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An ERK/Cdk5 axis controls the diabetogenic actions of PPARγ

Alexander S Banks1, Fiona E McAllister2, João Paulo G Camporez3

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

Nature
|November 20, 2014
PubMed

Insights

Cyclin-dependent kinase 5 (Cdk5) normally suppresses extracellular signal-regulated kinases (ERK) to prevent insulin resistance. Inhibiting MEK/ERK improves insulin sensitivity, offering a potential treatment for type 2 diabetes.

Area of Science:

  • Metabolic disease research
  • Molecular endocrinology
  • Diabetes pathogenesis

Background:

  • Obesity-induced insulin resistance is a precursor to type 2 diabetes.
  • Phosphorylation of peroxisome proliferator-activated receptor γ (PPARγ) at serine 273 by Cdk5 stimulates diabetogenic gene expression.
  • Current anti-diabetic drugs targeting PPARγ inhibit this phosphorylation.

Purpose of the Study:

  • To investigate the role of Cdk5 in adipose tissue on PPARγ phosphorylation and insulin resistance.
  • To identify the kinases responsible for PPARγ serine 273 phosphorylation in the absence of Cdk5.
  • To explore the therapeutic potential of targeting the identified kinase pathway for type 2 diabetes treatment.

Main Methods:

  • Generation of mice with adipose-specific Cdk5 ablation.
  • Proteomic analysis to identify activated kinases in knockout mice.
  • In vivo and in vitro experiments to confirm direct phosphorylation of PPARγ by ERK.
  • Pharmacological inhibition of MEK and ERK in obese mouse models.

Main Results:

  • Adipose-specific Cdk5 ablation paradoxically increased PPARγ serine 273 phosphorylation and worsened insulin resistance.
  • Extracellular signal-regulated kinases (ERK) were identified as activated kinases in Cdk5-ablated mice.
  • ERK directly phosphorylates PPARγ at serine 273, while Cdk5 suppresses ERK activity via MEK.
  • Pharmacological inhibition of MEK/ERK significantly improved insulin resistance in obese mice and rescued Cdk5 ablation effects.

Conclusions:

  • An ERK/Cdk5 signaling axis critically regulates PPARγ function in adipose tissue.
  • ERK-mediated phosphorylation of PPARγ contributes to insulin resistance.
  • Inhibitors of MEK/ERK signaling represent a promising therapeutic strategy for type 2 diabetes.

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