Anti-Inflammatory, Antioxidant, and WAT/BAT-Conversion Stimulation Induced by Novel PPAR Ligands: Results from Ex Vivo and In Vitro Studies

Activation of peroxisome proliferator-activated receptors (PPARs) not only regulates multiple metabolic pathways, but mediates various biological effects related to inflammation and oxidative stress. We investigated the effects of four new PPAR ligands containing a fibrate scaffold-the PPAR agonists ( (αEC 1.0 μM) and (γEC 0.012 μM)) and antagonists ( (αIC 6.5 μM) and (αIC 0.98 μM, with a weak antagonist activity on γ isoform))-on proinflammatory and oxidative stress biomarkers. The PPAR ligands and (0.1-10 μM) were tested on isolated liver specimens treated with lipopolysaccharide (LPS), and the levels of lactate dehydrogenase (LDH), prostaglandin (PG) E , and 8-iso-PGF α were measured. The effects of these compounds on the gene expression of the adipose tissue markers of browning, PPARα, and PPARγ, in white adipocytes, were evaluated as well. We found a significant reduction in LPS-induced LDH, PGE , and 8-iso-PGF α levels after treatment. On the other hand, decreased LPS-induced LDH activity. Compared to the control, stimulated uncoupling protein 1 (UCP1), PR-(PRD1-BF1-RIZ1 homologous) domain containing 16 (PRDM16), deiodinase type II (DIO2), and PPARα and PPARγ gene expression, in 3T3-L1 cells. Similarly, increased UCP1, DIO2, and PPARγ gene expression. caused a reduction in the gene expression of UCP1, PRDM16, and DIO2 when tested at 10 μM. In addition, significantly decreased PPARα gene expression. A significant reduction in PPARγ gene expression was also found after treatment. The novel PPARα agonist might be a promising lead compound and represents a valuable pharmacological tool for further assessment. The PPARγ agonist could play a minor role in the regulation of inflammatory pathways.