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.
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We thank V. Mootha for help with the analysis of microarray data and for critical comments. We thank M. Kirschner for a critical reading of the manuscript and for comments. We are grateful to R. Gupta and P. Cohen for critical comments on the manuscript. J.H.C., A.S.B., J.L.E., P.B., D.L., J.L.R. and B.M.S are supported by NIH DK31405. S.K. is supported by NIH grant DK087853. M.B. is supported by a grant from Deutsche Forschungsgemeinschaft (DFG) and the Clinical Research group ‘Atherobesity’ KFO 152 (project BL 833/1-1). P.R.G., M.J.C. and T.M.K. are supported in part by the by the Intramural Research Program of the N National Institute of Mental Health (P.R.G., M.J.C., T.M.K., U54-MH084512; H. Rosen Principal Investigator) and by the NIH National Institute of General Medical Sciences (P.R.G. and M.J.C., R01-GM084041).
The authors declare no competing financial interests.
Microarray data have been deposited in Gene Expression Omnibus: GSE22033.
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Choi, J., Banks, A., Estall, J. et al. Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARγ by Cdk5. Nature 466, 451–456 (2010). https://doi.org/10.1038/nature09291
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