Altered Tumor Necrosis Factor-α (TNF-α) Processing in Adipocytes and Increased Expression of Transmembrane TNF-α in Obesity

• Published in: Diabetes (New York, N.Y.) Vol. 51; no. 6; pp. 1876 - 1883
• Main Authors: HAIYAN XU, UYSAL, K. Teoman, BECHERER, J. David, ARNER, Peter, HOTAMISLIGIL, Gökhan S
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01.06.2002
• Subjects: 3T3 Cells; ADAM Proteins; ADAM17 Protein; Adipocytes; Adipocytes - metabolism; Adipose Tissue - metabolism; Adipose Tissue - ultrastructure; Adult; Animals; Antigens, CD - physiology; Biological and medical sciences; Body fat; Cell Membrane - metabolism; Cells, Cultured; Cytokines; Diabetes; Enzymes; Gene Expression; Growth factors; Humans; Immunosorbent Techniques; Insulin; Medical sciences; Medicin och hälsovetenskap; Metabolic diseases; Metalloendopeptidases - genetics; Metalloendopeptidases - metabolism; Mice; Middle Aged; Obesity; Obesity - metabolism; Physiological aspects; Physiology; Proteins; Receptors, Tumor Necrosis Factor - deficiency; Receptors, Tumor Necrosis Factor - physiology; Receptors, Tumor Necrosis Factor, Type I; Receptors, Tumor Necrosis Factor, Type II; RNA, Messenger - analysis; Tumor necrosis factor; Tumor Necrosis Factor-alpha - genetics; Tumor Necrosis Factor-alpha - metabolism; Tumor necrosis factor-TNF; United States; Sweden; Human; Transmembrane protein; Adipocyte; Obesity; Metabolic disorder; Cytokine; Nutritional status; Tumor necrosis factor α
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/diabetes.51.6.1876

Altered Tumor Necrosis Factor-α (TNF-α) Processing in Adipocytes and Increased Expression of Transmembrane TNF-α in Obesity Haiyan Xu 1 , K. Teoman Uysal 1 , J. David Becherer 2 , Peter Arner 3 and Gökhan S. Hotamisligil 1 1 Division of Biological Sciences and Department of Nutrition, Harvard School of Public Health, Boston, Massachusetts 2 Department of Molecular Biochemistry, Glaxo Wellcome Research and Development, Durham, North Carolina 3 Karolinska Institute, Department of Medicine, Huddinge University Hospital, Huddinge, Sweden Abstract Tumor necrosis factor-α (TNF-α) is synthesized as a 26-kDa transmembrane protein (mTNF-α), which may present on the cell surface or be processed to release the 17-kDa soluble form (sTNF-α). Because regulation of this ectodomain shedding might be critical in the generation of systemic versus local cytokine responses, we examined the rate of mTNF-α processing in adipocytes and its regulation in obesity. Here, we demonstrate that the 26-kDa mTNF-α 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-α converting enzyme in adipose tissue to account for the excess amount of mTNF-α produced in obesity. However, experiments in cultured fat cells stably expressing TNF-α demonstrated a significantly decreased rate of TNF-α cleavage in differentiated adipocytes compared with preadipocytes. Thus, a decreased processing rate of mTNF-α in mature adipocytes combined with an increase in TNF-α production may be a potential mechanism resulting in elevated membrane-associated TNF-α in adipose tissue in obesity. Footnotes Address correspondence and reprint requests to Gökhan S. Hotamisligil, Harvard School of Public Health, Division of Biological Sciences and Department of Nutrition, 665 Huntington Ave., Boston, MA 02115. E-mail: ghotamis{at}hsph.harvard.edu . Received for publication 28 June 2001 and accepted in revised form 26 February 2002. H.X. is currently employed by Millennium Pharmaceuticals, Cambridge, Massachusetts. DMEM, Dulbecco’s modified Eagle’s medium; ELISA, enzyme-linked immunosorbent assay; IRS-1, insulin receptor substrate-1; mTNF-α, transmembrane tumor necrosis factor-α; sTNF-α, soluble tumor necrosis factor-α; TACE, tumor necrosis factor-α converting enzyme; TGF-α, transforming growth factor-α; TNF, tumor necrosis factor; TNFR, TNF receptor. DIABETES