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Novel Peroxisome Proliferator-activated Receptor (PPAR) γ and PPARδ Ligands Produce Distinct Biological Effects
- Source :
- Journal of Biological Chemistry. 274:6718-6725
- Publication Year :
- 1999
- Publisher :
- Elsevier BV, 1999.
-
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.
- Subjects :
- Blood Glucose
medicine.medical_specialty
Protein Conformation
medicine.drug_class
Receptors, Cytoplasmic and Nuclear
Peroxisome proliferator-activated receptor
Biology
Ligands
Biochemistry
PPAR agonist
Cell Line
Diabetes Mellitus, Experimental
Mice
Transactivation
Mediator
In vivo
Internal medicine
Adipocytes
medicine
Animals
Humans
Thiazolidinedione
Receptor
Molecular Biology
chemistry.chemical_classification
Cell Differentiation
Cell Biology
Endocrinology
Nuclear receptor
chemistry
Transcription Factors
Subjects
Details
- ISSN :
- 00219258
- Volume :
- 274
- Database :
- OpenAIRE
- Journal :
- Journal of Biological Chemistry
- Accession number :
- edsair.doi.dedup.....d759ee2bf37a009fb5d374059ed9f683