Engineering the release of oxylipins through the skin

PROJECT SUMMARY/ABSTRACT Obesity and type 2 diabetes are increasing dramatically worldwide. Recent data has shown that obesity rates have more than doubled since 1980 and if these trends continue unabated, by 2030 estimates predict that approximately half the U.S. population will be obese, with 25% developing type 2 diabetes. Adipose tissue is an important site for initiation and aggravation of obesity and type 2 diabetes because it is a key endocrine organ that functions to maintain energy homeostasis, and recent studies have identified lipokines, or signaling lipids, released from adipose tissue as molecules that can mediate metabolic effects. One class of these lipokines are oxylipins, oxidized lipid metabolites that exert metabolic effects. An important oxylipin for metabolic control is the linoleic acid metabolite 12,13-diHOME, which is released from brown adipose tissue (BAT) in response to cold and exercise in rodents and humans and beneficially impacts glucose and fatty acid metabolism. 12,13-diHOME increases fatty acid uptake into brown adipose tissue, skeletal muscle, and cardiomyocytes, and is negatively correlated with circulating triglycerides and BMI in humans. However, due to its very short half-life, systemic regulation is difficult to maintain and thus its therapeutic potential has not been fully realized. To address this essential issue, we developed a paradigm-shifting approach to increase 12,13- diHOME via tissue nanotransfection (TNT), a non-viral gene delivery technology with high translational potential. TNT delivery of the genes Ephx1/2, coding for the enzymes that make bioactive 12,13-diHOME results in a sustained systemic increase of 12,13-diHOME in circulation and corresponds to reduced adiposity and improved metabolic health. In these proposed studies we will optimize a therapeutic upregulation of Ephx1/2 via TNT in pre-clinical models and comprehensively establish the physiological ramifications of a sustained systemic increase in 12,13-diHOME and provide new therapeutic approaches to combat obesity and type 2 diabetes. We will do this using the following two specific aims: 1) Determine the effectiveness, efficiency, and mechanisms through which TNT-based delivery of Ephx1/2 into the skin increases 12,13- diHOME in circulation and; 2) Determine the physiological ramifications of a sustained increase in the oxylipin 12,13-diHOME by TNT. The proposed studies have the potential to provide paradigm-shifting results and elucidate novel mechanisms to sustain oxylipin up-regulation and providing new therapeutic approaches to combat obesity and type 2 diabetes.