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

Jang Hyun Choi, Alexander S. Banks, Theodore M. Kamenecka, Scott A. Busby, Michael J. Chalmers, Naresh Kumar, Dana S. Kuruvilla, Youseung Shin, Yuanjun He, John B. Bruning, David P. Marciano, Michael D. Cameron, Dina Laznik, Michael J. Jurczak, Stephan C Schuerer, Dušica Vidović, Gerald I. Shulman, Bruce M. Spiegelman, Patrick R. Griffin

Research output: Contribution to journalArticle

329 Citations (Scopus)

Abstract

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 (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.

Original languageEnglish
Pages (from-to)477-481
Number of pages5
JournalNature
Volume477
Issue number7365
DOIs
StatePublished - Sep 22 2011

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Peroxisome Proliferator-Activated Receptors
Hypoglycemic Agents
Phosphorylation
Ligands
Pharmaceutical Preparations
rosiglitazone
pioglitazone
PPAR gamma
Cytoplasmic and Nuclear Receptors
Adipocytes
Osteogenesis
Weight Gain
Obesity
Insulin

ASJC Scopus subject areas

  • General

Cite this

Choi, J. H., Banks, A. S., Kamenecka, T. M., Busby, S. A., Chalmers, M. J., Kumar, N., ... Griffin, P. R. (2011). Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation. Nature, 477(7365), 477-481. https://doi.org/10.1038/nature10383

Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation. / Choi, Jang Hyun; Banks, Alexander S.; Kamenecka, Theodore M.; Busby, 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; Vidović, Dušica; Shulman, Gerald I.; Spiegelman, Bruce M.; Griffin, Patrick R.

In: Nature, Vol. 477, No. 7365, 22.09.2011, p. 477-481.

Research output: Contribution to journalArticle

Choi, JH, Banks, AS, Kamenecka, TM, Busby, SA, Chalmers, MJ, Kumar, N, Kuruvilla, DS, Shin, Y, He, Y, Bruning, JB, Marciano, DP, Cameron, MD, Laznik, D, Jurczak, MJ, Schuerer, SC, Vidović, D, Shulman, GI, Spiegelman, BM & Griffin, PR 2011, 'Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation', Nature, vol. 477, no. 7365, pp. 477-481. https://doi.org/10.1038/nature10383
Choi JH, Banks AS, Kamenecka TM, Busby SA, Chalmers MJ, Kumar N et al. Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation. Nature. 2011 Sep 22;477(7365):477-481. https://doi.org/10.1038/nature10383
Choi, Jang Hyun ; Banks, Alexander S. ; Kamenecka, Theodore M. ; Busby, 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 ; Vidović, Dušica ; Shulman, Gerald I. ; Spiegelman, Bruce M. ; Griffin, Patrick R. / Antidiabetic actions of a non-agonist PPARγ ligand blocking Cdk5-mediated phosphorylation. In: Nature. 2011 ; Vol. 477, No. 7365. pp. 477-481.
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