Development of novel diagnostic and therapeutic strategies for obesity and insulin resistance by identification of endogenous PPARγ ligands

通过鉴定内源性 PPARγ 配体开发肥胖和胰岛素抵抗的新型诊断和治疗策略

基本信息

批准号：
12557093
负责人：
KADOWAKI Takashi
金额：
$ 8.51万
依托单位：
The 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：
2000
资助国家：
日本
起止时间：
2000 至 2001
项目状态：
已结题

项目摘要

Our knockout mice studies revealed that PPARgamma was absolutely required for adipocyte differentiation (Mol. Cell. 4:597, 1999), and that IRS-1 and IRS-2 played a crucial role in the upregulation of the PPARgamma expression and adipocyte differentiation (Mol. Cell. Biol. 21:2521, 2001). Thiazolidinediones (TZD) ameliorated insulin resistance by increasing the number of small size adipocytes and decreasing hypertrophic adipocytes (J.Clin.Invest. 101:1354, 1998), which was associated with decreased molecules causing insulin resistance (J.Biol.Chem. 276: 41245, 2001) and also increased insulin senisitizing hormone adiponectin (J.Biol.Chem. 277: 25863, 2002). Insulin sensitizing effect of adiponectin appears to be mediated by an increase in fatty acid oxidation via activation of AMP kinase (Nature Medicine 8:1288, 2002) and PPARα (J.Biol.Chem. 278: 2461, 2003), thereby decreasing TG content (Nature Medicine 7:941, 2001). Unexpectedly, heterozygous CBP knockout mice showed increased insuli … More n sensitivity despite lipodystrophy. Heterozygous CBP knockout mice also showed increased effects of insulin sensitizing hormones such as leptin and adiponectin, and these may explain the phenotypes of heterozygous CBP knockout mice at least in part (Nature Genetics 30:221, 2002).We identified a SNP (Pro12Ala) of human PPARgamma gene. Subjects with Ala allele decreasing PPARgamma activity were associated with resistance to type 2 diabetes (BBRC. 271:212, 2000). PPARgamma antagonist protected against obesity, insulin resistance and type 2 diabetes of KKA^y mice (J.Clin.Invest. 108:1001, 2001). A genetic variation in the PPARgamma coactivator PGC (PPARgamma coactivator)-1 gene could confer insulin resistance and susceptibility to Type 2 diabetes (Diabetologja. 45:740, 2002). The adiponectin SNP associated with lower plasma adiponectin levels had a higher insulin resistance index and also a significantly increased risk of type 2 diabetes (Diabetes. 51:536,2002).Finally, we tried to identify the endogenous PPARgamma ligands, because PPARgamma ligands potentially can be involved in insulin sensitivity. Current fractionation studies using HPLC suggest a single peak of activity, indicating one or very few components. The chromatographic behavior of this activity indicates that it is not equivalent to 15-deoxy-12,14-PGJ2. Structural determination will shed light on the biochemical nature of this molecule and open the door to the study of its biosynthetic regulation. Less

我们的基因敲除小鼠研究表明，脂肪细胞分化绝对需要ppargamma（Mol。4：597，1999），IRS-1和IRS-2和IRS-2在PPARGAMMA表达和脂肪细胞分化的上调中起着至关重要的作用（Mol。Biol。Biol。Biol。Biol。Biol。21：2521：21：2521，2001，2001）。噻唑胺（TZD）通过增加小尺寸脂肪细胞的数量和减少肥厚性脂肪细胞（J.Clin.Invest。101：1354，1998）来改善胰岛素的耐药性，这与导致胰岛素耐药性降低相关（J.bin.bhem.bhem.276：276：4124.41245，这与降低的分子相关脂联素（J.Biol.Chem。277：25863，2002）。脂联素的胰岛素致敏作用似乎是通过激活AMP激酶（自然医学8：1288，2002）和PPARα（J.Biol.Chem.278：2461，2003）的激活来介导的，从而介导TG含量（自然药物7：941，2001）。出乎意料的是，杂合的CBP敲除小鼠表现出胰岛素的增加……尽管脂肪营养不良，但n敏感性更高。杂合CBP敲除小鼠还显示出胰岛素敏化激素（如瘦素和脂联素）的影响，这些激素可能至少在部分中解释了杂合CBP敲除小鼠的表型（自然遗传学30：221，2002）。患有ALA等位基因的受试者降低了ppargamma活性，与对2型糖尿病的耐药性有关（BBRC。271：212，2000）。 ppargamma拮抗剂免受肥胖症，胰岛素抵抗和2型糖尿病的保护（j.clin.invest。108：1001，2001）。 PPARGAMMA共激活因子PGC（PPARGAMMA共激活因子）-1基因的基因变异可以赋予2型糖尿病的胰岛素抵抗和易感性（Diabetologyja。45：740，2002）。与较低血浆脂联素水平相关的脂联素SNP具有较高的胰岛素抵抗指数，并且2型糖尿病的风险显着增加（糖尿病。51：536,2002）。最后，我们试图鉴定内源性ppargamma配体，因为Ppargamma配体可能参与胰岛素敏感性。当前使用HPLC的分馏研究表明活性的单个峰，表明一个或很少的成分。该活动的色谱行为表明它不等于15-脱氧-12,14-PGJ2。结构确定将阐明该分子的生化性质，并为其生物合成调节的研究打开大门。较少的