Journal of Biological Chemistry
Volume 276, Issue 44, 2 November 2001, Pages 41245-41254
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MECHANISMS OF SIGNAL TRANSDUCTION
The Mechanisms by Which Both Heterozygous Peroxisome Proliferator-activated Receptor γ (PPARγ) Deficiency and PPARγ Agonist Improve Insulin Resistance*

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Peroxisome proliferator-activated receptor (PPAR) γ is a ligand-activated transcription factor and a member of the nuclear hormone receptor superfamily that is thought to be the master regulator of fat storage; however, the relationship between PPARγ and insulin sensitivity is highly controversial. We show here that supraphysiological activation of PPARγ by PPARγ agonist thiazolidinediones (TZD) markedly increases triglyceride (TG) content of white adipose tissue (WAT), thereby decreasing TG content of liver and muscle, leading to amelioration of insulin resistance at the expense of obesity. Moderate reduction of PPARγ activity by heterozygous PPARγ deficiency decreases TG content of WAT, skeletal muscle, and liver due to increased leptin expression and increase in fatty acid combustion and decrease in lipogenesis, thereby ameliorating high fat diet-induced obesity and insulin resistance. Moreover, although heterozygous PPARγ deficiency and TZD have opposite effects on total WAT mass, heterozygous PPARγ deficiency decreases lipogenesis in WAT, whereas TZD stimulate adipocyte differentiation and apoptosis, thereby both preventing adipocyte hypertrophy, which is associated with alleviation of insulin resistance presumably due to decreases in free fatty acids, and tumor necrosis factor α, and up-regulation of adiponectin, at least in part. We conclude that, although by different mechanisms, both heterozygous PPARγ deficiency and PPARγ agonist improve insulin resistance, which is associated with decreased TG content of muscle/liver and prevention of adipocyte hypertrophy.

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Published, JBC Papers in Press, August 31, 2001, DOI 10.1074/jbc.M103241200

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This work was supported in part by a grant from the Research Fellowships of the Japan Society for the Promotion of Science for Young Scientists (to T. Y.), a grant-in-aid for the development of innovative technology, a grant-in-aid for creative basic research from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to T. K.), and by Health Science Research Grants (Research on Human Genome and Gene Therapy) from the Ministry of Health and Welfare (to T. K.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

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Contributed equally to this work.