Adipocyte mitochondrial distress drives the intercommunication between white and brown adipose tissues

项目摘要/摘要 三分之一的美国成年人患有肥胖症，这在很大程度上导致了 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 已经部署了大量资源来解决这一重大公共卫生威胁，事实是，目前 只有有限的干预方式被开发出来。对本病发病机制的深入认识 迫切需要肥胖以促进找到更有效的治疗方法。这款K01的首要目标是 该提案旨在调查两个主要肥胖者--白人和棕色之间的相互影响。 脂肪组织，并找出新的调节白色脂肪-棕色脂肪交流的因素。申请人 最近发现淀粉样前体蛋白(APP)在白色脂肪中的过度表达及其后续的 错误定位于线粒体会导致严重的线粒体功能障碍，从而促进肥胖和 胰岛素抵抗。从这种独特的APP诱导的线粒体窘迫模型中获得的初步数据显示 白色脂肪中的线粒体受阻会导致棕色脂肪的表型变白，相比之下，棕色脂肪-- 特定的线粒体窘迫会导致白色脂肪的“褐变”。因此，这项建议旨在测试 中心假设：1)APP诱导的线粒体窘迫是白色/棕色脂肪的中心决定因素 相互交流；2)白色/棕色脂肪的相互交流涉及尚未识别的信号；3)白色/棕色 脂肪的相互沟通会影响全身新陈代谢。在目标1中，白色或棕色脂肪特异的过度表达或 APP小鼠模型的删除将受到代谢特征和机制研究的影响。在……里面 目标2，将进行多层无偏见的策略，以发现神经元或激素因素 作为白色脂肪和棕色脂肪之间的通讯信号，预计这些因素将发挥重要作用 肥胖或抗肥胖的作用。同时，作为一项职业发展奖，这项提议还概述了 为申请人提供综合培训和研究计划，以完成 菲利普·E·谢勒博士和乔尔·K·埃尔姆奎斯特博士的指导，随后过渡到独立的 专门研究肥胖背景下新陈代谢活跃的组织串扰的研究员。 此外，德克萨斯大学西南医学中心提供的出色资源将使 申请人在确定潜在的新机制方面实现职业目标的潜力 肥胖的发病机制及治疗肥胖症的新疗法。与长期利益结合在一起 并确立了申请人学习脂肪组织生物学的能力，来自 新陈代谢领域的国际公认领导者，以及德克萨斯大学西南分校无与伦比的环境， 这一K01职业发展奖将是申请人在布朗接受额外培训的关键。 脂肪生物学，神经元对褐化活性的调节，基于蛋白质组学的分泌因子鉴定，以及 治疗发现，从而完全支持申请人成功过渡到独立。

Project Summary/Abstract One third of American adults are suffering from obesity, which significantly contributes to the prevalence of many other life-threatening diseases, such as type 2 diabetes, cardiovascular diseases, cancers, etc. Although substantial resources have been deployed to resolve this major public health threat, the fact is that currently only limited ways of intervention have been developed. An in-depth understanding of the pathogenesis of obesity to facilitate finding more effective therapeutics is urgently needed. The overarching goal of this K01 proposal is to investigate the crosstalk between two major players in the onset of obesity, white and brown adipose tissues, and to identify novel factors mediating the white fat-brown fat communication. The applicant recently has identified that overexpression of amyloid precursor protein (APP) in white fat and its subsequent mistargeting into mitochondria induces dramatic mitochondrial dysfunction, thereby promoting obesity and insulin resistance. Preliminary data obtained from this unique APP-induced mitochondrial distress model show that mitochondrial distress in white fat induces a “whitening” phenotype in brown fat, and in contrast, brown fat- specific mitochondrial distress causes “browning” in white fat. Therefore, this proposal is set out to test the central hypotheses: 1) APP-induced mitochondrial distress is a central determinant of white/brown fat intercommunication; 2) white/brown fat intercommunication involves yet unrecognized signals; 3) white/brown fat intercommunication impacts systemic metabolism. In Aim 1, white or brown fat-specific overexpression or deletion of APP mouse models will be subject to metabolic characterizations and mechanistic investigations. In Aim 2, multiple layers of unbiased strategies will be conducted to discover neuronal or hormonal factors that act as communicating signals between white and brown fat, and these factors are predicted to exert important obesogenic or anti-obesogenic roles. Meanwhile, as a career development award, this proposal also outlines an integrated training and research plan for the applicant to complete further academic training under the mentorship of Dr. Philipp E. Scherer and Dr. Joel K. Elmquist, ensuing the transition to an independent investigator specializing in the field of metabolically active tissue crosstalk in the context of obesity. Furthermore, the outstanding resources provided by UT Southwestern Medical Center will maximize the potential for the applicant to fulfill the career objectives in identifying novel mechanisms underlying pathogenesis of obesity and new therapeutics treating obesity. Combined, together with longstanding interest and established ability of the applicant in studying adipose tissue biology, excellent mentorship from internationally recognized leaders in the metabolism field, and unparalleled environment at UT Southwestern, this K01 career development award will be essential for the applicant to receive additional training in brown adipose biology, neuronal regulation of browning activity, proteomics based secreting factor identification, and therapeutic discovery, thereby fully supporting a successful transition to independence for the applicant.