Nuclear Receptors as Targets for Drug Development : Molecular Mechanisms for Regulation of Obesity and Insulin Resistance by Peroxisome Proliferator-Activated Receptor γ, CREB-Binding Protein, and Adiponectin
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概要
- 論文の詳細を見る
Obesity is defined as increased mass of adipose tissue, conferring a higher risk of cardiovascular and metabolic disorders such as diabetes, hyperlipidemia, and coronary heart disease. To investigate the role of transcriptional factors, which are involved in adipocytes differentiation and adiposity, we have generated peroxisome proliferator-activated receptor (PPAR) γ or CREB-binding protein (CBP)-deficient mice by gene targeting. Heterozygous PPARγ-deficient mice were protected from the development of insulin resistance due to adipocyte hypertrophy under a high-fat diet. Heterozygous CBP-deficient mice showed increased insulin sensitivity and were completely protected from body weight gain induced by a high-fat diet. PPARγ or CBP deficiency results in increased effects of hormones such as adiponectin and leptin. Adiponectin was decreased in obesity and lipoatrophy, and replenishment of adiponectin ameliorated insulin resistance. Moreover, adiponectin-deficient mice showed insulin resistance and atherogenic phenotype. Finally, cDNA encoding adiponectin receptors (AdipoR1/R2) have been identified by expression cloning. The expression of AdipoR1/R2 appears to be inversely regulated by insulin in physiological and pathophysiological states such as fasting/refeeding, insulin deficiency, and hyperinsulinemia models, and it is correlated with adiponectin sensitivity. These results facilitate the understanding of molecular mechanisms of adiponectin actions and obesity-linked diseases such as diabetes and atherosclerosis and propose the molecular targets for anti-diabetic and anti-atherogenic drugs.
- 社団法人 日本薬理学会の論文
- 2005-02-20
著者
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Kadowaki Takashi
Department of Health Science, Shiga University of Medical Science
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YAMAUCHI Toshimasa
Department of Metabolic Diseases, The University of Tokyo
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Kadowaki Takashi
Department Of Cardiovascular Medicine Graduate School Of Medicine University Of Tokyo
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Kadowaki Takashi
Department Of Metabolic Diseases Graduate School Of Medicine University Of Tokyo
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Yamauchi Toshimasa
Department Of Metabolic Diseases Graduate School Of Medicine University Of Tokyo
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Yamauchi Toshimasa
Department Of Integrated Molecular Science On Metabolic Disease 22nd Century Medical And Research Ce
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TSUCHIDA Atsushi
Department of Metabolic Diseases, Graduate School of Medicine, University of Tokyo
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Tsuchida Atsushi
Department Of Metabolic Diseases Graduate School Of Medicine University Of Tokyo
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Kadowaki Takashi
Department Of Cardiology Kawasaki Medical School
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