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Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARγ 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 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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Figure 1: Specific fat cell gene dysregulation by the Cdk5-mediated S273 phosphorylation of PPARγ.
Figure 2: Cdk5-mediated phosphorylation of PPARγ is increased in fat tissues of mice fed a high-fat diet.
Figure 3: Anti-diabetic PPARγ ligands block CDK5-mediated phosphorylation of PPARγ.
Figure 4: Differential HDX mass spectrometry data for PPARγ-ligand-binding domain (LBD) with and without rosiglitazone and MRL24.
Figure 5: Correlation between the inhibition of phosphorylation and improvement of insulin sensitivity by anti-diabetic PPARγ ligands.

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Gene Expression Omnibus

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Acknowledgements

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).

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J.H.C. and B.M.S. conceived and designed the experiments. J.H.C., A.S.B., J.L.E., S.K., P.B., D.L., J.L.R., M.J.C., T.M.K, M.B. and P.R.G performed the experiments. All authors analysed the data. J.H.C., A.S.B., J.L.E. and B.M.S. wrote the manuscript.

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Correspondence to Bruce M. Spiegelman.

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Microarray data have been deposited in Gene Expression Omnibus: GSE22033.

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This file contains Supplementary Figures 1-16 with legends and Supplementary Tables 1-4. (PDF 1157 kb)

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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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