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Am J Physiol Endocrinol Metab 284: E618-E626, 2003; doi:10.1152/ajpendo.00312.2002
0193-1849/03 $5.00
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Vol. 284, Issue 3, E618-E626, March 2003

Effect of heterozygous PPARgamma deficiency and TZD treatment on insulin resistance associated with age and high-fat feeding

Philip D. G. Miles1, Yaacov Barak5, Ronald M. Evans5, and Jerrold M. Olefsky2,3,4

Departments of 1 Surgery and 2 Medicine, University of California, San Diego, 3 San Diego Veterans Affairs Medical Center; 4 Whittier Diabetes Institute; and 5 Gene Expression Laboratory, Howard Hughes Medical Institute, Salk Institute, La Jolla, California 92093

Peroxisome proliferator-activated receptor-gamma (PPARgamma ) is the target receptor for thiazolidinedione (TZD) compounds, which are a class of insulin-sensitizing drugs used in the treatment of type 2 diabetes. Paradoxically, however, mice deficient in PPARgamma (PPARgamma +/-) are more insulin sensitive than their wild-type (WT) littermates, not less, as would be predicted. To determine whether PPARgamma deficiency could prevent the development of the insulin resistance associated with increasing age or high-fat (HF) feeding, insulin sensitivity was assessed in PPARgamma +/- and WT mice at 2, 4, and 8 mo of age and in animals fed an HF diet. Because TZDs elicit their effect through PPARgamma receptor, we also examined the effect of troglitazone (a TZD) in these mice. Glucose metabolism was assessed by hyperinsulinemic euglycemic clamp and oral glucose tolerance test. Insulin sensitivity declined with age for both groups. However, the decline in the PPARgamma +/- animals was substantially less than that of the WT animals, such that, by 8 mo of age, the PPARgamma +/- mice were markedly more insulin sensitive than the WT mice. This greater sensitivity in PPARgamma +/- mice was lost with TZD treatment. HF feeding led to marked adipocyte hypertrophy and peripheral tissue and hepatic insulin resistance in WT mice but also in PPARgamma +/- mice. Treatment of these mice with troglitazone completely prevented the adipocyte hypertrophy and normalized insulin action. In conclusion, PPARgamma deficiency partially protects against age-related insulin resistance but does not protect against HF diet-induced insulin resistance.

peroxisome proliferator-activated receptor-gamma deficiency; high-fat diet; aging; insulin resistance; thiazolidinedione; mice


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