“噻唑烷二酮”类降糖药物如“罗西格列酮”和“匹格列酮”已知通过核受体PPARγ发挥作用，但它们胰岛素敏化效应之机制的某些方面仍然是个谜。现在，Choi等人报告，PPARγ 被Cdk5的磷酸化与小鼠由高脂肪饮食所诱导的肥胖有关。几种可以降血糖的PPARγ配体直接抑制Cdk5 对 PPARγ的这种作用，从而支持一种更为正常的非糖尿病型基因表达模式。另外，“罗西格列酮”对人体中这种PPARγ磷酸化的抑制也与其降糖效应密切相关。
这一不同寻常的药理机制为肥胖症/糖尿病发病机理中的Cdk5-PPARγ联系、为这些疾病中以及代谢综合症（即多种疾病的综合，它们会增加心血管疾病和糖尿病的发病风险）中PPARγ配体的治疗作用提出了一个新模型。
推荐原文出处：
Nature doi:10.1038/nature09291
Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARγ by Cdk5
Jang Hyun Choi,Alexander S. Banks,Jennifer L. Estall,Shingo Kajimura,Pontus Bostr?m,Dina Laznik,Jorge L. Ruas,Michael J. Chalmers,Theodore M. Kamenecka,Matthias Blüher,Patrick R. Griffin" Bruce M. Spiegelman
Obesity induced in mice by high-fat feeding activates the protein kinase Cdk5 (cyclin-dependent kinase 5) in adipose tissues. This results in phosphorylation of the nuclear receptor PPARγ (peroxisome proliferator-activated receptor γ), 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 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. All these findings 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.
