@article{1614999f5c004c42b83c422911e07182,
title = "The role of pparϣ as a thrifty gene both in mice and humans",
abstract = "The biological role of peroxisome proliferator-activated receptor ϣ (PPARϣ) was investigated by gene targeting and case±control study of the Pro12Ala PPARϣ2 polymorphism. Homozygous PPARϣ-deficient embryos died at 10.5–11.5 days post conception (dpc) due to placental dysfunction. Heterozygous PPARϣ-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy under a high-fat diet, whose phenotypes were abrogated by PPARϣ agonist treatment. Heterozygous PPARϣ-deficient mice showed over-expression 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 PPARϣ in high-fat diet-induced obesity due to adipocyte hypertrophy and insulin resistance, which requires both alleles of PPARϣ. A Pro12Ala polymorphism has been detected in the human PPARϣ2 gene. Since this amino acid substitution may cause a reduction in the transcriptional activity of PPARϣ, 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 PPARϣ2 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 in both mice and humans, PPARg is a thrifty gene mediating type 2 diabetes.",
keywords = "Obesity, Thiazolidinediones",
author = "Kazuo Hara and Naoto Kubota and Kazuyuki Tobe and Yasuo Terauchi and Hiroshi Miki and Kajuro Komeda and Hiroyuki Tamemoto and Toshimasa Yamauchi and Ryoko Hagura and Chikako Ito and Yauso Akanuma and Takashi Kadowaki",
note = "Funding Information: 1Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, 2The Institute for Diabetes Care and Research, Asahi Life Foundation, Tokyo 100-0005, 3Division of Laboratory Animal Science, Animal Research Center, Tokyo Medical University, Tokyo 160-8402, 4Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512, 5Hiroshima Atomic Bomb Casualty Council Health Management Center, Hiroshima 730-0052, Japan Funding Information: To investigate whether PPARg plays a role in insulin resistance and onset of type 2 diabetes in humans, we compared the frequency of Ala12 bearer in the non-related type 2 diabetic and non-diabetic subjects. Non-diabetic subjects who were over the age of 60, had HbA1c values lower than 6´0 %, and no family history of type 2 diabetes were recruited from an unselected population who underwent a routine health check-up at the Hiroshima Atomic Bomb Casualty Council Health Management Center. The diabetic subjects were recruited from the outpatient clinic of the Institute for Diabetes Care and Research, Asahi Life Foundation and the Department of Metabolic Diseases, Tokyo University. This study was performed under informed consent from all subjects and was approved by the Ethics Committee of Tokyo University. The frequency of subjects bearing the Ala12 allele was significantly lower in the diabetic group (3´6 %) than in the non-diabetic group (8´3 %, P ˆ 0´003† see Table 1 (Hara et al. 2000). Subjects with the Ala12 allele had a decreased risk for type 2 diabetes [odds ratio …OR† ˆ 0´413; 95 %CI; 0´220–0´735] (Hara et al. 2000). After adjustment for age, gender, and BMI, this reduced risk was still observed …OR ˆ 0´324; 95 %CI; 0´152–0´658) (Hara et al. 2000). To assess the insulin resistance and b-cell function of subjects, we used the homeostasis model assessment (HOMA-IR and HOMA-b, respectively) (Matthews et al. 1985). Neither",
year = "2000",
month = dec,
doi = "10.1079/09658219738860",
language = "英語",
volume = "84",
pages = "S235--S239",
journal = "British Journal of Nutrition",
issn = "0007-1145",
publisher = "Cambridge University Press",
number = "S2",
}