An ERK/Cdk5 axis controls the diabetogenic actions of PPARγ

Obesity-linked insulin resistance is a major precursor to the development of type 2 diabetes. Previous work has shown that phosphorylation of PPAR gamma (peroxisome proliferator-activated receptor gamma) at serine 273 by cydin-dependent kinase 5 (Cdk5) stimulates diabetogenic gene expression in adipose tissues(1). Inhibition of this modification is a key therapeutic mechanism for anti-diabetic drugs that bind PPAR gamma, such as the thiazolidinediones and PPAR gamma partial agonists or non-agonists(2). For a better understanding of the importance of this obesity-linked PPAR gamma phosphorylation, we created mice that ablated Cdk5 specifically in adipose tissues. These mice have both a paradoxical increase in PPAR gamma 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 PPAR gamma 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 wildtype and ob/ob mice, and also completely reverses the deleterious effects of the Cdk5 ablation. These data show that an ERK/Cdk5 axis controls PPAR gamma function and suggest that MEK/ERK inhibitors may hold promise for the treatment of type 2 diabetes.