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

作者：Choi Jang Hyun; Banks Alexander S; Kamenecka Theodore M; Bu**y Scott A; Chalmers Michael J; Kumar Naresh; Kuruvilla Dana S; Shin Youseung; He Yuanjun; Bruning John B; Marciano David P; Cameron Michael D; Laznik Dina; Jurczak Michael J; Schuerer Stephan C; Vidovic Dusica; Shulman Gerald I; Spiegelman Bruce M^*; Griffin Patrick R

来源：Nature, 2011, 477(7365): 477-U131.

DOI：10.1038/nature10383

PPAR gamma is the functioning receptor for the thiazolidinedione (TZD) class of antidiabetes drugs including rosiglitazone and pioglitazone(1). These drugs are full classical agonists for this nuclear receptor, but recent data have shown that many PPAR gamma-based drugs have a separate biochemical activity, blocking the obesity-linked phosphorylation of PPAR gamma by Cdk5 (ref. 2). Here we describe novel synthetic compounds that have a unique mode of binding to PPAR gamma, 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 gamma 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 gamma.

• 出版日期2011-9-22