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- Title
Antidiabetic actions of a non-agonist PPAR? ligand blocking Cdk5-mediated phosphorylation.
- Authors
Jang Hyun Choi; Banks, Alexander S.; Kamenecka, Theodore M.; Busby, Scott A.; Chalmers, Michael J.; Kumar, Naresh; Kuruvilla, Dana S.; Youseung Shin; Yuanjun He; Bruning, John B.; Marciano, David P.; Cameron, Michael D.; Laznik, Dina; Jurczak, Michael J.; Schürer, Stephan C.; Vidović, Dušica; Shulman, Gerald I.; Spiegelman, Bruce M.; Griffin, Patrick R.
- Abstract
PPAR? is the functioning receptor for the thiazolidinedione (TZD) class of antidiabetes drugs including rosiglitazone and pioglitazone. These drugs are full classical agonists for this nuclear receptor, but recent data have shown that many PPAR?-based drugs have a separate biochemical activity, blocking the obesity-linked phosphorylation of PPAR? by Cdk5 (ref. 2). Here we describe novel synthetic compounds that have a unique mode of binding to PPAR?, 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 PPAR? 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 PPAR?.
- Publication
Nature, 2011, Vol 477, Issue 7365, p477
- ISSN
0028-0836
- Publication type
Academic Journal
- DOI
10.1038/nature10383