title: TNF-alpha downregulates eNOS expression and mitochondrial biogenesis in fat and muscle of obese rodents.
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.
authors.affiliation: Integrated Laboratories Network, Center for Study and Research on Obesity, Department of Pharmacology, School of Medicine, University of Milan, Milan, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Valerio
authors.forename: Annalisa
authors.initials: A
authors.lastname: Cardile
authors.forename: Valeria
authors.initials: V
authors.lastname: Cozzi
authors.forename: Renata
authors.initials: R
authors.lastname: Bracale
authors.forename: Laura
authors.initials: L
authors.lastname: Tedesco
authors.forename: Addolorata
authors.initials: A
authors.lastname: Pisconti
authors.forename: Letizia
authors.initials: L
authors.lastname: Palomba
authors.forename: Orazio
authors.initials: O
authors.lastname: Cantoni
authors.forename: Emilio
authors.initials: E
authors.lastname: Clementi
authors.forename: Salvador
authors.initials: S
authors.lastname: Moncada
authors.forename: Michele O
authors.initials: MO
authors.lastname: Carruba
authors.forename: Enzo
authors.initials: E
authors.lastname: Nisoli
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism*; D000818:Animals; D002478:Cells, Cultured; D045304:Cytochromes c / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D015536:Down-Regulation / Q000187:drug effects / Q000235:genetics; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D006609:High Mobility Group Proteins / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism*; D051266:Nuclear Respiratory Factor 1 / Q000235:genetics; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D011924:Rats, Zucker; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000494:pharmacology / Q000502:physiology*
chemical_list: D004268:DNA-Binding Proteins; D006609:High Mobility Group Proteins; D020030:Nitric Oxide Donors; C495634:Nrf1 protein, mouse; D051266:Nuclear Respiratory Factor 1; D018124:Receptors, Tumor Necrosis Factor; C081930:Tfam protein, mouse; D014409:Tumor Necrosis Factor-alpha; D000255:Adenosine Triphosphate; D045304:Cytochromes c; D052250:Nitric Oxide Synthase Type III; D003576:Electron Transport Complex IV