Lipocalin-2, a mitokine that mediates white to brown fat crosstalk

项目总结/摘要 三分之一的美国成年人患有肥胖症。肥胖症对 许多其他威胁生命的疾病，如2型糖尿病， 心血管疾病，癌症等，虽然大量的资源已经 尽管我们投入了大量资金来解决这一重大的公共卫生威胁，但事实是，目前， 已经开发了治疗肥胖症的药物治疗方法。一个在- 迫切需要深入了解肥胖的原因， 更有效的治疗方法。人体内有两种类型的脂肪组织：白色和 棕色脂肪组织它们具有不同的形态，并执行不同的功能。 当白色脂肪以脂质的形式储存过多的能量时，棕色脂肪消耗 通过适应性产热产生过多的能量（即，产生热量）。一个共同 人类肥胖的一种现象是棕色脂肪转化为白色脂肪，这是一个过程， 确定为白化。逆转棕色脂肪美白激活棕色脂肪功能， 发挥抗肥胖作用。本研究的总体目标是研究 脂质运载蛋白2（LCN-2），促进棕色脂肪美白的潜在因子。申请人 最近对他的脂肪细胞线粒体功能障碍进行了一系列筛查， 模型LCN-2可能是促使白色转化为棕色的主导因子 脂肪组织串扰以诱导棕色脂肪变白。因此，本建议载于 为了评估中心假设：LCN-2，一种来自白色脂肪的分泌因子， 引起线粒体窘迫和促进棕色脂肪美白。在目标1中，细胞 将使用培养系统（体外）来证明LCN-2需要棕色 脂肪美白在目标2中，将提供来自小鼠（体内）的证据以进一步评价 LCN-2在棕色脂肪变白和代谢后果中的作用（即，冷 不耐受和肥胖）。本研究将通过对小说的定义来填补一个知识空白 美白因素，了解如何棕色脂肪组织成为白化。 此外，该研究具有转化价值，因为LCN-2的中和 LCN-2受体本身或其抑制剂具有巨大的改善 棕色AT美白，反过来，以确定创新的疗法，减轻肥胖。

Project Summary/Abstract One third of American adults are suffering from obesity. Obesity significantly contributes to the prevalence of numerous other life-threatening diseases, such as type 2 diabetes, cardiovascular diseases, cancers, etc. Although substantial resources have been invested to resolve this major public health threat, the fact is that, currently, only limited methods of pharmacological therapeutics have been developed to treat obesity. An in- depth understanding of the reasons for obesity is urgently needed to facilitate finding more effective therapeutics. There are two types of fat tissue in humans: white and brown adipose tissue. They have different morphologies and perform distinct functions. While white fat stores excessive energy in the form of lipids, brown fat consumes excessive energy through adaptive thermogenesis (i.e., generating heat). A common phenomenon in human obesity is the conversion of brown fat into white fat, a process identified as whitening. Reversing brown fat whitening activates brown fat function and exerts anti-obesity effects. The overarching goal of this study is to investigate the role of lipocalin 2 (LCN-2), a potential factor that promotes brown fat whitening. The applicant recently performed a series of screenings in his adipocyte mitochondrial dysfunction model. LCN-2 was suggested to be a leading factor that drives the white to brown adipose tissue crosstalk to induce brown fat whitening. Therefore, this proposal is set out to evaluate the central hypotheses: LCN-2, a secreting factor from the white fat, is induced by mitochondrial distress and promotes brown fat whitening. In Aim 1, cell culture systems (in vitro) will be utilized to demonstrate that LCN-2 is required in brown fat whitening. In Aim 2, evidence from mice (in vivo) will be provided to further evaluate the role of LCN-2 in brown fat whitening and metabolic consequences (i.e., cold intolerance and obesity). This study will fill a knowledge gap through defining a novel whitening factor in understanding how the brown adipose tissue becomes whitened. Furthermore, this study has translational merits because either neutralization of LCN-2 per se or inhibition of the LCN-2 receptor holds an enormous potential to ameliorate brown AT whitening and, in turn, to identify innovative therapeutics that alleviate obesity.