Novel peroxisome proliferator-activated receptor (PPAR) γ and PPARδ ligands produce distinct biological effects

The peroxisome proliferator-activated receptors (PPARs) include three receptor subtypes encoded by separate genes: PPAR alpha; PPAR delta, and PPAR gamma, PPAR gamma 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 PPAR gamma and PPAR delta 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 PPAR gamma and PPAR delta directly interacted with a nuclear receptor co-activator (CREB-binding protein) in an agonist-dependent manner. Only the PPAR gamma agonists were able to promote differentiation of 3T3-L1 preadipocytes, In diabetic db/db mice all PPAR gamma agonists were orally active insulin-sensitizing agents producing reductions of elevated plasma glucose and triglyceride concentrations. In contrast, selective in vivo activation of PPAR delta did not significantly affect these parameters. In vivo PPAR alpha 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 PPAR gamma and PPAR delta; 2) ligand-dependent activation of PPAR delta involves an apparent conformational change and association of the receptor ligand binding domain with CREB-binding protein; 3) PPAR gamma activation (but not PPAR delta or PPAR alpha activation) is sufficient to potentiate preadipocyte differentiation; 4) non-thiazolidinedione PPAR gamma agonists improve hyperglycemia and hypertriglyceridemia in vivo; 5) although PPAR alpha activation is sufficient to affect triglyceride metabolism, PPAR delta activation does not appear to modulate glucose or triglyceride levels.