n-3 PUFA derived epoxides and thermogenesis for obesity prevention

项目摘要/摘要 肥胖仍然是全球最大的公共卫生挑战之一。肥胖与各种因素有关 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。 新冠肺炎是一种由冠状病毒SARS-CoV-2引起的传染病。因此，小说 治疗和预防人类肥胖仍然需要方法和新一代的研究人员。棕色 脂肪组织(BAT)，一种负责非颤抖产热的脂肪类型，现已知存在于成年人中 人类，已成为增加能量消耗和改善系统代谢的新靶点 预防肥胖。此外，还有一个褐变过程，即白色脂肪中出现米色脂肪细胞。 组织(WAT)仓库对寒冷或其他刺激的反应也有报道。然而，对于我们的 知识，除了寒冷之外，还没有实际有效的方法来刺激人类的产热 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)是一种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)，剂量低得多，当由一种药物抑制剂稳定时 可溶性环氧化物水解酶(降解环氧脂肪酸的酶)，显著增加核心身体 在饮食诱导的肥胖中，温度和热量的产生以及血液甘油三酯和血糖水平的改善。 17，18-EEQ的生热效果优于19，20-环氧二十二碳五烯酸(EDP，a 二十二碳六烯酸(DHA)衍生的环氧脂肪酸)，比已报道的EPA或鱼油有效得多 富含EPA和DHA。因此，这项提议的目标是(目标1)阐明分子和 17，18-EEQ促进小鼠棕色和米色脂肪细胞产热的生化机制 测定17，18-EEQ与19，20-EDP的体外疗效比较 在增加人棕色和米色脂肪细胞的产热和增加能量消耗和 改善移植小鼠体内的代谢。鉴于产热在人类肥胖中的关键作用 治疗和预防，迫切需要寻找新的、有效的和安全的药物和分子靶点来 促进生热，增加能量消耗。这个拟议项目的成果是(1) 对17，18-EEQ生物学理解的重大进展，导致了促进 棕色和米色脂肪细胞的生热作用；(2)本科生和 研究生学习脂肪细胞生物学和肥胖症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.