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Nature. 2015 Jan 15;517(7534):391-5. doi: 10.1038/nature13887. Epub 2014 Nov 17.

An ERK/Cdk5 axis controls the diabetogenic actions of PPARγ.

Author information

1
Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
2
Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA.
3
Yale Mouse Metabolic Phenotyping Center and Departments of Internal Medicine and Cellular and Molecular Physiology, Yale University School of Medicine, New Haven, Connecticut 06510, USA.
4
Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.
5
1] Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA [2] Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.

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.

PMID:
25409143
PMCID:
PMC4297557
DOI:
10.1038/nature13887
[Indexed for MEDLINE]
Free PMC Article

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