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Novel peroxisome proliferator-activated receptor (PPAR) gamma and PPARdelta ligands produce distinct biological effects

Academic Article
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Overview

authors

  • Berger, J.
  • Leibowitz, M. D.
  • Doebber, T. W.
  • Elbrecht, A.
  • Zhang, B.
  • Zhou, G. C.
  • Biswas, C.
  • Cullinan, C. A.
  • Hayes, N. S.
  • Li, Yuxing
  • Tanen, M.
  • Ventre, J.
  • Wu, M. S.
  • Berger, G. D.
  • Mosley, R.
  • Marquis, R.
  • Santini, C.
  • Sahoo, S. P.
  • Tolman, R. L.
  • Smith, Roy
  • Moller, D. E.

publication date

  • 1999

journal

  • Journal of Biological Chemistry  Journal

abstract

  • The peroxisome proliferator-activated receptors (PPARs) include three receptor subtypes encoded by separate genes: PPARalpha, PPARdelta, and PPARgamma. PPARgamma has been implicated as a mediator of adipocyte differentiation and the mechanism by which thiazolidinedione drugs exert in vivo insulin sensitization. Here we characterized novel, non-thiazolidinedione agonists for PPARgamma and PPARdelta that were identified by radioligand binding assays. In transient transactivation assays these ligands were agonists of the receptors to which they bind. Protease protection studies showed that ligand binding produced specific alterations in receptor conformation. Both PPARgamma and PPARdelta directly interacted with a nuclear receptor co-activator (CREB-binding protein) in an agonist-dependent manner. Only the PPARgamma agonists were able to promote differentiation of 3T3-L1 preadipocytes. In diabetic db/db mice all PPARgamma agonists were orally active insulin-sensitizing agents producing reductions of elevated plasma glucose and triglyceride concentrations. In contrast, selective in vivo activation of PPARdelta did not significantly affect these parameters. In vivo PPARalpha activation with WY-14653 resulted in reductions in elevated triglyceride levels with minimal effect on hyperglycemia. We conclude that: 1) synthetic non-thiazolidinediones can serve as ligands of PPARgamma and PPARdelta; 2) ligand-dependent activation of PPARdelta involves an apparent conformational change and association of the receptor ligand binding domain with CREB-binding protein; 3) PPARgamma activation (but not PPARdelta or PPARalpha activation) is sufficient to potentiate preadipocyte differentiation; 4) non-thiazolidinedione PPARgamma agonists improve hyperglycemia and hypertriglyceridemia in vivo; 5) although PPARalpha activation is sufficient to affect triglyceride metabolism, PPARdelta activation does not appear to modulate glucose or triglyceride levels.

subject areas

  • Adipocytes
  • Animals
  • Blood Glucose
  • Cell Differentiation
  • Cell Line
  • Diabetes Mellitus, Experimental
  • Humans
  • Ligands
  • Mice
  • Protein Conformation
  • Receptors, Cytoplasmic and Nuclear
  • Transcription Factors
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Identity

International Standard Serial Number (ISSN)

  • 0021-9258

Digital Object Identifier (DOI)

  • 10.1074/jbc.274.10.6718

PubMed ID

  • 10037770
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Additional Document Info

start page

  • 6718

end page

  • 6725

volume

  • 274

issue

  • 10

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