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The role of PPARγ as a thrifty gene both in mice and humans

Published online by Cambridge University Press:  09 March 2007

Kazuo Hara ,
Naoto Kubota ,
Kazuyuki Tobe ,
Yasuo Terauchi ,
Hiroshi Miki ,
Kajuro Komeda ,
Hiroyuki Tamemoto ,
Toshimasa Yamauchi ,
Ryoko Hagura  and
Chikako Ito
...Show all authors
Kazuo Hara
Affiliation:
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655 The Institute for Diabetes Care and Research, Asahi Life Foundation, Tokyo 100-0005
Naoto Kubota
Affiliation:
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655
Kazuyuki Tobe
Affiliation:
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655
Yasuo Terauchi
Affiliation:
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655
Hiroshi Miki
Affiliation:
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655
Kajuro Komeda
Affiliation:
Division of Laboratory Animal Science, Animal Research Center, Tokyo Medical University, Tokyo 160-8402
Hiroyuki Tamemoto
Affiliation:
Department of Molecular Medicine, Institute for Molecular and Cellular Regulation, Gunma University, Gunma 371-8512
Toshimasa Yamauchi
Affiliation:
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655
Ryoko Hagura
Affiliation:
The Institute for Diabetes Care and Research, Asahi Life Foundation, Tokyo 100-0005
Chikako Ito
Affiliation:
Hiroshima Atomic Bomb Casualty Council Health Management Center, Hiroshima 730–0052, Japan
Yauso Akanuma
Affiliation:
The Institute for Diabetes Care and Research, Asahi Life Foundation, Tokyo 100-0005
Takashi Kadowaki*
Affiliation:
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655
*
*Corresponding author: Takashi Kadowaki, M.D., Ph.D. Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8655, Japan, tel +81 3 3815 5411 ext. 33111, fax +81 3 5689 7209, email kadowaki-3im@h.u-tokyo.ac.jp
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Abstract

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The biological role of peroxisome proliferator-activated receptor γ (PPARγ) was investigated by gene targeting and case±control study of the Pro12Ala PPARγ2 polymorphism. Homozygous PPARγ-deficient embryos died at 10.5–11.5 days post conception (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, whose phenotypes were abrogated by PPARγ agonist treatment. Heterozygous PPARγ-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 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 in both mice and humans, PPARg is a thrifty gene mediating type 2 diabetes.

Keywords

ObesityThiazolidinediones
Type
Research Article
Information
British Journal of Nutrition , Volume 84 , Issue S2 , December 2000 , pp. S235 - S239
Copyright
Copyright © The Nutrition Society 2000

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