Glutathione Peroxidase 3 Mediates the Antioxidant Effect of Peroxisome Proliferator-Activated Receptor γ in Human Skeletal Muscle Cells

Abstract

Oxidative stress plays an important role in the pathogenesis of insulin resistance and type 2 diabetes mellitus and in diabetic vascular complications. Thiazolidinediones (TZDs), a class of peroxisome proliferatoractivated receptor ␥ (PPAR␥) agonists, improve insulin sensitivity and are currently used for the treatment of type 2 diabetes mellitus. Here, we show that TZD prevents oxidative stress-induced insulin resistance in human skeletal muscle cells, as indicated by the increase in insulin-stimulated glucose uptake and insulin signaling. Importantly, TZD-mediated activation of PPAR␥ induces gene expression of glutathione peroxidase 3 (GPx3), which reduces extracellular H 2 O 2 levels causing insulin resistance in skeletal muscle cells. Inhibition of GPx3 expression prevents the antioxidant effects of TZDs on insulin action in oxidative stress-induced insulinresistant cells, suggesting that GPx3 is required for the regulation of PPAR␥-mediated antioxidant effects. Furthermore, reduced plasma GPx3 levels were found in patients with type 2 diabetes mellitus and in db/db/DIO mice. Collectively, these results suggest that the antioxidant effect of PPAR␥ is exclusively mediated by GPx3 and further imply that GPx3 may be a therapeutic target for insulin resistance and diabetes mellitus.

Glutathione peroxidase 3, a new retinoid target gene, is crucial for human skeletal muscle precursor cell survival

“…GPx3 mediates the antioxidant effects of agonists of peroxisomeproliferator activated receptor (PPAR), a class of molecules that improves insulino sensibility in skeletal muscle and is used to treat type II diabetes. PPAR induced GPx3 expression by binding to peroxisome-proliferator response element (PPRE) in the GPx3 promoter (Chung et al, 2009). We believe that RA-mediated regulation of the GPx3 gene is indirect because the kinetics of GPx3 induction was slow, peaking at 48 hours.…”

Increased susceptibility to oxidative damage in post-diabetic human myotubes

“…Oxidative stress has been implicated in the development of insulin resistance [24][25][26][27][28]; however the role of ROS in diabetic skeletal muscle is an emerging field. Recently, Chung et al demonstrated that treatment of human skeletal muscle cells with high levels of hydrogen peroxide led to destruction of the insulin signalling pathway, but that pretreatment with troglitazone could prevent this ROS-induced insulin resistance [29]. The production of ROS by skeletal muscle and the mechanisms by which this tissue mitigates oxidative damage in the context of type 2 diabetes are areas of great interest.…”

Berberine mitigates methotrexate-induced oxidative stress and inflammation in the cerebrum of rats

“…Nrf2 activation is associated with down-regulation of NF-κB and iNOS (Mahmoud and Al Dera, 2015) and decreased production of pro-inflammatory cytokines (Mahmoud andAl Dera, 2015, Kamel et al, 2016;Mahmoud et al, 2017a,b,d,e). In addition, PPARγ activation modulates the expression of several antioxidant genes (Girnun et al, 2002, Chung et al, 2009 and induce anti-inflammatory responses (Yu et al, 2002).…”