Department of Cancer Biology and Division of Metabolism and Chronic Disease, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
Nature. 2010 Jul 22;466(7305):451-6. doi: 10.1038/nature09291.
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 PPARgamma (peroxisome proliferator-activated receptor gamma), a dominant regulator of adipogenesis and fat cell gene expression, at serine 273. This modification of PPARgamma 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 PPARgamma by Cdk5 is blocked by anti-diabetic PPARgamma 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 PPARgamma 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 PPARgamma may be involved in the pathogenesis of insulin-resistance, and present an opportunity for development of an improved generation of anti-diabetic drugs through PPARgamma.
高脂喂养诱导的肥胖会激活脂肪组织中的蛋白激酶 Cdk5（周期蛋白依赖性激酶 5）。这导致核受体 PPARγ（过氧化物酶体增殖物激活受体 γ）的丝氨酸 273 磷酸化，PPARγ 是脂肪生成和脂肪细胞基因表达的主要调节剂。这种 PPARγ 的修饰不会改变其脂肪生成能力，但会导致大量基因的表达失调，这些基因在肥胖中表达发生改变，包括胰岛素敏感的脂肪因子脂联素的表达减少。Cdk5 对 PPARγ 的磷酸化可被抗糖尿病的 PPARγ 配体（如罗格列酮和 MRL24）阻断。这种抑制作用在体内和体外都起作用，并且完全独立于经典受体转录激动作用。同样，罗格列酮抑制肥胖患者的 PPARγ 磷酸化与该药物的抗糖尿病作用密切相关。所有这些发现都强烈表明，Cdk5 介导的 PPARγ 磷酸化可能与胰岛素抵抗的发病机制有关，并为通过 PPARγ 开发新一代抗糖尿病药物提供了机会。
