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Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARgamma by Cdk5

Jang Hyun Choi1, Alexander S Banks, Jennifer L Estall

  • 1Department of Cancer Biology and Division of Metabolism and Chronic Disease, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA.

Nature
|July 24, 2010
PubMed

Insights

High-fat diets activate Cdk5, phosphorylating PPARgamma in fat tissue. This disrupts gene expression and reduces adiponectin, contributing to insulin resistance. Blocking this phosphorylation may offer new anti-diabetic treatments.

Area of Science:

  • Metabolic disease research
  • Molecular endocrinology
  • Adipose tissue biology

Background:

  • Obesity is linked to insulin resistance and altered fat cell gene expression.
  • Peroxisome proliferator-activated receptor gamma (PPARgamma) is a key regulator of fat cell function.
  • The role of specific protein modifications in obesity-related metabolic dysfunction is an active area of research.

Purpose of the Study:

  • To investigate the role of cyclin-dependent kinase 5 (Cdk5) in obesity-induced metabolic changes.
  • To determine the effect of Cdk5 on PPARgamma activity and gene expression in adipose tissue.
  • To explore the therapeutic potential of targeting Cdk5-mediated PPARgamma phosphorylation for insulin resistance.

Main Methods:

  • Induction of obesity in mice using high-fat feeding.
  • Analysis of protein kinase Cdk5 activation and PPARgamma phosphorylation in adipose tissue.
  • Gene expression profiling to identify dysregulated genes, including adiponectin.
  • In vitro and in vivo experiments using anti-diabetic PPARgamma ligands (rosiglitazone, MRL24).

Main Results:

  • High-fat feeding activated Cdk5 in adipose tissue, leading to PPARgamma phosphorylation at serine 273.
  • PPARgamma phosphorylation did not affect adipogenic capacity but dysregulated genes associated with obesity, including reduced adiponectin.
  • Anti-diabetic PPARgamma ligands blocked Cdk5-mediated PPARgamma phosphorylation independently of transcriptional agonism.
  • Rosiglitazone's inhibition of PPARgamma phosphorylation correlated with its anti-diabetic effects in obese patients.

Conclusions:

  • Cdk5-mediated phosphorylation of PPARgamma is implicated in the pathogenesis of insulin resistance.
  • Targeting Cdk5-mediated PPARgamma modification offers a novel therapeutic strategy for insulin resistance.
  • Development of next-generation anti-diabetic drugs could focus on modulating PPARgamma phosphorylation.

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