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Submitted on ,
Accepted on ,
- and Thiazolidinedione-Regulated Pathways in Obesity
Division of Biological Sciences & Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA, 02115; Millennium Pharmaceuticals, Cambridge, MA 02142
* To whom correspondence should be addressed.
Thiazolidinediones (TZDs) are potent insulin sensitizing compounds and high affinity ligands for the transcription factor PPAR
. 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 have 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 depend on TNF.
•
Thiazolidinedione •
Obesity •
Inflammation •
Diabetes
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