Role of Soluble Epoxide Hydrolase in Health and Disease

Soluble epoxide hydrolase (sEH) has been investigated as a potential target of novel therapeutics in the prevention and treatment of metabolic disease. sEH is the predominant enzyme responsible for the degradation of epoxyeicosatrienoic acids (EETs), highly active compounds that produce strong anti-inflammatory, analgesic, and vasodilatory effects. EETs have been highly researched in the treatment of metabolic diseases including diabetes and obesity, however, most current research employs the use of whole-body sEH genetic deletion or inhibition, some with conflicting results. Therefore, we created pancreas- and adipose- specific sEH genetic deletion models to investigate the role of sEH in the development and progression of type 2 diabetes and obesity, respectively. We found that pancreas-specific sEH genetic deletion reduces ER stress and apoptosis while enhancing autophagy and glucose-stimulated insulin secretion in models of diabetes in vitro and in vivo. We also found that adipose-specific sEH genetic deletion protects mice against high-fat diet-induced increases in total body weight and fat mass while having no effects on caloric intake. Finally, we found that adipose-specific sEH genetic deletion protected mice against reductions in both insulin responsiveness and glucose tolerance. Our research indicates sEH plays a significant role in the development of metabolic disease and warrants further research into targeting sEH inhibition as a potential novel therapeutic for type 2 diabetes and obesity.