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 tissues1. 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-agonists2. 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.

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We thank E. Rosen for providing us with the adiponectin Cre mice before their initial publication; members of the Spiegelman laboratory (Dana-Farber Cancer Institute) and D. Cohen (Brigham and Women's Hospital) for discussions; and C. Palmer and K. LeClair for reading the manuscript. B.M.S. acknowledges National Institutes of Health (NIH) grant DK31405. A.B. acknowledges NIH grant DK93638, the Harvard University Milton Fund, and the Harvard Digestive Disease Center, Core D.

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  1. Division of Endocrinology, Diabetes and Hypertension, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA

    • Alexander S. Banks
    •  & Peter-James H. Zushin
  2. Department of Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Fiona E. McAllister
    • , Steven P. Gygi
    •  & Bruce M. Spiegelman
  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

    • João Paulo G. Camporez
    • , Michael J. Jurczak
    •  & Gerald I. Shulman
  4. Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA

    • Dina Laznik-Bogoslavski
    •  & Bruce M. Spiegelman


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A.B., B.M.S., F.E., S.G., J.P.C., M.J. and G.S. designed the experiments. A.B., D.B., F.E., J.C.P. and P.Z. performed the experiments. A.B., B.M.S. and F.E. wrote the manuscript.

Competing interests

B.M.S. is a consultant to and shareholder in Ember Therapeutics. The remaining authors declare no competing interests.

Corresponding authors

Correspondence to Alexander S. Banks or Bruce M. Spiegelman.

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