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- Title
An ERK/Cdk5 axis controls the diabetogenic actions of PPARγ.
- Authors
Banks, Alexander S.; McAllister, Fiona E.; Camporez, João Paulo G.; Zushin, Peter-James H.; Jurczak, Michael J.; Laznik-Bogoslavski, Dina; Shulman, Gerald I.; Gygi, Steven P.; Spiegelman, Bruce M.
- Abstract
Obesity-linked insulin resistance is a major precursor to the development of type 2 diabetes. Previous work has shown that phosphorylation of PPARγ (peroxisome proliferator-activated receptor γ) 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 PPARγ, such as the thiazolidinediones and PPARγ partial agonists or non-agonists. For a better understanding of the importance of this obesity-linked PPARγ phosphorylation, we created mice that ablated Cdk5 specifically in adipose tissues. These mice have both a paradoxical increase in PPARγ 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 PPARγ 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 PPARγ function and suggest that MEK/ERK inhibitors may hold promise for the treatment of type 2 diabetes.
- Subjects
OBESITY; INSULIN resistance; TYPE 2 diabetes; PEROXISOME proliferator-activated receptors; CYCLIN-dependent kinases; GENE expression
- Publication
Nature, 2015, Vol 517, Issue 7534, p391
- ISSN
0028-0836
- Publication type
Article
- DOI
10.1038/nature13887