n-3 PUFA derived epoxides and thermogenesis for obesity prevention

项目概要/摘要 肥胖仍然是全球最大的公共卫生挑战之一。肥胖与各种疾病有关 合并症，包括2型糖尿病、血脂异常和心血管疾病，导致寿命缩短 以及更高的医疗费用。最近的研究表明，肥胖也与高患病率有关 以及COVID-19（一种由冠状病毒SARS-CoV-2引起的传染病）的严重程度。因此，小说 仍然需要新的方法和新一代的研究人员来治疗和预防人类肥胖。布朗 脂肪组织（BAT），一种负责非颤抖性产热的脂肪类型，现在已知存在于成年人中， 已经成为增加能量消耗和改善全身代谢的新靶点， 预防肥胖。此外，还提供了一种布朗宁工艺，即，在白色脂肪中出现米色脂肪细胞 也已经报道了响应于冷或其他刺激的组织（WAT）库。然而，对我们的 知识，仍然没有实际和有效的方法来刺激人体产热，除了冷 暴露或β-肾上腺素能刺激，这与副作用和低依从性有关。我们有 发现17，18-环氧二十碳四烯酸（EEQ，n-3多不饱和脂肪酸二十碳五烯酸 酸（EPA）衍生的环氧脂肪酸），当通过药理学抑制剂稳定时， 可溶性环氧化物水解酶（降解环氧脂肪酸的酶），显著增加核心体 在饮食诱导的肥胖症中，温度和热量产生以及血液甘油三酯和葡萄糖水平的改善。 17，18-EEQ的产热效果优于19，20-环氧二十二碳五烯酸（EDP， 二十二碳六烯酸（DHA）衍生的环氧脂肪酸），比EPA或鱼油更有效 富含EPA和DHA。因此，本提案的目标是（目的1）阐明分子和 17，18-EEQ促进小鼠褐色和米色脂肪细胞产热的生化机制 目的2：测定17，18-EEQ与19，20-EDP的疗效比较 增加人类棕色和米色脂肪细胞的产热和增加能量消耗， 改善移植小鼠体内的代谢。鉴于产热在人类肥胖中的重要作用， 治疗和预防，迫切需要确定新的，有效的，安全的药物和分子靶点， 促进产热并增加能量消耗。本项目的成果是（1） 对17，18-EEQ生物学理解的重大进展，导致新的策略，以提高 棕色和米色脂肪细胞中的产热;（2）本科生和 研究生在脂肪细胞生物学和肥胖领域的生物医学研究。

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.