PPARy ligands

Natural PPARy Ligands. Endogenous ligands demonstrated to bind and activate PPARy in vitro include unsaturated fatty acids and their derivatives such as prostaglandin J2 (15-deoxy-A12,l4-PGJ2). Consistent... 

The exact mechanism by which PPARy ligands affect insulin resistance (improved glucose uptake by peripheral tissues, most notably skeletal muscle) remains unclear. 

Peptide deformylase inhibitors, 44 (2006) 109 Peroxisome proliferator-acrtvated receptor gamma (PPARy) ligands, 42 (2004) 1 Pharmacology of Alzheimer s disease,... 

Following the discovery of PPARy as a probable molecular target for the thiazolidinediones, several approaches have been taken in order to rapidly screen for additional PPARy ligands or agonists. Initial assays con-... 

The techniques described above have been used to search for new PPARy ligands or agonists that possess greater potency, alternative selectivity profiles, and improved in vivo efficacy. 

Hosokawa, M., Kudo, M., Maeda, H., Kohno, H., Tanaka, T., and Miyashita, K. 2004. Fucoxanthin induces apoptosis and enhances the antiproliferative effect of the PPARy ligand, troglitazone, on colon cancer cells. Biochem. Biophys. Acta, 1675, 113-119. 

Figure 1A A portion of the X-ray structure (205) cf rosiglitazone co-crystallized with the PPARy ligand-binding domain (LED) and a fragment of the coactivator protein SRC-1, showing the bound con-fo rmation of rosiglitazone. Coordinates were obtained from the Protein Data Bank (212) and displayed with RasMol.

A recent study reported by d Abramo and colleagues has shown that the PPARy agonist troglitazone, was able to significantly reduce the phosphorylation of tau [22], However, these effects of this PPARy ligand were independent of the transcriptional activity of the receptor and represent an off-target effect of this TZD. 

These findings remain puzzling and PPARy ligands need to be examined more thoroughly to elucidate their true in vivo receptor modulating abilities. Possibly, receptors in addition to PPARy are involved in the antidiabetic effects of these molecules. Several recent reports have disclosed that some PPARy ligands bind to a receptor on mitochondria referred to as mitoNEET and that this receptor is responsible for at least a portion of their antidiabetic activity [81]. 

In addition to the potential development hurdles discussed above, short-term in vivo studies with PPARy ligands do not appear to accurately predict results from longer term toxicology studies. As adverse events with PPARy ligands may accumulate over time, toxicology studies become lengthy in order to accurately identify potential liabilities. 

Collins AR, Noh G, Hsueh WA, et al. PPARy ligands attenuate angiotensin-II accelerated atherosclerosis in male low density receptor deficient (LDLR-/-) mice[abstract 292-PP]. Diabetes. 2001 50(suppl 2) A72-A73. 

Choi, J.H., Banks, A.S., Kamenecka, T.M., et al. (2011) Antidiabetic actions of a non-agonist PPARy ligand blocking Cdk5-mediated phosphorylation. Nature, 477 (7365), 477-481. 

I. Shimomura, and Y. Matsuzawa. PPARy Ligands Increase Expression and Plasma Concentration of Adiponectin, an Adipose-Derived Protein, Diabetes 50 2094—2099. (2001)... 

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