title: Autoamplification of tumor necrosis factor-alpha: a potential mechanism for the maintenance of elevated tumor necrosis factor-alpha in male but not female obese mice.
abstract: Although tumor necrosis factor-alpha (TNF-alpha) is elevated in adipose tissue in obesity and may contribute to the cardiovascular and metabolic risks associated with this condition, the mechanisms leading to elevated TNF-alpha remain elusive. We hypothesized that autoamplification of TNF-alpha contributes to the maintenance of elevated TNF-alpha in obesity. Treatment of 3T3-L1 adipocytes with TNF-alpha, or injection of TNF-alpha into C57BL/6J mice, up-regulated TNF-alpha mRNA in adipocytes and in adipose tissues, respectively. Ob/ob male but not female mice lacking TNF-alpha receptors showed significantly lower levels of adipose TNF-alpha mRNA when compared with TNF-alpha receptor-expressing ob/ob mice. Thus, the lack of endogenous TNF-alpha signaling reduced adipose TNF-alpha mRNA in ob/ob male mice. Additionally, hyperinsulinemia potentiated this TNF-alpha-mediated autoamplification response in adipose tissues and in adipocytes in a synergistic and dose-dependent manner. Studies in which TNF-alpha was injected into lean mice lacking individual TNF-alpha receptors indicated that TNF-alpha autoamplification in adipose tissues was mediated primarily via the p55 TNF-alpha receptor whereas the p75 TNF-alpha receptor appeared to augment this response. Finally, TNF-alpha autoamplification in adipocytes occurred via the protein kinase C signaling pathway and the transcription factor nuclear factor-kappaB. Thus, TNF-alpha can positively autoregulate its own biosynthesis in adipose tissue, contributing to the maintenance of elevated TNF-alpha in obesity.
authors.affiliation: Division of Vascular Biology, La Jolla Institute for Molecular Medicine, San Diego, CA 92121, USA.
authors.forename: Jaap G
authors.initials: JG
authors.lastname: Neels
authors.forename: Manjula
authors.initials: M
authors.lastname: Pandey
authors.forename: Gökhan S
authors.initials: GS
authors.lastname: Hotamisligil
authors.forename: Fahumiya
authors.initials: F
authors.lastname: Samad
mesh_terms: D016475:3T3 Cells; D017667:Adipocytes; D000818:Animals; D004622:Embryo, Mammalian; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D005786:Gene Expression Regulation; D006706:Homeostasis / Q000235:genetics*; D006946:Hyperinsulinism / Q000378:metabolism; D007328:Insulin / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009765:Obesity / Q000235:genetics / Q000378:metabolism*; D011493:Protein Kinase C / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D013851:Thinness / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics / Q000378:metabolism*
chemical_list: D007328:Insulin; D012333:RNA, Messenger; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D011493:Protein Kinase C