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

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 and Bruce M. Spiegelman ()
Additional contact information
Jang Hyun Choi: Harvard Medical School
Alexander S. Banks: Harvard Medical School
Jennifer L. Estall: Harvard Medical School
Shingo Kajimura: Harvard Medical School
Pontus Boström: Harvard Medical School
Dina Laznik: Harvard Medical School
Jorge L. Ruas: Harvard Medical School
Michael J. Chalmers: The Scripps Research Institute, Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, USA
Theodore M. Kamenecka: The Scripps Research Institute, Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, USA
Matthias Blüher: University of Leipzig, Liebigstr. 20, Leipzig, Germany
Patrick R. Griffin: The Scripps Research Institute, Scripps Florida, 130 Scripps Way, Jupiter, Florida 33458, USA
Bruce M. Spiegelman: Harvard Medical School

Nature, 2010, vol. 466, issue 7305, 451-456

Abstract: 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 PPARγ (peroxisome proliferator-activated receptor γ), a dominant regulator of adipogenesis and fat cell gene expression, at serine 273. This modification of PPARγ 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 PPARγ by Cdk5 is blocked by anti-diabetic PPARγ 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 PPARγ 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 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.

Date: 2010
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DOI: 10.1038/nature09291

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