miR-27 mediated regulation of mitochondrial function in thermogenic adipocytes

项目总结/摘要 肥胖流行是一个全球性的公共卫生问题，导致2型糖尿病的风险增加， 心血管疾病内白色脂肪细胞的肥大、炎症和过量脂质积聚 脂肪组织是导致代谢功能障碍的肥胖症的标志。与白色脂肪细胞不同，米色 脂肪细胞富含线粒体，并消耗能量以产生热量（产热），以响应 刺激，如冷暴露。这种活动与抵抗饮食诱导的肥胖有关，因此 米色脂肪细胞的活化和扩增可以抵消肥胖表型。在米色脂肪细胞 激活时，通过平衡线粒体生物合成与自噬来维持最佳产热功能， 介导的线粒体降解（线粒体自噬），这是精细协调，以维持线粒体 体内平衡使用我们新开发的米色脂肪细胞分化和激活的模型， iPS细胞，我们发现米色脂肪细胞的产热激活发生在分泌增强后， 含有多种microRNA（miR）的外泌体，包括miR-27 a/B。miR-27同源物（miR-27 a/B） 是抑制参与线粒体生物发生的基因（如FOXJ 3）的抗产热miR， 线粒体自噬（包括MFF）。miR-27 a/B在产热激活过程中在米色脂肪细胞中下调， 这与它们作为线粒体活化、周转和生物发生的抑制剂的预测作用一致。这 该项目测试了与米色脂肪细胞激活机制相关的几个假设。我们建议 miR-27通过靶向FOXJ 3和MFF抑制脂肪细胞产热，miR-27 a/B和miR-27 b/MFF的缺失可导致脂肪细胞产热减少。 FOXJ 3/MFF介导途径增加激活线粒体活性和产热。我们也 我们提出miR-27 a/B的体内遗传靶向将使我们能够鉴定这些miR在体内的作用， 米色脂肪细胞活化、线粒体蛋白调节、产热和抗肥胖。 这些问题将在两个有重点的具体目标中进行测试： 具体目标1。确定miR-27调节米色脂肪细胞线粒体功能的机制。 具体目标2。确定miR-27抑制对米色脂肪组织对miR-27的应答的影响。 温度挑战和高脂肪饮食。 这些研究有望发现新的分子机制，为研究 增加米色脂肪生成并逆转肥胖相关疾病。

Project Summary/Abstract The obesity epidemic is a global public health issue, that leads to an increased risk for type 2 diabetes and cardiovascular disease. Hypertrophy, inflammation, and excess lipid accumulation in white adipocytes within fat tissue are hallmarks of obesity that contribute to metabolic dysfunction. Unlike white adipocytes, beige adipocytes are rich in mitochondria, and expend energy to generate heat (thermogenesis) in response to stimuli such as cold exposure. This activity is associated with resistance to diet-induced obesity, and thus activation and expansion of beige adipocytes can counteract the obesity phenotype. During beige adipocyte activation, optimal thermogenic function is maintained by balancing mitochondrial biogenesis with autophagy- mediated mitochondrial degradation (mitophagy), which is finely coordinated to maintain mitochondrial homeostasis. Using our newly developed model of beige adipocyte differentiation and activation from human iPS cells, we discovered that thermogenic activation of beige adipocytes occurs following enhanced secretion of exosomes containing a variety of microRNAs (miRs), including miR-27a/b. miR-27 homologs (miR-27a/b) are anti-thermogenic miRs that suppress genes involved in mitochondrial biogenesis (such as FOXJ3) and mitophagy (including MFF). miR-27a/b are down-regulated in beige adipocytes during thermogenic activation, consistent with their predicted role as inhibitors of mitochondrial activation, turnover, and biogenesis. This project tests several hypotheses related to mechanisms of beige adipocyte activation. We propose that the miR-27 suppresses adipocyte thermogenesis by targeting FOXJ3 and MFF and that loss of miR-27a/b and increase in FOXJ3/MFF-mediated pathways activate mitochondrial activity and thermogenesis. We also propose that in vivo genetic targeting of miR-27a/b will allow us to identify the in vivo role of these miRs in beige adipocyte activation, regulation of mitochondrial proteins, thermogenesis and resistance to obesity. These questions will be tested in two focused specific aims: Specific Aim 1. Identify the mechanism of miR-27 regulation of beige adipocyte mitochondrial function. Specific Aim 2. Determine the effect of miR-27 suppression on the response of beige adipose tissue to temperature challenge and high-fat diet. These studies are expected to identify novel molecular mechanisms that may provide a new platform to increase beige adipogenesis and reverse obesity-related disorders.