| First Author | Banks AS | Year | 2015 |
| Journal | Nature | Volume | 517 |
| Issue | 7534 | Pages | 391-5 |
| PubMed ID | 25409143 | Mgi Jnum | J:217537 |
| Mgi Id | MGI:5614513 | Doi | 10.1038/nature13887 |
| Citation | Banks AS, et al. (2015) An ERK/Cdk5 axis controls the diabetogenic actions of PPARgamma. Nature 517(7534):391-5 |
| abstractText | Obesity-linked insulin resistance is a major precursor to the development of type 2 diabetes. Previous work has shown that phosphorylation of PPARgamma (peroxisome proliferator-activated receptor gamma) at serine 273 by cyclin-dependent kinase 5 (Cdk5) stimulates diabetogenic gene expression in adipose tissues. Inhibition of this modification is a key therapeutic mechanism for anti-diabetic drugs that bind PPARgamma, such as the thiazolidinediones and PPARgamma partial agonists or non-agonists. For a better understanding of the importance of this obesity-linked PPARgamma phosphorylation, we created mice that ablated Cdk5 specifically in adipose tissues. These mice have both a paradoxical increase in PPARgamma phosphorylation at serine 273 and worsened insulin resistance. Unbiased proteomic studies show that extracellular signal-regulated kinase (ERK) kinases are activated in these knockout animals. Here we show that ERK directly phosphorylates serine 273 of PPARgamma in a robust manner and that Cdk5 suppresses ERKs through direct action on a novel site in MAP kinase/ERK kinase (MEK). Importantly, pharmacological inhibition of MEK and ERK markedly improves insulin resistance in both obese wild-type and ob/ob mice, and also completely reverses the deleterious effects of the Cdk5 ablation. These data show that an ERK/Cdk5 axis controls PPARgamma function and suggest that MEK/ERK inhibitors may hold promise for the treatment of type 2 diabetes. |
