PPARγ antagonist ameliorates obesity, insulin resistance and atherosclerosis.

为了阐明高脂饮食诱导胰岛素抵抗和肥胖的机制，我们制备了PPARγ基因敲除小鼠。PPARγ基因杂合子对高脂饮食诱导的肥胖和胰岛素抵抗具有抗性（Molecula Cell 4：597，1999）。我们还证明，用高脂肪饮食喂养的小鼠经PPARγ拮抗剂处理后对胰岛素抵抗和肥胖具有抗性（Nature Medicine 7：941，2001; J，Biol，Chem.276：41245，2001），这表明脂肪细胞中PPARγ功能的降低导致脂肪细胞大小的减小和全身胰岛素抵抗的改善（J. Cin.In vest.一百零八：1001，2001）。我们还发现，用PPARγ拮抗剂处理的PPARγ+/-小鼠和高脂喂养小鼠的较小脂肪细胞中瘦素和脂联素基因的表达降低。此外，我们证明CBP基因破坏的杂合子对肥胖、胰岛素抵抗和高脂肪饮食的糖尿病有更强的抵抗力，这为增加能量消耗提供了证据。 关于我们 瘦素敏感性和血清脂联素水平的升高是导致胰岛素敏感性降低的主要原因（Nature Genetics 30：221，2002）。我们还证明，脂联素通过激活AMP激酶和PPARγ配体促进储存在肝脏和骨骼肌中的脂质燃烧，从而降低胰岛素靶器官的甘油三酯含量（Nature Medicine 8：1288，2002; J.Biol.Chem.278：2461，2003）。我们进一步证明，在与脂联素过表达转基因小鼠杂交的apoE-/-小鼠中观察到动脉粥样硬化病变的改善（J. Biol. Chem. 278：2461，2003）。因此，我们产生了胰岛素受体底物（IRS）-1缺陷的小鼠（Tamemoto等人：Nature 372：182-186，1994）PI 3激酶p85调节亚基（Terauchi等人：Nature Genetics 21：230-235，1999）和PPARγ基因（Kubota等人：摩尔Cell 4：567-609，1999）。这些小鼠使我们能够剖析（1）胰岛素抵抗和胰岛素分泌功能障碍如何导致糖尿病的发展，（2）每个器官如肝脏，骨骼肌，脂肪组织和胰腺β细胞的缺陷如何导致糖尿病的发展。我们还能够找到补偿靶基因的途径。尽管IRS-1缺陷小鼠具有胰岛素抗性，但它们具有正常的葡萄糖耐量，因为胰岛素抗性通过与β细胞增生相关的高胰岛素血症得到补偿（Yamauchi等人：摩尔cell. 16：3074-3084，1996）。通过将IRS-1^<-/->小鼠与具有胰岛素分泌功能障碍的葡萄糖激酶缺陷小鼠杂交，我们得出结论，胰岛素抵抗和胰岛素分泌功能障碍对于糖尿病的发展是必需的（Terauchi，et al.：J. Clin. Invest.九十九：861-866，1997）。我们还证明IRS-1^<-/->小鼠是“X综合征”的模型，因为它们显示出骨骼肌中的胰岛素抗性、高胆固醇血症、低HDL Chol、高血压和内皮功能障碍（Abe等人：J. Cin.Invest. 101：1784-1788，1998。）。我们还发现了一种新的胰岛素受体底物（IRS-2），它补偿IRS-1并介导IRS-1^-/->小鼠中的胰岛素作用（Tobe等人：270：5698-5701，1995）。目前，我们产生了IRS-2缺陷小鼠，并证明这些小鼠由于肝脏中的胰岛素抵抗和β细胞生长失败而发展为糖尿病（Kubota等人：Diabetes 49：1880-1889，2000）。我们还报道了IRS-2^<-/->小鼠由于下丘脑中的瘦素抗性而发展肥胖和脂肪肝（Tobe等人：J. Biol. Chem. 276-38337-38340，2001）。少

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 … More 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