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Peroxisome Proliferator-Activated Receptor- Deficiency Does Not Alter Insulin Sensitivity in Mice Maintained on Regular or High-Fat Diet: Hyperinsulinemic-Euglycemic Clamp Studies

Third Department of Medicine (M.H.), First Faculty of Medicine, Charles University, 128 08 Prague 2, Czech Republic; and Mouse Metabolism Laboratory (O.G.) and Diabetes Branch (D.L.), National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, Maryland 20892-1758

Address all correspondence and requests for reprints to: Martin Haluzik, Third Department of Medicine, First Faculty of Medicine, Charles University, U nemocnice 1, 128 08, Prague 2, Czech Republic. E-mail: mhalu{at}lf1.cuni.cz.

Chronic peroxisome proliferator-activated receptor (PPAR)- activation improves glucose metabolism in rodent models of insulin resistance and diabetes; however, PPAR- deficiency was also reported to protect against high-fat diet (HFD)-induced insulin resistance. The aim of this study was to clarify the role of PPAR- in the development of insulin resistance using PPAR- knockout (KO) mice and wild-type controls (WT). Both WT and PPAR- KO mice on HFD gained significantly more weight relative to chow-fed groups and displayed an increase in insulin levels and a decrease in adiponectin levels. Hyperinsulinemic-euglycemic clamp performed in the nonfasting state demonstrated that HFD caused a marked reduction in whole body, muscle, and white and brown adipose tissue glucose uptake in both WT and PPAR- KO mice relative to chow-fed groups. Suppression of endogenous glucose production during the clamp was markedly blunted in both WT and PPAR- KO HFD-fed mice, indicating liver insulin resistance. The magnitude of HFD-induced changes in the clamp parameters of insulin sensitivity was comparable in PPAR- KO and WT mice. In conclusion, these data show that PPAR- deficiency does not alter insulin sensitivity in mice fed normal chow diet and does not protect against HFD-induced insulin resistance as measured by hyperinsulinemic-euglycemic clamp in nonfasted state.

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