Role of energy metabolism in the brown fat program

能量代谢在棕色脂肪计划中的作用

基本信息

批准号：
9135635
负责人：
John Francis Keaney
金额：
$ 16.75万
依托单位：
UNIV OF MASSACHUSETTS MED SCH WORCESTER
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-15 至 2017-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9135635
关键词：
Ablation Adipocytes Adipose tissue Adopted Adrenergic Agents Agonist Binding Biochemical Biological Brown Fat Burn injury Calcium Calories Cell Nucleus Cell Respiration Cells Complex Data Defect Diabetes Mellitus Diet Ectopic Expression Electron Microscopy Energy Metabolism Event Fatty acid glycerol esters Food Gene Expression Genes Genetic Genetic Transcription Health Heating Homeostasis Housing Human Image Immunoblotting In Situ Insulin Resistance Lipids Metabolic Metabolic Control Microscopy Mitochondria Mitochondrial Proteins Molecular Mus Non-Insulin-Dependent Diabetes Mellitus Nuclear Obesity PPARG gene Pathway interactions Phenotype Play Resolution Respiration Role Signal Transduction Slice Specificity Sucrose Testing Therapeutic Thermogenesis Time Transcriptional Regulation adrenergic base feeding fight against inhibitor/antagonist innovation novel oxidation programs promoter respiratory transcription factor two-photon

项目摘要

DESCRIPTION (provided by applicant): We propose that mitochondrial respiration is a potent transcriptional regulator of oxidative and thermogenic genes expression. This proposal will define the biological relevance of this transcriptional control, the signals that mitochondria use o govern transcription and the subsequent transcriptional events in the nucleus that regulate oxidative and thermogenic gene expression. Due to its fat burning capacity, brown/beige adipose tissue (hereafter referred to as brown fat) may prove promising in controlling obesity and type 2 diabetes. Fueled by lipid oxidation, mitochondria are engines of heat that exploit uncoupled respiration via induction and activation of oxidative and thermogenic gene programs. Under thermoneutral conditions, brown fat adopts a lipid storage phenotype, but when activated by cold or beta-agonists, it adopts a thermogenic phenotype. The transcriptional pathways that govern these two metabolic states are under intense study in order to identify novel pathways amenable to therapeutic application. From a biochemical perspective, mitochondrial respiration plays a crucial role in determining the metabolic state of brown fat. Our preliminary data indicate that the role of mitochondrial respiration extends well beyond biochemical metabolic control. We hypothesize that the status of mitochondrial respiratory capacity governs transcription of oxidative and thermogenic genes. Specifically, we propose that impaired respiratory capacity is a transcriptional checkpoint for oxidative and thermogenic gene expression, whereas increased respiratory capacity is a transcriptional trigger. Our preliminary data has also identified the signal that mitochondrial respiration uses to control nuclear transcription. Because perturbation of the mitochondrial signal may differ depending on how mitochondrial respiration is impaired, our findings may explain why some respiratory defects have differential effects on thermogenic gene expression. Finally, we have identified key transcription factors that are influenced by the mitochondrial signal. Two Specific Aims will test our hypothesis: (1) Determine the biological and therapeutic implications of mitochondrial respiratory capacity in oxidative and thermogenic gene control; (2) Determine how the mitochondrial respiratory checkpoint signals and dictates oxidative and thermogenic gene expression.

描述（由申请人提供）：我们提出线粒体呼吸是氧化和生热基因表达的有效转录调节剂。该提议将定义这种转录控制的生物学相关性、线粒体使用的信号来控制转录和随后的转录事件。由于其脂肪燃烧能力，棕色/米色脂肪组织（以下简称棕色脂肪）可能在控制肥胖和 2 型糖尿病方面具有前景。脂质氧化，线粒体是通过诱导和激活氧化和产热基因程序来利用非耦合呼吸的热引擎，在热中性条件下，棕色脂肪采用脂质储存表型，但当被冷或β-激动剂激活时，它采用产热表型。控制这两种代谢状态的转录途径正在深入研究，以便确定适合治疗应用的新途径。从生化角度来看，线粒体呼吸在确定棕色的代谢状态中起着至关重要的作用。我们的初步数据表明。线粒体呼吸的作用远远超出了生化代谢控制的范围，我们认为线粒体呼吸能力的状态控制着氧化和产热基因的转录，具体来说，我们认为受损的呼吸能力是氧化和产热基因表达的转录检查点。我们的初步数据还确定了线粒体呼吸用于控制核转录的信号，因为线粒体信号的扰动可能会根据线粒体呼吸受损的方式而有所不同。解释为什么某些呼吸缺陷对产热基因表达有不同的影响。最后，我们确定了受线粒体信号影响的关键转录因子，这两个具体目标将检验我们的假设：（1）确定线粒体呼吸能力的生物学和治疗意义。氧化和产热基因控制；（2）确定线粒体呼吸检查点如何发出信号并决定氧化和产热基因表达。