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Exclusive Action of Transmembrane TNF in Adipose Tissue Leads to Reduced Adipose Mass and Local But Not Systemic Insulin Resistance

Harvard School of Public Health, Division of Biological Sciences and Department of Nutrition, Boston, Massachusetts 02115

Address all correspondence and requests for reprints to: Gökhan S. Hotamisligil, M.D., Ph.D., Harvard School of Public Health, 665 Huntington Avenue, Boston, Massachusetts 02115. E-mail: . ghotamis{at}hsph.harvard.edu

Aberrant TNF expression in adipocytes is a molecular mechanism by which insulin action is modulated in adipose tissue. While this might be a compensatory response to limit adipose expansion, neither the mechanisms underlying this local effect nor its systemic biological consequences have been studied. It is also not clear whether TNF-induced insulin resistance in adipocyte alone is responsible for systemic insulin resistance in the absence of obesity. In a transgenic mouse model deficient in endogenous TNF, we demonstrate that specific expression of the transmembrane TNF (mTNF) in adipocytes leads to decreased whole body adipose mass, and local, but not systemic insulin resistance. These data demonstrate that exclusive action of TNF in adipose tissue strongly inhibits insulin action at this site and leads to reduced adiposity in mice. However, this isolated adipocyte insulin resistance in the context of reduced fat mass and/or the absence of obesity is insufficient to alter systemic glucose homeostasis.

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