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，我们建立了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抵抗力(Molecula Cell4：5971999)。我们还证明，以PPARγ拮抗剂处理的高脂饮食喂养的小鼠对胰岛素抵抗和肥胖具有抵抗(自然医学7：941,2001；J，Biol，Chem。276：41245,2001年)，表明脂肪细胞中PPARγ功能的降低导致脂肪细胞尺寸的缩小和系统性胰岛素抵抗的改善(J.Cin.在背心。我们还观察了PPARγ+/-小鼠和高脂喂养小鼠经PPARγ拮抗剂处理后瘦素和脂联素基因表达的降低。此外，我们还证明，在高脂肪饮食中，cbp基因中断的杂合子对肥胖、胰岛素抵抗和糖尿病的抵抗力要强得多，这为增加…的能量消耗提供了证据。我们还证明，脂联素通过激活AMPK和PPARγ配体促进储存在肝脏和骨骼肌中的脂肪燃烧，从而降低胰岛素靶器官的甘油三酯含量(自然医学8：1288,2002；J.Biol)。化学。278：2461,2003)。我们进一步证明，在apoE-/-小鼠与脂联素过度表达的转基因小鼠杂交后，动脉粥样硬化病变得到改善(J.Biol。化学。278：2461,2003)。为了研究胰岛素抵抗的机制，我们用基因打靶的方法建立了几个模型小鼠。因此，FAI，我们产生了胰岛素受体底物(IR)-1(Tamemoto等人：Natural 372：182-186,1994)和PPARγ基因(久保田等人：Mol.)缺乏的小鼠。牢房4：567-609,1999)。这些小鼠使我们能够解剖(1)胰岛素抵抗和胰岛素分泌障碍是如何导致糖尿病的发展，(2)肝脏、骨骼肌、脂肪组织和胰腺β细胞等每个器官的缺陷是如何导致糖尿病的发展的。我们还能够找到补偿目标基因的途径。尽管IRS-1缺陷小鼠存在胰岛素抵抗，但它们仍保持正常的糖耐量，因为胰岛素抵抗可通过伴随β细胞增殖的高胰岛素血症得到补偿(Yamuchi等：Mol.手机。比奥尔。16：3074-3084,1996)。通过将IRS-1^&lt；-/-&gt；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都是糖尿病发展所必需的(Teruchi等人：J.Clin。投资。我们还证明了IRS-1^&lt；-/-&gt；小鼠是“X综合征”的模型，因为它们在骨骼肌中表现出胰岛素抵抗、高甘油三酯血症、低高密度脂蛋白胆固醇、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)，它可以补偿IRS-1并介导IRS-1小鼠的胰岛素作用(Tobe等人：J.Biol)。化学。270：5698-5701,1995)。目前，我们建立了IRS-2缺陷小鼠，并证明这些小鼠由于肝脏胰岛素抵抗和β细胞生长障碍而发展为糖尿病(久保田等人：糖尿病49：1880-1889,2000)。我们还报告了IRS-2^&lt；-/-&gt；小鼠由于下丘脑瘦素抵抗而发生肥胖和脂肪肝(Tobe等人：J.Biol。化学。276-38337-38340,2001年)。较少

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