| Co-Investigator(Kenkyū-buntansha) |
TERAUCHI Yasuo the University of Tokyo, Facully of Medicine, Research Associate, 医学部附属病院, 助手 (40359609)
YAMAUCHI Toshimasa the University of Tokyo, Facully of Medicine, medical staff, 医学部附属病院, 医員
KADOWAKI Takashi the University of Tokyo, Facully of Medicine, Associate Professor, 医学部附属病院, 助教授 (30185889)
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| Research Abstract |
In order to clarify the mechanism of high-fat diet-induced insulin resistance and obesity, we generated PPARγ knockout mice. Hetrozygotes for PPARγ gene were resistant to high fat diet-induced obesity and insulin resistance (Molecula Cell 4: 597, 1999). We also demonstrated that mice fed with high fat diet treated with PPARγ antagonists were resistant to insulin resistance and obesity (Nature Medicine 7: 941, 2001; J, Biol, Chem. 276: 41245, 2001), suggesting that reduced function of PPARγ in adipocytes results in the reduction of adipocyte size and amelioration if systemic insulin resistance (J. Cin.In vest. 108: 1001, 2001).
We also the reduced expression of leptin and adiponectin gene in smaller adipocytes from PPARγ+/-mice and high-fat fed mice treated with PPARγ antagonist. In addition, we demonstrated that heterozygotes for CBP gene disruption are much more resistant to obesity and insulin resistance and diabetes on a high fat diet, providing evidence that increesed energy consump
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tion and insulin sensitivity was due to increase leptin sensitivity and serum adiponectin levels (Nature Genetics 30: 221, 2002).
We also demonstrated that adiponectin reduced triglyceride contents of insulin's target organ by promoting the combustion of lipid stored in liver and skeletal muscle through the activation of AMP kinase and PPARγ ligand (Nature Medicine 8: 1288, 2002; J. Biol. CHem. 278: 2461, 2003). We further demonstrated that improved atherosclerotic lesion was observed in apoE-/-mice which crossed with adiponectin overxpressed transgenic mice(J. Biol. Chem. 278: 2461, 2003).
In order to study the mechanism of insulin resistance, we generated several model mice by gene targeting. So fai, we generated mice deficient in insulin receptor substrate (IRS)-1 (Tamemoto, et al.: Nature 372: 182-186, 1994) PI3 kinase p85 regulatory subunit (Terauchi, et al.: Nature Genetics 21: 230-235, 1999) and PPARγ gene (Kubota, et al.: Mol. Cell 4: 567-609, 1999). These mice enabled us to dissect (1)how insulin resistance and insulin secretory dysfunction lead to the development of diabetes, (2)how defects in each organ such us liver, skeletal muscle, adipose tissue and pancreatic β cells are responsible for the development of diabetes. We also were able to find pathways which compensate for the targeted gene. Although IRS-1 deficient mice were insulin resistant, they remaind normal glucose tolerance, because insulin resistance was compensated by hyperinsulinemia associated with β cell hyperplasia (Yamauchi, et al.: Mol. cell. Biol. 16: 3074-3084, 1996). By crossing IRS-1^<-/-> mice with glucokinase deficient mice with insulin secretory dysfunction, we came to the conclusion that both insulin resistance and insulin secretory dysfunction are necessary for the development of diabetes (Terauchi, et al.: J. Clin. Invest. 99: 861-866, 1997).
We also demonstrated that IRS-1^<-/-> mice were a model for "Syndrome X" because they showed insulin resistance in skeletal muscle, hypertriglycerolemia, lower HDL Chol, hypertension and endothelial dysfunction (Abe, et al.: J. Cin.Invest. 101: 1784-1788, 1998.). We also found a novel insulin receptor substrate, (IRS-2) which compensated IRS-1 and mediated insulin action in IRS-1^<-/-> mice (Tobe, et al.: J. Biol. Chem. 270: 5698-5701, 1995). Currently, we generated IRS-2 deficient mice and demonstrated that these mice developed diabetes due to insulin resistance in liver and β cell growth failure (Kubota, et al.: Diabetes 49: 1880-1889, 2000). We also reported that IRS-2^<-/-> mice developed obesity and fatty liver due to leptin resistance in the hypothrlamus (Tobe, et al.: J. Biol. Chem. 276-38337-38340, 2001). Less
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