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

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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-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 pages8
JournalJournal of Clinical Investigation
Volume116
Issue number10
DOIs
Publication statusPublished - Oct 2 2006

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ASJC Scopus subject areas

  • Medicine(all)

Cite this

Valerio, A., Cardile, A., Cozzi, V., Bracale, R., Tedesco, L., Pisconti, A., Palomba, L., Cantoni, O., Clementi, E., Moncada, S., Carruba, M. O., & Nisoli, E. (2006). TNF-α downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents. Journal of Clinical Investigation, 116(10), 2791-2798. https://doi.org/10.1172/JCI28570