Insulin sensitizing
thiazolidinediones (TZDs) are generally considered to work as agonists for the
nuclear receptor peroxisome proliferative activated receptor-gamma (
PPAR gamma). However, TZDs also have acute, non-genomic metabolic effects and it is unclear which actions are responsible for the beneficial pharmacology of these compounds. We have taken advantage of an analog, based on the metabolism of
pioglitazone, which has much reduced ability to activate
PPAR gamma. This analog (PNU-91325) was compared to
rosiglitazone, the most potent
PPAR gamma activator approved for human use, in a variety of studies both in vitro and in vivo. The data demonstrate that
PNU-91325 is indeed much less effective than
rosiglitazone at activating
PPAR gamma both in vitro and in vivo. In contrast, both compounds bound similarly to a mitochondrial binding site and acutely activated
PI-3 kinase-directed phosphorylation of AKT, an action that was not affected by elimination of
PPAR gamma activation. The two compounds were then compared in vivo in both normal C57 mice and diabetic KKAy mice to determine whether their pharmacology correlated with
biomarkers of
PPAR gamma activation or with the expression of other gene transcripts. As expected from previous studies, both compounds improved
insulin sensitivity in the diabetic mice, and this occurred in spite of the fact that there was little increase in expression of the classic
PPAR gamma target
biomarker adipocyte binding protein-2 (aP2) with
PNU-91325 under these conditions. An examination of transcriptional profiling of key target tissues from mice treated for one week with both compounds demonstrated that the relative pharmacology of the two
thiazolidinediones correlated best with an increased expression of an array of
mitochondrial proteins and with expression of
PPAR gamma coactivator 1-alpha (PGC1 alpha), the master regulator of mitochondrial biogenesis. Thus, important pharmacology of the
insulin sensitizing TZDs may involve acute actions, perhaps on the mitochondria, that are independent of direct activation of the
nuclear receptor PPAR gamma. These findings suggest a potential alternative route to the discovery of novel
insulin sensitizing drugs.