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

我们的基因敲除小鼠研究表明，PPARγ对于脂肪细胞的分化是绝对必要的(摩尔。牢房。4：597,1999)，IRS-1和IRS-2在PPAR-γ表达上调和脂肪细胞分化(Mol.牢房。比奥尔。21：2521,2001)。噻唑烷二酮(TZD)通过增加小型脂肪细胞数量和减少肥大脂肪细胞来改善胰岛素抵抗(J.Clin.Invest。101：1354,1998)，这与导致胰岛素抵抗的分子减少有关(J.Biol.Chem.也增加了胰岛素衰老激素脂联素(J.Biol.Chem.2002年：25863)。脂联素的胰岛素增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)，从而降低TG含量(自然医学7：941,2001)。出乎意料的是，杂合子CBP基因敲除小鼠表现出胰岛素…的增加尽管有脂营养不良，但对n更敏感。CBP杂合基因敲除小鼠也表现出胰岛素增敏激素如瘦素和脂联素的作用增加，这至少可以部分解释CBP杂合基因敲除小鼠的表型(自然遗传学30：221,2002)。我们发现了人类PPAR伽马基因的一个SNP(Pro12Ala)。具有降低PPAR-γ活性的ALA等位基因的受试者与2型糖尿病的抵抗(BBRC。271：212,2000)。PPARGamma拮抗剂可预防肥胖、胰岛素抵抗和Kka^y小鼠的2型糖尿病(J.Clin.Invest。108：1001,2001)。PPARGamma辅活化子PGC(PPARGamma辅活化子)-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(Diabetologja。45：740,2002)。脂联素SNP与较低的血浆脂联素水平相关，具有较高的胰岛素抵抗指数，并显著增加患2型糖尿病(糖尿病)的风险。51：536,2002)。最后，我们试图鉴定内源性PPAR伽马配体，因为PPAR伽马配体可能参与胰岛素敏感性。目前使用高效液相色谱分离的研究表明，活性只有一个峰，表明只有一个或很少的成分。该活性的层析行为表明它不等同于15-脱氧-12，14-PGJ2。结构测定将阐明该分子的生化性质，并为研究其生物合成调节打开大门。较少

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