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

脂肪细胞线粒体窘迫驱动白色和棕色脂肪组织之间的相互交流

基本信息

批准号：
10213402
负责人：
Yu An
金额：
$ 12.28万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10213402
关键词：
Academic Training Adipocytes Adipose tissue Adult Affect American Amyloid Beta A4 Precursor Protein Amyloid beta-Protein Precursor Area Biochemical Biology Brain Brown Fat Cardiovascular Diseases Communication Conditioned Culture Media Data Disease Distress Endocrine Energy Metabolism Environment Event Fatty acid glycerol esters Goals Grant Histologic Homeostasis Hormonal In Vitro Insulin Resistance International Intervention Investigation K-Series Research Career Programs Knowledge Life Link Liver Maintenance Malignant Neoplasms Mediating Medical center Mentors Mentorship Metabolic Metabolic Diseases Metabolism Methods Mitochondria Modeling Mus Neurons Non-Insulin-Dependent Diabetes Mellitus Obesity Organ Pathogenesis Perfusion Phenotype Physiological Physiology Predictive Factor Prevalence Protein Overexpression Proteomics Public Health Publishing Regulation Research Research Personnel Resources Role Signal Transduction Skeletal Muscle Sympathetic Nervous System Temperature Testing Therapeutic Tissues Training Transgenic Mice United States adipocyte differentiation adipokines base career comorbidity driving force glucose metabolism in silico in vivo insight interest mitochondrial dysfunction mouse model novel novel therapeutics obesity treatment obesogenic overexpression response therapeutic target therapeutically effective transcriptome

项目摘要

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.

项目摘要/摘要美国三分之一的美国成年人患有肥胖症，这极大地导致了许多其他威胁生命的疾病，例如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主要公共卫生威胁，事实是目前仅开发了有限的干预方式。深入了解迫切需要肥胖以促进寻找更有效的治疗剂。这个K01的总体目标提案是调查肥胖症，白色和棕色的两个主要参与者之间的串扰脂肪组织，并确定介导白脂褐色脂肪通讯的新因素。申请人最近已经确定白脂肪中淀粉样蛋白前体蛋白（APP）的过表达及其随后错位到线粒体中会引起戏剧性的线粒体功能障碍，从而促进肥胖和胰岛素抵抗。从这个独特的应用程序引起的线粒体遇险模型显示的初步数据显示白色脂肪中的线粒体困扰会引起棕色脂肪的“美白”表型，相反，棕色脂肪特定的线粒体遇险会导致白脂肪中的“褐变”。因此，该提案是为了测试中央假设：1）APP诱导的线粒体遇险是白色/棕色脂肪的中心决定者间交流； 2）白/棕色脂肪间歇性涉及尚未识别的信号； 3）白色/棕色脂肪互通会影响系统性代谢。在AIM 1中，白色或棕色脂肪特异性的过表达或 APP鼠标模型的删除将受到代谢特征和机理研究的约束。在 AIM 2，将进行多层公正策略，以发现神经元或激素因素充当白脂肪和棕色脂肪之间的信号，预计这些因素将执行重要肥胖或抗肥大作用。同时，作为职业发展奖，该提议也概述了申请人综合培训和研究计划，旨在完成根据 Philipp E. Scherer博士和Joel K. Elmquist博士的Menorship，确保过渡到独立在肥胖症的背景下，专门研究代谢活性组织串扰的领域。此外，UT西南医学中心提供的未偿还资源将最大化申请人实现职业目标的潜力肥胖症和新疗法的发病机理治疗肥胖症。结合在一起，长期以来兴趣并确定了应用在研究脂肪组织生物学的能力，来自国际公认的新陈代谢领域，以及UT西南部无与伦比的环境，该K01职业发展奖对于申请人接受Brown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和治疗发现，从而充分支持成功过渡到申请人的独立性。