The Lipidomics of Adipose Tissue Thermogenesis

项目概要/摘要 肥胖是一种全球性流行病，由于肥胖人数不断增加，造成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，例如 心血管疾病、2 型糖尿病和某些癌症。制定预防或治疗策略 因此，人类肥胖极为重要。最近，人们的极大兴趣集中在 人类棕色脂肪的代谢能力以及治疗方案的发现和标准化 激活棕色脂肪产热并消耗能量。为了激活棕色脂肪组织，一些 已经采取了研究策略，包括药物干预和生理寒冷 曝光。不幸的是，许多化合物在小鼠体内发生的生热效应在小鼠体内并未观察到。 人类，尽管最近激活人类 BAT 的 B-3 肾上腺素激动剂已被 报道称。为此，提出了一种创新方法，其中我计划研究生物活性脂质作为 在棕色脂肪组织中具有潜在促产热作用的新型循环因子。最近， 研究表明，脂质分子可以作为激素分泌，在体内充当信号分子 远端器官。这些脂质通过与胰岛素的相互作用来促进胰岛素敏感性和葡萄糖耐量。 蛋白质位于细胞膜上。传统上，脂质不被认为是潜在的内分泌物质 因素。考虑到这一点，我研究了脂质作为介导的分泌分子的潜力， 至少部分是对寒冷挑战的生理反应。初步研究有了新发现 脂质一种特定目标脂质种类在暴露于的小鼠和人类的循环中增加 此外，全身注射这种脂质可以增加产热作用。这个方法很有创新性 因为脂质分子以前没有被报道为产热的分泌介质。在这个 建议，我将系统地确定这种脂质对全身能量代谢的影响，并确定 用我们的靶标治疗后介导增强生热作用的潜在分子机制 脂质。这些结果可能对肥胖症治疗方法的开发产生重大影响 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.