Obesity-associated unfolded protein response, oxidative stress, and NRF2 signaling

Obesity has become a major global health problem. It is characterized by increased body fat storage and is associated with excessive food intake. Although obesity is often thought of as a simple problem involving fat accumulation in the body, it is a complex disease that alters cellular defense systems and causes low-grade chronic inflammation, which can contribute metabolic syndrome. Even though obesity is an inflammatory disease, an increase in the formation of reactive oxygen species (ROS) is also observed due to excess nutrition. Excessive ROS production contributes to obesity progression and endoplasmic reticulum (ER) stress. In response to oxidative stress, cells activate antioxidant defense mechanisms either through unfolded protein response (UPR) pathways or via UPR-independent signaling pathways. Nuclear factor-erythroid 2-related factor-2 (NRF2) controls the transcription of multiple genes encoding antioxidant and cytoprotective proteins. NRF2 is of interest in obesity research as it can be activated with or without UPR elements and plays a role in the regulation of antioxidant response. Targeting NRF2 through multiple approaches has been shown to reduce or prevent obesity and obesity associated metabolic complications. This review examines the molecular mechanisms of NRF2 activation in obesity, with particular focus on its bidirectional crosstalk with the UPR and discusses the therapeutic implications of targeting this axis in obesity and its related metabolic dysfunction.