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

Abstract

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 (1a (αEC50 1.0 μM) and 1b (γEC50 0.012 μM)) and antagonists (2a (αIC50 6.5 μM) and 2b (αIC50 0.98 μM, with a weak antagonist activity on γ isoform))—on proinflammatory and oxidative stress biomarkers. The PPAR ligands 1a-b and 2a-b (0.1–10 μM) were tested on isolated liver specimens treated with lipopolysaccharide (LPS), and the levels of lactate dehydrogenase (LDH), prostaglandin (PG) E2, and 8-iso-PGF2α 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, PGE2, and 8-iso-PGF2α levels after 1a treatment. On the other hand, 1b decreased LPS-induced LDH activity. Compared to the control, 1a 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, 1b increased UCP1, DIO2, and PPARγ gene expression. 2a-b caused a reduction in the gene expression of UCP1, PRDM16, and DIO2 when tested at 10 μM. In addition, 2a-b significantly decreased PPARα gene expression. A significant reduction in PPARγ gene expression was also found after 2b treatment. The novel PPARα agonist 1a might be a promising lead compound and represents a valuable pharmacological tool for further assessment. The PPARγ agonist 1b could play a minor role in the regulation of inflammatory pathways.

PM2.5, component cause of severe metabolically abnormal obesity: An in silico, observational and analytical study

“…It has been demonstrated that the PPAR signaling pathway plays a key role in activating the browning process as a strategy to counteract obesity [ 120 , 121 ]. Therefore, the uncoupling of oxidative phosphorylation that should occur in the mitochondria of white adipocytes through browning to dissipate excess energy in the form of heat before storing it in TG droplets may be disrupted by the downregulation of Ucp1 transcription with exposure to HFD and PM 2.5.…”

Plasticity of Adipose Tissues: Interconversion among White, Brown, and Beige Fat and Its Role in Energy Homeostasis

“…YBX1 has been identified as a key factor in orchestrating the transition of pre-adipocytes to beige fat cells within a novel genomic mechanism. Peroxisome proliferator-activated receptor gamma (PPARγ) is highly expressed in adipose tissue [79,[82][83][84], playing a critical regulatory role in adipocyte differentiation and closely correlating with the regulation of inflammation in adipose tissue [85]. Chromatin-binding protein high-mobility group nucleosome-binding domain (HMGN) has been shown to regulate the rate of browning in white adipose tissue [86].…”

The Role of NF-κB, PPAR-α, and PPAR-γ in Older Adults with Metabolic Syndrome

“…PPAR receptors have become important therapeutic targets by playing a role in the improvement of inflammation and oxidative stress [37]. In animal studies, it was indicated that the inhibition of the NF-κB pathway can potentially improve diabetic neuropathy [38], diabetes related peripheral vascular disease [39], and obesity-related cardiac inflammation [40].…”