Abstract
The biological role of peroxisome proliferator-activated receptorγ (PPARγ) was investigated by gene targeting and case-control study of the Prol2Ala PPARγ 2 polymorphism. Homozygous PPARγ-deficient embryos died due to placental dysfunction. Heterozygous PPARγ-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy under a high-fat diet. Heterozygous PPARγ-deficient mice showed overexpression and hypersecretion of leptin, which may explain these phenotypes. This study reveals a hitherto unpredicted role for PPARγ in high-fat diet-induced obesity due to adipocyte hypertrophy and insulin resistance, which requires both alleles of PPARγ. A Prol2Ala polymorphism has been detected in the human PPARγ 2 gene. Since this amino acid substitution may cause a reduction in the transcriptional activity of PPARγ, this polymorphism may be associated with decreased insulin resistance and decreased risk of type 2 diabetes. To investigate this hypothesis, we performed a case-control study of the Prol2Ala PPARγ 2 polymorphism. In an obese group, subjects with A1a12 were more insulin sensitive than those without. The frequency of Ala12 was significantly lower in the diabetic group, suggesting that this polymorphism protects against type 2 diabetes. These results revealed that both in mice and humans, PPARγ is a thrifty gene mediating type 2 diabetes.
