The role of PPARγ in high-fat diet-induced obesity and insulin resistance

It has been well demonstrated that insulin resistance plays an important role in the clustering of coronary risk factors through the progression of atherosclerosis in animal models of insulin resistance. In humans, a high-fat diet is the major cause of obesity and insulin resistance. In this study, we investigated the role of peroxisome proliferator-activated receptor γ (PPARγ) in high-fat diet induced-obesity and insulin resistance by gene targeting and case-control study using the common PPARγ2 polymorphism in human subjects. Homozygous PPARγ-deficient embryos died at 10.5-11.5 dpc 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 and the phenotypes were abrogated by PPARγ agonist treatment. Heterozygous PPARγ-deficient mice showed overexpression and hypersecretion of leptin despite the smaller size of adipocytes and decreased fat mass, which may explain these phenotypes at least in part. 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 Pro12Ala polymorphism has been detected in the human PPARγ2 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 Pro12Ala PPARγ2 polymorphism. In an obese group, subjects with Ala12 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.