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Dissection of the Mechanism of Obesity-induced Insulin Resistance

肥胖引起的胰岛素抵抗机制剖析

基本信息

批准号：
09557077
负责人：
TOBE Kazuyuki
金额：
$ 6.98万
依托单位：
University of Tokyo
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1997
资助国家：
日本
起止时间：
1997 至 1999
项目状态：
已结题

项目摘要

Troglitazone (CS-045) is one of the thiazolidinediones that activate the peroxisome proliferator-activated receptor γ (PPARγ), which is expressed primarily in adipose tissues. To eluciadate the mechanism by which troglitazone relieves insulin resistance in vivo, we studied its effects on the white adipose tissues of an obese animal model (obese Zucker rat). Administration of troglitazone for 15 d normalized mild hyperglycemia and marked hyperinsulinemia in these rats. Plasma triglyceride level was decreased by troglitazone in both obese and lean rats. Troglitazone did not change the total weight of white adipose tissues but increased the number of small adipocytes (<2,500μmィイD12ィエD1) approximately fourfold in both retroperitoneal and subcutaneous adipose tissues of obese rats. It also decreased the number of large adipocytes (> 5,000μmィイD12ィエD1) by〜50%. In fact, the percentage of apoptotic nuclei was 〜2.5-fold higher in the troglitazone-treated retroperitoneal white adipose tissue, tha … More n, control. Concomitantly, troglitazone normalized the, expression levels of TNF- α which were elevated by 2-and 1.4-fold in the retroperitoneal and mesenteric white adipose tissues of the obese rats, respectively. Troglitazone also caused a dramatic decrease in the expression levels of leptin, which were increased by 4-10-fold in the white adipose tissues of obese rats. These results suggest that the primary action of troglitazone may be to increase the number of small adipocytes in white adipose tissues, presumably via PPARγ. The increase number of small adipocytes and the decreased number of large adipocytes in white adipose tissues of troglitazone-treated obese rats appear to be an important mechanism by which increased expression levels of TNF- α and higher levels of plasma lipids are normalized, leading to alleviation of insulin resistance(Okuno et al., J. Clin. Invest. 101, 1354-1361, 1998). Furthermore, we have made PPARγ deficient mice. Under high diet PPARγ(+/-) mice have been shown to be protected from obesity and insulin resistance with higher serum levels of leptin compared with those in wild-type mice(Kubota et al, Mol. Cell. 4, 597-609, 1999). suggesting that PPARγ activity promotes increased obesity and insulin resistance under high fat diet. Furthermore, through the search of diabetic patients, the number of the 5ubJects with PPARγ Prol2Ala allele(less activity form of PPARγ2) in diabetic group are less than that in control non-diabetic group(Hara et al, diabetologia in press). Less

Troglitazone (CS-045) 是一种噻唑烷二酮类药物，可激活过氧化物酶体增殖物激活受体 γ (PPARγ)，该受体主要在脂肪组织中表达。为了阐明曲格列酮缓解体内胰岛素抵抗的机制，我们研究了其对肥胖动物模型（肥胖 Zucker 大鼠）白色脂肪组织的影响。给予曲格列酮 15 天使这些大鼠的轻度高血糖和显着的高胰岛素血症正常化。曲格列酮可降低肥胖和瘦大鼠的血浆甘油三酯水平。曲格列酮不会改变白色脂肪组织的总重量，但使肥胖大鼠腹膜后和皮下脂肪组织中小脂肪细胞（<2,500μmiiD12iiD1）的数量增加约四倍。它还使大脂肪细胞（> 5,000μmィイD12ィエD1）的数量减少〜50%。事实上，在曲格列酮治疗的腹膜后白色脂肪组织中，凋亡细胞核的百分比比对照高约 2.5 倍。与此同时，曲格列酮使肥胖大鼠腹膜后和肠系膜白色脂肪组织中 TNF-α 的表达水平正常化，分别升高 2 倍和 1.4 倍。曲格列酮还导致瘦素表达水平急剧下降，在肥胖大鼠的白色脂肪组织中瘦素表达水平增加了4-10倍。这些结果表明，曲格列酮的主要作用可能是通过 PPARγ 增加白色脂肪组织中小脂肪细胞的数量。曲格列酮治疗的肥胖大鼠的白色脂肪组织中小脂肪细胞数量的增加和大脂肪细胞数量的减少似乎是一个重要机制，通过该机制，TNF-α表达水平的增加和血浆脂质水平的升高得以正常化，从而导致胰岛素抵抗的减轻（Okuno等人，J. Clin. Invest. 101, 1354-1361， 1998）。此外，我们还制作了 PPARγ 缺陷小鼠。与野生型小鼠相比，高饮食下的PPARγ(+/-)小鼠已被证明可以免受肥胖和胰岛素抵抗的影响，其瘦素血清水平更高(Kubota等人，Mol.Cell.4, 597-609, 1999)。表明 PPARγ 活性会促进高脂肪饮食下肥胖和胰岛素抵抗的增加。此外，通过对糖尿病患者的搜索，糖尿病组中具有PPARγ Prol2Ala等位基因（PPARγ2活性较低的形式）的5个ubJects数量少于对照非糖尿病组（Hara等，diabetologia in press）。较少的