Role of energy metabolism in the brown fat program

 描述（由申请人提供）：我们提出线粒体呼吸是氧化和产热基因表达的有效转录调节因子。该提案将定义这种转录控制的生物相关性，线粒体使用的信号控制转录和随后的细胞核中的转录事件，调节氧化和产热基因表达。由于其脂肪燃烧能力，棕色/米色脂肪组织（以下称为棕色脂肪）可能被证明在控制肥胖和2型糖尿病方面有希望。在脂质氧化的推动下，线粒体是热引擎，通过诱导和激活氧化和产热基因程序来利用解偶联呼吸。在热中性条件下，棕色脂肪采取脂质储存表型，但当被冷或β-激动剂激活时，它采取产热表型。控制这两种代谢状态的转录途径正在进行深入研究，以确定适合治疗应用的新途径。从生物化学的角度来看，线粒体呼吸在决定棕色脂肪的代谢状态中起着至关重要的作用。我们的初步数据显示 线粒体呼吸的作用远远超出了生化代谢控制。我们推测，线粒体呼吸能力的状态控制氧化和产热基因的转录。具体来说，我们建议，呼吸能力受损是一个转录检查点的氧化和产热基因表达，而增加呼吸能力是一个转录触发。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。由于线粒体信号的扰动可能会有所不同，这取决于线粒体呼吸如何受损，我们的研究结果可以解释为什么一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。两个具体目标将检验我们的假设：（1）确定线粒体呼吸能力在氧化和产热基因控制中的生物学和治疗意义;（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。

 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.