miR-27 mediated regulation of mitochondrial function in thermogenic adipocytes

miR-27介导的产热脂肪细胞线粒体功能调节

• 批准号: 10630240
• 负责人: Aaron Clifford Brown
• 金额: $ 43万
• 依托单位: MAINEHEALTH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-16 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10630240
• 关键词: Ablation; Adipocytes; Adipose tissue; Alleles; Autophagocytosis; Biogenesis; Biological Assay; Body Temperature; Body Weight decreased; Burn injury; Cardiovascular Diseases; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Data; Diet; Disease; Economic Burden; Electron Transport; Energy Metabolism; Excision; Fatty acid glycerol esters; Genes; Genetic; Genus Hippocampus; Goals; Healthcare Systems; Heart Diseases; High Fat Diet; Homeostasis; Homologous Gene; Human; Hypertrophy; Impairment; In Vitro; Inflammation; Intervention; Knock-out; Link; Lipids; Measures; Mediating; Metabolic; Metabolic dysfunction; Metabolism; MicroRNAs; Mitochondria; Mitochondrial Proteins; Modeling; Molecular; Mus; Mutant Strains Mice; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity Epidemic; Obesity associated disease; Pathway interactions; Phenocopy; Phenotype; Polyribosomes; Process; Production; Public Health; Regulation; Reporter; Research; Resistance; Respiration; Rewarming; Risk; Role; Stimulus; Stroke; System; Technology; Temperature; Testing; Therapeutic; Thermogenesis; Tissues; Up-Regulation; Weight Gain; Weight maintenance regimen; adipocyte differentiation; adipose derived stem cell; blood glucose regulation; comorbidity; cost; diet-induced obesity; dosage; energy balance; exosome; fighting; improved; in vivo; induced pluripotent stem cell; inhibitor; lipid biosynthesis; mouse model; nanoparticle; novel; novel therapeutics; obesity development; overexpression; paralogous gene; response; stem cell differentiation; therapy development; tool; transcription factor

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.

项目摘要/摘要 肥胖流行是一个全球公共卫生问题，导致2型糖尿病的风险增加 心血管疾病。白色脂肪细胞中的肥大，炎症和过量的脂质积累 脂肪组织是肥胖的标志，导致代谢功能障碍。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（热生成） 刺激，例如冷暴露。该活性与对饮食诱发的肥胖性的抗性有关，因此 米色脂肪细胞的激活和膨胀可以抵消肥胖表型。在米色脂肪细胞中 激活，最佳的热功能是通过平衡线粒体生物发生与自噬 - 介导的线粒体降解（线粒体），该降解很好地协调以维持线粒体 稳态。使用我们新开发的米色脂肪细胞分化模型和人类激活 IPS细胞，我们发现米色脂肪细胞的热激活发生在增强的分泌后 包含各种microRNA（miR）的外泌体的粒子，包括miR-27a/b。 miR-27同源物（miR-27a/b） 是抑制参与线粒体生物发生（例如FOXJ3）和 线粒体（包括MFF）。在热激活过程中，miR-27a/b在米色脂肪细胞中下调， 与它们作为线粒体激活，周转和生物发生的抑制剂的预测作用一致。这 项目测试与米色脂肪细胞激活机制有关的几种假设。我们建议 miR-27通过靶向FOXJ3和MFF抑制脂肪细胞的热发生以及miR-27a/b的损失和 FOXJ3/MFF介导的途径的增加激活了线粒体活性和热发生。我们也是 提出，miR-27a/b的体内遗传靶向将使我们能够识别这些miR的体内作用 米色脂肪细胞激活，线粒体蛋白的调节，热生成和对肥胖的抗性。 这些问题将以两个重点的特定目的进行测试： 具体目的1。确定miR-27米色脂肪细胞线粒体功能的机理。 具体目标2。确定miR-27抑制对米色脂肪组织对 温度挑战和高脂饮食。 这些研究有望确定新的分子机制，这些机制可能为您提供一个新的平台 增加米色脂肪形成并反向肥胖相关疾病。