Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation

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PPARγ is the functioning receptor for the thiazolidinedione (TZD) class of antidiabetes drugs including rosiglitazone and pioglitazone1. These drugs are full classical agonists for this nuclear receptor, but recent data have shown that many PPARγ-based drugs have a separate biochemical activity, blocking the obesity-linked phosphorylation of PPARγ by Cdk5 (ref. 2). Here we describe novel synthetic compounds that have a unique mode of binding to PPARγ, completely lack classical transcriptional agonism and block the Cdk5-mediated phosphorylation in cultured adipocytes and in insulin-resistant mice. Moreover, one such compound, SR1664, has potent antidiabetic activity while not causing the fluid retention and weight gain that are serious side effects of many of the PPARγ drugs. Unlike TZDs, SR1664 also does not interfere with bone formation in culture. These data illustrate that new classes of antidiabetes drugs can be developed by specifically targeting the Cdk5-mediated phosphorylation of PPARγ.

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Figure 1: Novel PPARγ ligands lack classical agonism, block phosphorylation at Ser 273.
Figure 2: Structural and in vitro functional analysis of SR1664.
Figure 3: Antidiabetic activity of SR1664 in high-fat diet (HFD) mice.
Figure 4: SR1664 has potent antidiabetic activity and does not promote fluid retention in ob/ob mice.


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We are grateful for support from S. Novick for assistance in the HDX studies and from R. D. Garcia-Ordonez in protein production and mutagenesis. We are grateful for support from B. Pascal and S. Willis for software analysing the HDX data. We are grateful to R. Gupta and P. Cohen for their critical comments on the manuscript. This work was supported in part by the Intramural Research Program of the National Institutes of Health (NIH), National Institute of Mental Health (grant U54-MH074404, H. Rosen principal investigator), the National Institute of General Medical Sciences (grant R01-GM084041, P.R.G.) and the National Institute of Diabetes and Digestive and Kidney Diseases (grant 1RC4DK090861, B.M.S.). This work also supported by NIH DK31405 to B.M.S.

Author information

B.M.S. and P.R.G. conceived the project and designed research; J.H.C., A.S.B., T.M.K., S.A.B., M.J.C., N.K., D.S.K., Y.S., Y.H., J.B.B., D.P.M., M.D.C., D.L., M.J.J., S.C.S., and D.V. performed research; J.H.C., A.S.B., T.M.K., S.A.B., M.J.C., N.K., D.K., J.B.B., D.M., M.D.C., D.L., M.J.J., S.C.S., D.V., G.I.S., B.M.S and P.R.G. analysed data; and B.M.S., A.S.B. and P.R.G. wrote the paper with contributions from all authors.

Correspondence to Bruce M. Spiegelman or Patrick R. Griffin.

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