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

Abstract

Peroxisome proliferator-activated receptor-γ (PPARγ) 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 PPARγ ( PPARγ+/− ) are more insulin sensitive than their wild-type (WT) littermates, not less, as would be predicted. To determine whether PPARγ deficiency could prevent the development of the insulin resistance associated with increasing age or high-fat (HF) feeding, insulin sensitivity was assessed in PPARγ+/− and WT mice at 2, 4, and 8 mo of age and in animals fed an HF diet. Because TZDs elicit their effect through PPARγ 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 PPARγ+/− animals was substantially less than that of the WT animals, such that, by 8 mo of age, the PPARγ+/− mice were markedly more insulin sensitive than the WT mice. This greater sensitivity in PPARγ+/− 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 PPARγ+/− mice. Treatment of these mice with troglitazone completely prevented the adipocyte hypertrophy and normalized insulin action. In conclusion, PPARγ deficiency partially protects against age-related insulin resistance but does not protect against HF diet-induced insulin resistance.