Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5.
Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5.
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作者：
高脂喂养引起的小鼠肥胖可激活脂肪组织中的蛋白激酶cdk5。这导致核受体PPARγ（脂肪形成和脂肪细胞基因表达的主要调节因子）在丝氨酸273处的磷酸化。PPARγ的这种修饰不会改变其成脂能力，但会导致大量基因的失调，这些基因的表达在肥胖中发生改变，包括胰岛素敏感脂肪因子脂联素的表达减少。抗糖尿病的PPARγ配体如罗格列酮和MRL24可阻断cdk5对PPARγ的磷酸化。这种抑制在体内和体外都有效，令人惊讶的是，它完全独立于经典的受体转录激动作用。同样，罗格列酮对肥胖患者PPARγ磷酸化的抑制作用与该药的抗糖尿病作用密切相关。这些数据有力地表明，cdk5介导的PPARγ磷酸化可能参与胰岛素抵抗的发病机制，并为通过PPARγ开发改进一代的抗糖尿病药物提供了机会。
Obesity induced in mice by high-fat feeding activates the protein kinase cdk5 in adipose tissues. This results in phosphorylation of the nuclear receptor PPARγ, a dominant regulator of adipogenesis and fat cell gene expression, at serine 273. This modification of PPARγ does not alter its adipogenic capacity, but leads to dysregulation of a large number of genes whose expression is altered in obesity, including a reduction in the expression of the insulin-sensitizing adipokine, adiponectin. The phosphorylation of PPARγ by cdk5 is blocked by anti-diabetic PPARγ ligands, such as rosiglitazone and MRL24. This inhibition works both in vivo and in vitro, and surprisingly, is completely independent of classical receptor transcriptional agonism. Similarly, inhibition of PPARγ phosphorylation in obese patients by rosiglitazone is very tightly associated with the anti-diabetic effects of this drug. These data strongly suggest that cdk5-mediated phosphorylation of PPARγ may be involved in the pathogenesis of insulin-resistance, and present an opportunity for development of an improved generation of anti-diabetic drugs through PPARγ.
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DOI：
10.1073/pnas.011404098
发表时间：
2001-01-02
影响因子：
11.1
作者：
Li, C;Wong, WH
通讯作者：
Wong, WH
影响因子：
--
作者：
Gregoire, Francine M.;Zhang, Fang;Lavan, Brian E.
通讯作者：
Lavan, Brian E.
影响因子：
29
作者：
Kloeting, Nora;Graham, Timothy E.;Kahn, Barbara B.
通讯作者：
Kahn, Barbara B.
影响因子：
4.8
作者：
Östberg, T;Svensson, S;Jendeberg, L
通讯作者：
Jendeberg, L
影响因子：
56.9
作者：
FLIER, JS;COOK, KS;SPIEGELMAN, BM
通讯作者：
SPIEGELMAN, BM