Dataset Information

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

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. 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?.

SUBMITTER: Choi JH

PROVIDER: S-EPMC3179551 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

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

Choi Jang Hyun JH Banks Alexander S AS Kamenecka Theodore M TM Busby Scott A SA Chalmers Michael J MJ Kumar Naresh N Kuruvilla Dana S DS Shin Youseung Y He Yuanjun Y Bruning John B JB Marciano David P DP Cameron Michael D MD Laznik Dina D Jurczak Michael J MJ Schürer Stephan C SC Vidović Dušica D Shulman Gerald I GI Spiegelman Bruce M BM Griffin Patrick R PR

Nature 20110904 7365

PPARγ 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 PPARγ-based drugs have a separate biochemical activity, blocking the obesity-linked phosphorylation of PPARγ by Cdk5. Here we describe novel synthetic compounds that have a unique mode of binding to PPARγ, completely lack classical transcriptional agonism and ...[more]

PMID: 21892191

Similar Datasets

Project description:Peroxisome proliferator-activated receptor gamma (PPARγ) is a member of a nuclear receptor superfamily and acts as a ligand-dependent transcription factor, playing key roles in maintenance of adipose tissue and in regulation of glucose and lipid homeostasis. This receptor is the target of thiazolidinediones, a class of antidiabetic drugs, which improve insulin sensitization and regulate glycemia in type 2 diabetes. Despite the beneficial effects of drugs, such as rosiglitazone and pioglitazone, their use is associated with several side effects, including weight gain, heart failure, and liver disease, since these drugs induce full activation of the receptor. By contrast, a promising activation-independent mechanism that involves the inhibition of cyclin-dependent kinase 5 (CDK5)-mediated PPARγ phosphorylation has been related to the insulin-sensitizing effects induced by these drugs. Thus, we aimed to identify novel PPARγ ligands that do not possess agonist properties by conducting a mini-trial with 80 compounds using the sequential steps of thermal shift assay, 8-anilino-1-naphthalenesulfonic acid fluorescence quenching, and a cell-based transactivation assay. We identified two non-agonist PPARγ ligands, AM-879 and P11, and one partial-agonist, R32. Using fluorescence anisotropy, we show that AM-879 does not dissociate the NCOR corepressor in vitro, and it has only a small effect on TRAP coactivator recruitment. In cells, AM-879 could not induce adipocyte differentiation or positively regulate the expression of genes associated with adipogenesis. In addition, AM-879 inhibited CDK5-mediated phosphorylation of PPARγ in vitro. Taken together, these findings supported an interaction between AM-879 and PPARγ; this interaction was identified by the analysis of the crystal structure of the PPARγ:AM-879 complex and evidenced by AM-879's mechanism of action as a putative PPARγ non-agonist with antidiabetic properties. Moreover, we present an optimized assay pipeline capable of detecting ligands that physically bind to PPARγ but do not cause its activation as a new strategy to identify ligands for this nuclear receptor.

Dataset Information

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

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets