n-3 PUFA derived epoxides and thermogenesis for obesity prevention

项目总结/文摘

Project Summary/Abstract Obesity remains one of the biggest public health challenges worldwide. Obesity is associated with various comorbidities, including type 2 diabetes, dyslipidemia, and cardiovascular diseases, leading to a shorter lifespan and higher medical costs. Recent studies have indicated that obesity is also associated with the high prevalence and severity of COVID-19, an infectious disease caused by coronavirus SARS-CoV-2. Therefore, novel approaches and new generations of researchers are still needed to treat and prevent human obesity. Brown adipose tissue (BAT), a fat type responsible for non-shivering thermogenesis and now known to exist in adult humans, has emerged as a novel target to increase energy expenditure and improve systemic metabolism for obesity prevention. In addition, a browning process, i.e., the appearance of beige adipocytes within white adipose tissue (WAT) depots in response to cold or other stimulations, has also been reported. However, to our knowledge, there are still no practical and effective ways to stimulate thermogenesis in humans except for cold exposure or β-adrenergic stimulation, which is associated with side effects and low compliance. We have discovered that 17,18-epoxyeicosatetraenoic acid (EEQ, an n-3 polyunsaturated fatty acid eicosapentaenoic acid (EPA)-derived epoxy fatty acid) at a much low dose, when stabilized by a pharmacological inhibitor of soluble epoxide hydrolase (the enzyme that degrades epoxy fatty acids), significantly increased core body temperature and heat production and improved blood triglycerides and glucose levels in diet-induced obesity. The thermogenic efficacy of 17,18-EEQ is better than 19,20-epoxydocosapentaenoic acid (EDP, a docosahexaenoic acid (DHA)-derived epoxy fatty acid) and much potent than the reported EPA or fish oil enriched with EPA and DHA. Therefore, the goal of this proposal is to (Aim 1) elucidate the molecular and biochemical mechanisms by which 17,18-EEQ promotes thermogenesis in mouse brown and beige adipocytes in vitro compared with 19,20-EDP and (Aim 2) determine the efficacy of 17,18-EEQ compared with 19,20-EDP in increasing thermogenesis in human brown and beige adipocytes and increasing energy expenditure and improving metabolism in transplanted mice in vivo. In light of the critical roles of thermogenesis in human obesity treatment and prevention, it is urgent to identify novel, effective, and safe agents and molecular targets to promote thermogenesis and increase energy expenditure. The outcomes for this proposed project are (1) significant advancement of the understanding of 17,18-EEQ biology, leading to novel strategies to boost thermogenesis in brown and beige adipocytes; (2) extensive exposure and training of both undergraduate and graduate students to biomedical research in the areas of adipocyte biology and obesity.