The short isoform of PGC-1alpha in the control of brown adipose tissue thermogenesis

PGC-1α 短亚型控制棕色脂肪组织生热作用

• 批准号: 9043057
• 负责人: Ji Suk Chang
• 金额: $ 33.3万
• 依托单位: LSU PENNINGTON BIOMEDICAL RESEARCH CTR
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9043057
• 关键词: Acetylation; Adipocytes; Adipose tissue; Adrenergic Agents; Adrenergic Agonists; Adult; Age; Alternative Splicing; Biogenesis; Body fat; Brown Fat; Cardiovascular Diseases; Cell Nucleus; Complex; DNA; Deacetylase; Deacetylation; Dyslipidemias; Electron Transport; Energy Metabolism; Epidemic; Fatty acid glycerol esters; Gene Expression; Genes; Genetic Transcription; Health; Heating; Human; Mediating; Metabolic Diseases; Mitochondria; Mitochondrial DNA; Molecular Genetics; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nuclear; Nucleic Acid Regulatory Sequences; Obesity; Outcome Study; Play; Process; Protein Isoforms; Recruitment Activity; Regulation; Research; Research Project Grants; Respiration; Respiratory physiology; Rodent; Role; Stress; System; Testing; Thermogenesis; Transcription Coactivator; Transcriptional Regulation; Translations; Work; base; global health; in vivo; insight; mitochondrial genome; mitochondrial uncoupling protein; natural hypothermia; new therapeutic target; novel; oxidation; respiratory; response; uncoupling protein 1

 DESCRIPTION (provided by applicant): Obesity is a global health epidemic associated with metabolic disorders such as type 2 diabetes. While white adipose tissue accumulates fat as energy storage, brown adipose tissue (BAT) dissipates energy as heat by mitochondrial uncoupling protein 1 (UCP1). Studies in rodents have shown that activation of non-shivering thermogenesis in BAT increases energy expenditure and protects against obesity. Adult humans also have functional BAT whose thermogenic capacity increases with cold exposure and decreases with age and body fat mass, suggesting that activation of BAT might be useful for treating human obesity. Efficient mitochondrial respiration through the electron transport chain (ETC) is essential for BAT thermogenesis since it provides the energy required for UCP1-mediated heat production. The ETC consists of four large multisubunit complexes (I- IV). The majority of ETC complex subunits are encoded by nuclear DNA and are imported into mitochondria, but 11 essential subunits of ETC complexes I, III, and IV are encoded by mitochondrial DNA (mtDNA). Thus, coordinated regulation of nuclear and mitochondrial genomes in response to cold is critically important for the biogenesis of functional ETC complexes. Although the basal transcription machinery of mitochondria has been identified and characterized, the regulatory mechanisms involved in mitochondrial gene expression remains an open question. We recently discovered a short isoform of PGC-1a (designated NT-PGC-1a) that is produced by alternative splicing of the PGC-1a gene. NT-PGC-1a is a functional transcriptional coactivator and its expression is highly induced by cold in BAT. Cold-induced NT-PGC-1a translocates to the nucleus and drives the expression of UCP1 and a number of mitochondrial genes. Surprisingly, while PGC-1a resides in the nucleus, a small fraction of NT-PGC-1a localizes to mitochondria and is recruited to the mtDNA, raising the possibility that mitochondrial NT-PGC-1a directly regulates mtDNA transcription to increase mtDNA-encoded ETC gene expression in response to cold. In this research project, we aim to test our hypothesis that simultaneous localization of NT-PGC-1a in both nucleus and mitochondria is the mechanism that coordinates nuclear and mitochondrial gene expression, contributing to cold-induced mitochondrial adaptation and thermogenesis. Aim 1 is to evaluate the role of NT-PGC-1a in the regulation of mtDNA transcription. Aim 2 is to determine the mechanism by which NT-PGC-1a activity is increased in the nucleus and mitochondria during cold stress. Aim 3 is to evaluate the effects of NT-PGC-1a deletion on mitochondrial respiratory activity and adaptive thermogenesis in vivo. This research will uncover the previously unappreciated role of NT-PGC-1a in regulating mitochondrial transcription in brown adipocytes and will highlight the importance of this process for adaptive thermogenesis and energy expenditure in BAT.

 描述（由适用提供）：肥胖是与代谢疾病（例如2型糖尿病）相关的全球健康流行病。白色脂肪组织会积聚脂肪作为能量储存，而棕色脂肪组织（BAT）则通过线粒体解偶联蛋白1（UCP1）散发能量作为热量。对啮齿动物的研究表明，蝙蝠中不动的热发生的激活会增加能量消耗并预防肥胖。成年人还具有功能性的蝙蝠，其热能能力随着冷暴露而增加，并且随着年龄和体内脂肪量的减少，这表明BAT的激活可能对治疗人类肥胖可能有用。通过电子传输链（ETC）进行有效的线粒体呼吸对于BAT热生成至关重要，因为它为UCP1介导的热量产生提供了所需的能量。 ETC由四个大型多育种复合物（I-IV）组成。大多数ETC复杂亚基由核DNA编码，并进口到线粒体中，但是11个ETC复合物I，III和IV的基本亚基由线粒体DNA（mtDNA）编码。这对于响应感冒的核和线粒体基因组的协调调节对于功能等复合物的生物发生至关重要。尽管已经鉴定出和表征了线粒体的基本转录机制，但与线粒体基因表达相关的调节机制仍然是一个悬而未决的问题。我们最近发现了通过PGC-1A基因的替代剪接产生的PGC-1A（指定NT-PGC-1A）的短同工型。 NT-PGC-1A是一种功能转录共激活因子，其表达是由蝙蝠中的冷诱导的。冷诱导的NT-PGC-1A易位到核，并驱动UCP1和许多线粒体基因的表达。令人惊讶的是，虽然PGC-1A居住在核us中，但一小部分NT-PGC-1A本地定位于线粒体并被募集到mtDNA中，从而提高了线粒体NT-PGC-1A直接调节mtDNA转录以增加mtdna coded Gene fene for Cold forncy for Cold的可能性。在这项研究项目中，我们旨在检验假设，即在核和线粒体中NT-PGC-1A的简单定位是协调核和线粒体基因表达的机制，有助于冷诱导的线粒体适应和热生成。目的1是评估NT-PGC-1A在MTDNA转录调节中的作用。目标2是确定在冷应激期间核和线粒体中NT-PGC-1A活性增加的机制。目标3是评估NT-PGC-1A缺失对体内线粒体呼吸活性和适应性热发生的影响。这项研究将揭示NT-PGC-1A先前未批准的作用在棕色脂肪细胞中的线粒体转录中，并将强调这一过程对于BAT中的自适应热生成和能量消耗的重要性。