor Necrosis Factor
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Tfam protein, mouse
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Tumor Necrosis Factor-alpha
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Adenosine Triphosphate
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Cytochromes c
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Nitric Oxide Synthase Type III
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Electron Transport Complex IV