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Interaction of Tumor Necrosis Factor-- and Thiazolidinedione-Regulated Pathways in Obesity

Division of Biological Sciences and Department of Genetics and Complex Diseases (K.E.W., K.T.U., S.W., G.S.H.), Harvard School of Public Health, Boston, Massachusetts 02115; and Millennium Pharmaceuticals (Q.Y., H.C.), Cambridge, Massachusetts 02142

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.

Thiazolidinediones (TZDs) are potent insulin-sensitizing compounds and high-affinity ligands for the transcription factor peroxisomal proliferator-activated receptor . The mechanism through which TZDs improve insulin sensitivity, however, is not clear. In this study, we asked whether the ability of TZD to suppress and antagonize TNF is an underlying mechanism for its molecular and physiological effects, using obese (ob/ob) mice lacking TNF function. We found that the lipid-lowering effects of TZD are completely independent of TNF suppression, and the insulin-sensitizing effects of TZD are partially independent. TZD treatment improved insulin sensitivity in ob/ob mice both with and without functional TNF, albeit with different absolute potency. To characterize the potential interdependency of TZD- and TNF-regulated pathways at the molecular level, we also performed four-way transcriptional profiling of white adipose tissue of TZD- and vehicle-treated ob/ob mice, with and without TNF function. The majority of metabolic genes identified were regulated independent of the presence of TNF, whereas most effects on inflammatory mediators were dependent on TNF. This study demonstrates that the insulin-sensitizing action of TZD occurs partially through TNF-independent mechanisms, although a subset of the molecular effects of TZD treatment in adipose tissue depends on TNF.

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