title: The role of PPARgamma in high-fat diet-induced obesity and insulin resistance.
abstract: 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 gamma (PPARgamma) in high-fat diet induced-obesity and insulin resistance by gene targeting and case-control study using the common PPARgamma2 polymorphism in human subjects. Homozygous PPARgamma-deficient embryos died at 10.5-11.5 dpc due to placental dysfunction. Heterozygous PPARgamma-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 PPARgamma agonist treatment. Heterozygous PPARgamma-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 PPARgamma in high-fat diet-induced obesity due to adipocyte hypertrophy and insulin resistance, which requires both alleles of PPARgamma. A Pro12Ala polymorphism has been detected in the human PPARgamma2 gene. Since this amino acid substitution may cause a reduction in the transcriptional activity of PPARgamma, 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 PPARgamma2 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, PPARgamma is a thrifty gene mediating Type 2 diabetes.
authors.affiliation: Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku 113-8655, Tokyo, Japan. kadowaki-3im@h.u-tokyo.ac.jp
authors.forename: Takashi
authors.initials: T
authors.lastname: Kadowaki
authors.forename: Kazuo
authors.initials: K
authors.lastname: Hara
authors.forename: Naoto
authors.initials: N
authors.lastname: Kubota
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Tobe
authors.forename: Yasuo
authors.initials: Y
authors.lastname: Terauchi
authors.forename: Toshimasa
authors.initials: T
authors.lastname: Yamauchi
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Eto
authors.forename: Hiroko
authors.initials: H
authors.lastname: Kadowaki
authors.forename: Mitsuhiko
authors.initials: M
authors.lastname: Noda
authors.forename: Ryoko
authors.initials: R
authors.lastname: Hagura
authors.forename: Yauso
authors.initials: Y
authors.lastname: Akanuma
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D004032:Diet; D004041:Dietary Fats; D006801:Humans; D007333:Insulin Resistance / Q000502:physiology; D008954:Models, Biological; D009765:Obesity / Q000209:etiology / Q000503:physiopathology*; D011110:Polymorphism, Genetic; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics / Q000502:physiology*; D012097:Repressor Proteins / Q000502:physiology; D014157:Transcription Factors / Q000235:genetics / Q000502:physiology*
chemical_list: D004041:Dietary Fats; D018160:Receptors, Cytoplasmic and Nuclear; D012097:Repressor Proteins; D014157:Transcription Factors