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

我们对敲除小鼠的研究表明，脂肪细胞分化绝对需要PPARgamma (Mol. Cell. 4:597, 1999)， IRS-1和IRS-2在PPARgamma表达上调和脂肪细胞分化中起关键作用（Mol. Cell. 4:597, 1999）。《圣经》21:25 - 21,2001)。噻唑烷二酮（TZD）通过增加小脂肪细胞数量和减少肥厚脂肪细胞来改善胰岛素抵抗（j . clini . invest .）。[j] .中国生物医学工程杂志。脂联素对胰岛素敏感性的影响[j] .中国生物医学工程杂志。(2)。脂联素的胰岛素增敏作用似乎是通过激活AMP激酶介导的脂肪酸氧化增加（Nature Medicine 8:12 88,2002）和PPARα (J.Biol.Chem.)。278: 2461,2003)，从而降低TG含量（Nature Medicine 7:941, 2001）。出乎意料的是，杂合子CBP敲除小鼠显示出更高的胰岛素敏感性，尽管脂肪营养不良。杂合子CBP敲除小鼠也显示出胰岛素增敏激素（如瘦素和脂联素）的作用增加，这可能至少部分地解释了杂合子CBP敲除小鼠的表型（Nature Genetics 30:21 1, 2002）。我们鉴定出了人PPARgamma基因的一个SNP （Pro12Ala）。携带Ala等位基因降低PPARgamma活性的受试者与2型糖尿病（BBRC）抵抗相关。271:212, 2000)。PPARgamma拮抗剂对KKA^y小鼠肥胖、胰岛素抵抗和2型糖尿病的预防作用[j]。108:1001, 2001)。PPARgamma协同激活因子PGC (PPARgamma coactivator)-1基因的遗传变异可能导致胰岛素抵抗和2型糖尿病的易感性（diabologia . 45:7 40,2002）。与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，并且显著增加2型糖尿病的风险（diabetes . 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。目前使用高效液相色谱法进行的分离研究表明，活性只有一个峰，表明只有一个或很少的成分。该活性的色谱行为表明它不等同于15-脱氧-12,14- pgj2。结构测定将揭示该分子的生化性质，并为研究其生物合成调控打开大门。少

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