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

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