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

Abstract

Obesity induced in mice by high-fat feeding activates the protein kinase Cdk5 (cyclin-dependent kinase 5) in adipose tissues. This results in phosphorylation of the nuclear receptor PPARgamma (peroxisome proliferator-activated receptor gamma), a dominant regulator of adipogenesis and fat cell gene expression, at serine 273. This modification of PPARgamma does not alter its adipogenic capacity, but leads to dysregulation of a large number of genes whose expression is altered in obesity, including a reduction in the expression of the insulin-sensitizing adipokine, adiponectin. The phosphorylation of PPARgamma by Cdk5 is blocked by anti-diabetic PPARgamma ligands, such as rosiglitazone and MRL24. This inhibition works both in vivo and in vitro, and is completely independent of classical receptor transcriptional agonism. Similarly, inhibition of PPARgamma phosphorylation in obese patients by rosiglitazone is very tightly associated with the anti-diabetic effects of this drug. All these findings strongly suggest that Cdk5-mediated phosphorylation of PPARgamma may be involved in the pathogenesis of insulin-resistance, and present an opportunity for development of an improved generation of anti-diabetic drugs through PPARgamma.

• Authors: Jang Hyun Choi, Alexander S Banks, Jennifer L Estall, Shingo Kajimura, Pontus Boström, Dina Laznik, Jorge L Ruas, Michael J Chalmers, Theodore M Kamenecka, Matthias Blüher, Patrick R Griffin, Bruce M Spiegelman
• Journal: Nature (Nature) Vol. 466 Issue 7305 Pg. 451-6 (Jul 22 2010) ISSN: 1476-4687 [Electronic] England
• PMID: 20651683 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Dietary Fats
• Insulin
• Ligands
• PPAR gamma
• Thiazolidinediones
• Rosiglitazone
• Phosphoserine
• Cyclin-Dependent Kinase 5

Topics

• Adipose Tissue (drug effects, metabolism, physiopathology)
• Amino Acid Sequence
• Animals
• Cell Line
• Cyclin-Dependent Kinase 5 (antagonists & inhibitors, genetics, metabolism)
• Diabetes Mellitus, Experimental (complications, drug therapy, metabolism)
• Dietary Fats (pharmacology)
• Humans
• Insulin (metabolism)
• Ligands
• Mice
• Models, Molecular
• Obesity (chemically induced, complications, metabolism, physiopathology)
• PPAR gamma (agonists, metabolism)
• Phosphorylation (drug effects)
• Phosphoserine (metabolism)
• Protein Conformation
• Rosiglitazone
• Thiazolidinediones (pharmacology, therapeutic use)