Obesity-linked PPARγ phosphorylation may trigger insulin resistance
MedWire News: Study findings published in the journal Nature suggest that Cdk5-mediated phosphorylation of the nuclear receptor peroxisome proliferator-activated receptor (PPAR)γ, an obesity-linked process, reduces adiponectin levels and provokes insulin resistance.
Researchers found that use of both full and partial agonists reversed the phosphorylation effects and improved production of adiponectin. They say these data provide an opportunity to develop an improved generation of PPARγ-associated anti-diabetes drugs similar to thiazolidinediones.
Bruce Spiegelman (Harvard Medical School, Boston, Massachusetts, USA) and colleagues discovered that cyclin-dependent kinase 5 (Cdk-5) is activated in mice fed a high-fat diet.
Once active, Cdk-5 was observed to prompt phosphorylation of PPARγ at Ser273, leading to dysregulation of a subset of genes including those encoding adipsin, involved in regulating fat storage, and adiponectin, a regulator of insulin sensitivity.
Exposure to anti-diabetes PPARγ ligands or agonists (e.g. MRL24) inhibited the Cdk-5 mediated phosphorylation and reversed the associated changes in gene expression. The partial agonist MRL24 was found to do this as well or better than rosiglitazone, a full PPARγ agonist.
"Given that both have potent anti-diabetic activities, it is likely that a substantial portion of the therapeutic benefits of PPARγ ligands in metabolic disease is through inhibition of Cdk5-mediated phosphorylation," write the researchers.
"The field has become interested in finding drugs that can promote increased insulin sensitization but not activate the classical fat cell generating pathway of PPARγ," said study author Patrick Griffin (The Scripps Research Institute, Florida, USA).
"We examined the mechanism of action of compounds that bind to PPARγ that improve insulin sensitivity but have minimal induction of fat. It was clear from the studies that these compounds have a unique but overlapping mechanism with the class of drugs used clinically that target PPARγ," he added.
Spiegelman and co-investigators conclude: "All these findings strongly suggest that Cdk5-mediated phosphorylation of PPARγ may be involved in the pathogenesis of insulin-resistance, and present an opportunity for development of an improved generation of anti-diabetic drugs through PPARγ."
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By Helen Albert