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

项目概要/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肥胖的流行 许多其他危及生命的疾病，如2型糖尿病、心血管疾病、癌症等。 已部署大量资源来解决这一重大公共卫生威胁，事实是，目前 仅制定了有限的干预方式。深入了解发病机制 迫切需要针对肥胖症寻找更有效的治疗方法。 K01 的总体目标 提议是调查肥胖发病的两个主要参与者——白人和棕色人种之间的相互影响 脂肪组织，并确定介导白色脂肪与棕色脂肪通讯的新因素。申请人 最近发现白色脂肪中淀粉样前体蛋白（APP）的过度表达及其后续 线粒体的错误定位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。从这个独特的 APP 诱导的线粒体窘迫模型获得的初步数据显示 白色脂肪中的线粒体窘迫会诱导棕色脂肪中的“美白”表型，相反，棕色脂肪 特定的线粒体窘迫会导致白色脂肪“褐变”。因此，提出这个建议是为了测试 中心假设：1) APP 诱导的线粒体窘迫是白色/棕色脂肪的核心决定因素 相互通讯； 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 脂肪互通影响全身代谢。在目标 1 中，白色或棕色脂肪特异性过度表达或 删除 APP 小鼠模型将进行代谢特征和机制研究。在 目标 2，将采取多层公正的策略来发现神经元或激素因素， 作为白色和棕色脂肪之间的沟通信号，这些因素预计将发挥重要作用 致肥胖或抗肥胖作用。同时，作为职业发展奖励，本提案还概述了 申请人完成进一步学术培训的综合培训和研究计划 在 Philipp E. Scherer 博士和 Joel K. Elmquist 博士的指导下，最终过渡为独立的 专门研究肥胖背景下代谢活跃组织串扰领域的研究人员。 此外，UT西南医学中心提供的优秀资源将最大限度地提高 申请人在识别潜在的新颖机制方面实现职业目标的潜力 肥胖的发病机制和治疗肥胖的新疗法。结合长期的兴趣 并建立了申请人研究脂肪组织生物学的能力，来自优秀的指导 代谢领域国际公认的领导者，以及德州大学西南分校无与伦比的环境， 该 K01 职业发展奖对于申请人接受棕色的额外培训至关重要 脂肪生物学、褐变活性的神经元调节、基于蛋白质组学的分泌因子鉴定，以及 治疗发现，从而全力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.