title: Altered tumor necrosis factor-alpha (TNF-alpha) processing in adipocytes and increased expression of transmembrane TNF-alpha in obesity.
abstract: Tumor necrosis factor-alpha (TNF-alpha) is synthesized as a 26-kDa transmembrane protein (mTNF-alpha), which may present on the cell surface or be processed to release the 17-kDa soluble form (sTNF-alpha). Because regulation of this ectodomain shedding might be critical in the generation of systemic versus local cytokine responses, we examined the rate of mTNF-alpha processing in adipocytes and its regulation in obesity. Here, we demonstrate that the 26-kDa mTNF-alpha is present in adipose tissue and that its production is significantly increased in different rodent obesity models as well as in obese humans. There was no apparent deficiency in the level of the major TNF-alpha converting enzyme in adipose tissue to account for the excess amount of mTNF-alpha produced in obesity. However, experiments in cultured fat cells stably expressing TNF-alpha demonstrated a significantly decreased rate of TNF-alpha cleavage in differentiated adipocytes compared with preadipocytes. Thus, a decreased processing rate of mTNF-alpha in mature adipocytes combined with an increase in TNF-alpha production may be a potential mechanism resulting in elevated membrane-associated TNF-alpha in adipose tissue in obesity.
authors.affiliation: Division of Biological Sciences, Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 02115, USA.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Xu
authors.forename: K Teoman
authors.initials: KT
authors.lastname: Uysal
authors.forename: J David
authors.initials: JD
authors.lastname: Becherer
authors.forename: Peter
authors.initials: P
authors.lastname: Arner
authors.forename: Gökhan S
authors.initials: GS
authors.lastname: Hotamisligil
mesh_terms: D016475:3T3 Cells; D051722:ADAM Proteins; D000072198:ADAM17 Protein; D017667:Adipocytes / Q000378:metabolism*; D000273:Adipose Tissue / Q000378:metabolism / Q000648:ultrastructure; D000328:Adult; D000818:Animals; D015703:Antigens, CD / Q000502:physiology; D002462:Cell Membrane / Q000378:metabolism; D002478:Cells, Cultured; D015870:Gene Expression; D006801:Humans; D007163:Immunosorbent Techniques; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism*; D012333:RNA, Messenger / Q000032:analysis; D018124:Receptors, Tumor Necrosis Factor / Q000172:deficiency / Q000502:physiology; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics* / Q000378:metabolism*
chemical_list: D015703:Antigens, CD; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D047889:Receptors, Tumor Necrosis Factor, Type II; D014409:Tumor Necrosis Factor-alpha; D051722:ADAM Proteins; D008666:Metalloendopeptidases; D000072198:ADAM17 Protein