The Lipidomics of Adipose Tissue Thermogenesis

项目摘要/摘要 肥胖是一种全球性的流行病，由于越来越大的肥胖症，造成了巨大的经济负担和健康成本 超重或肥胖的人口比例以及广泛的相关后遗症，如 心血管疾病、2型糖尿病和一些癌症。预防或治疗策略的发展 因此，人类肥胖是极其重要的。最近，人们的极大兴趣集中在 人类棕色脂肪的代谢能力和治疗方案的发现和标准化 激活棕色脂肪生热，消耗能量。为了激活棕色脂肪组织，有几种 已经采取了研究策略，包括药物干预和生理性感冒 曝光。不幸的是，在老鼠身上发现的许多化合物的生热作用并没有观察到 人类，尽管最近激活人类蝙蝠的B-3肾上腺素能激动剂最近已经被 据报道。为此，提出了一种创新的方法，其中我计划将生物活性脂质作为一种 棕色脂肪组织中具有潜在促热作用的一类新的循环因子。最近， 研究表明，脂分子可以作为荷尔蒙分泌，作为信号分子在 远端器官。这些脂质通过与以下物质相互作用促进胰岛素敏感性和糖耐量 位于细胞膜上的蛋白质。传统上，脂类并不被认为是潜在的内分泌。 各种因素。考虑到这一点，我研究了脂类作为分泌分子发挥中介作用的可能性， 至少在一定程度上，是对寒冷挑战的生理反应。初步研究已经取得了这一新发现 暴露在空气中的小鼠和人类循环中的脂质一特定靶标脂质物种增加 冷的时候，全身注射这种脂类可以增加产热。这种方法是创新的。 因为以前没有报道过脂分子是产热的分泌性介体。在这 建议，我将系统地测定这种脂质对全身能量代谢的影响，并确定 靶点治疗后促进产热的潜在分子机制 脂类。这些结果可能对肥胖症的治疗和治疗的发展产生重大影响 心血管疾病。

Project Summary/Abstract Obesity is a global pandemic with enormous financial burden and health cost due both to the increasingly large proportion of the population who are overweight or obese and the broad range of associated sequelae such as cardiovascular disease, type 2 diabetes, and some cancers. The development of strategies to prevent or treat human obesity is therefore extremely important. Recently, a great deal of interest has been centered on the metabolic capacity of brown fat in humans and the discovery and standardization of treatment regiments that activate brown fat thermogenesis and expend energy. In order to activate brown adipose tissue, several research strategies have been pursued, including both pharmacological interventions and physiologic cold exposure. Unfortunately, the thermogenic effect of many compounds that occurs in mice is not observed in humans, although recently B-3 adrenergic agonists that activate human BAT have been recently been reported. To this end, an innovative approach is proposed wherein I plan to investigate bioactive lipids as a novel class of circulating factors with potential pro-thermogenic effects in brown adipose tissue. Recently, studies have demonstrated that lipid molecules can act as hormones secreted to act as signaling molecules in distal organs. These lipids promote insulin sensitivity and glucose tolerance through their interaction with proteins located on the cell membrane. Conventionally, lipids have not been considered as potential endocrine factors. With this in mind, I have investigated the potential of lipids to act as secreted molecules that mediate, at least in part, the physiologic response to cold challenge. Preliminary studies have made the novel discovery that the lipid one specific target lipid species increases in circulation of mice and humans that are exposed to cold and further, systemic injection of this lipid can increase thermogenesis. This approach is innovative because lipid molecules have not been previously reported as secreted mediators of thermogenesis. In this proposal, I will systematically determine the effect of this lipid on whole body energy metabolism and determine the underlying molecular mechanisms that mediate enhanced thermogenesis after treatment with our target lipid. These results could a have significant impact in the development of treatments for obesity and cardiovascular disease.