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，这极大地促进了肥胖症的流行。 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。 为了解决这一重大公共卫生威胁，已经部署了大量资源，事实是， 只制定了有限的干预办法。深入了解其发病机制 迫切需要找到更有效的治疗肥胖的方法。本K 01的总体目标 一项提案是调查肥胖症发病的两个主要参与者，白色和棕色人种之间的相互影响 脂肪组织，并鉴定介导白色脂肪-棕色脂肪通讯的新因子。申请人 最近已经确定淀粉样前体蛋白（APP）在白色脂肪中的过度表达及其随后的 错误地进入线粒体会引起线粒体功能障碍，从而促进肥胖， 胰岛素抵抗从这个独特的APP诱导的线粒体损伤模型中获得的初步数据显示， 白色脂肪中的线粒体损伤诱导棕色脂肪中的“变白”表型，相反，棕色脂肪- 特定的线粒体损伤导致白色脂肪的“布朗宁”。因此，本提案旨在测试 中心假设：1）APP诱导的线粒体损伤是白色/棕色脂肪的中心决定因素 相互交流; 2）白色/棕色脂肪相互交流涉及尚未识别的信号; 3）白色/棕色 脂肪相互作用影响全身代谢。在目标1中，白色或棕色脂肪特异性过表达或 APP小鼠模型的缺失将进行代谢表征和机理研究。在 目标2，将进行多层无偏策略，以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，这些因素被预测会发挥重要作用。 肥胖或抗肥胖作用。同时，作为职业发展奖，该提案还概述了 为申请人提供一个综合培训和研究计划，以完成 Philipp E.博士的指导。谢勒和乔尔·K.埃尔姆奎斯特，随后过渡到一个独立的 他是肥胖症背景下代谢活性组织串扰领域的专门研究者。 此外，UT西南医学中心提供的优秀资源将最大限度地提高 潜在的申请人，以实现职业目标，在确定新的机制， 肥胖症的发病机制和治疗肥胖症的新疗法。结合长期以来的兴趣 并建立了申请人在研究脂肪组织生物学的能力，优秀的导师， 国际公认的代谢领域的领导者，在UT西南无与伦比的环境， 这个K 01职业发展奖对于申请人接受布朗的额外培训至关重要 脂肪生物学、布朗宁活性的神经元调节、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.