Regulation of Mitochondrial Remodeling in Adipose Thermogenesis

脂肪产热中线粒体重塑的调节

• 批准号: 10718432
• 负责人: Feng Yue
• 金额: $ 38.43万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2028-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10718432
• 关键词: Adipocytes; Adipose tissue; Animal Model; Architecture; Biochemical; Bioenergetics; Biogenesis; Biological Assay; Biology; Body Composition; Brown Fat; Cardiac; Cardiovascular Diseases; Cells; Chronic Disease; Complex; Consumption; Coupled; Crista ampullaris; Data; Dependovirus; Deposition; Energy Metabolism; Family; Fatty acid glycerol esters; Goals; Health; High Fat Diet; Histology; Homeostasis; Human; Immunoprecipitation; In Vitro; Inner mitochondrial membrane; Knock-out; Knockout Mice; Knowledge; Ligation; Link; Lipids; Liposomes; LoxP-flanked allele; Mediating; Membrane; Membrane Proteins; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Mitochondria; Mitochondrial DNA; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; OPA1 gene; Obese Mice; Obesity; Obesity Epidemic; Outcome; Pathologic; Pathway interactions; Phenotype; Physiological; Predisposition; Protein Family; Proteins; Proteomics; Regulation; Regulatory Pathway; Reporting; Resolution; Risk; Role; Series; Serology; Shapes; Signal Pathway; Symptoms; Testing; Thermogenesis; Three-Dimensional Imaging; Translations; associated symptom; cold stress; combat; diet-induced obesity; feeding; gain of function; glucose tolerance; imaging system; in vitro Assay; in vivo; insulin sensitivity; knock-down; loss of function; member; metabolomics; mitochondrial metabolism; mouse model; novel; obesity treatment; overexpression; prevent; protein reconstitution; skeletal muscle growth; spatiotemporal; therapeutic development; therapeutic target

PROJECT SUMMARY The global epidemic of obesity poses formidable challenges to human health associated with risks of chronic diseases such as type 2 diabetes and cardiovascular disease. Obesity is driven by systemic energy surplus with excessive fat deposition in white adipocytes (WAs). Brown adipocytes (BAs) that are specialized in dissipating energy through non-shivering thermogenesis and increasing energy expenditure represent a potential therapeutic target in obesity treatments. However, there is a critical knowledge gap in fully understanding the molecular mechanisms underlying BA function. Our long-term goal is therefore to explore the novel molecular regulation of BAs in order to facilitate the development of therapeutic strategies to combat obesity. By performing quantitative mitochondrial proteomics, we recently identified Family With Sequence Similarity 210, Member A (FAM210A), an uncharacterized protein, as a critical regulator of thermogenesis in brown adipose tissue (BAT). Emerging studies reported a potential role of FAM210A in regulating skeletal muscle growth and pathological cardiac remodeling, however the function of FAM210A in thermogenic BAs is completely unknown. Using newly developed Fam210a floxed mice, we provided strong preliminary data supporting an essential physiological role of FAM210A in BAT thermogenesis. We showed that 1) FAM210A is highly induced by cold and coupled with cold-induced mitochondrial cristae remodeling; 2) Adipocyte-specific knockout (KO) of Fam210a in mice leads to the whitening of BAT and cold intolerance; 3) Loss of Fam210a causes metabolic dysfunction of BAT; 4) Fam210a KO induces the depletion of mitochondria and disruption of cristae architecture. Based on this exciting discovery, the overall goal of this proposed study is to elucidate the cellular and molecular mechanisms by which FAM210A functions in BAs to regulate thermogenesis, and investigate the physiological role of adipose FAM210A in systemic metabolism. To achieve this goal, we propose three specific aims. In Aim 1, using mice and cells with inducible deletion of Fam210a in adipocytes, we will evaluate the regulatory role of FAM210A in mitochondrial metabolism, synthesis, and degradation in BAs in vivo and in vitro. Employing high-resolution three-dimensional imaging systems, we will dissect the function of FAM210A in controlling cold-induced cristae membrane remodeling. In Aim 2, we will define the molecular mechanisms through which FAM210A regulates mitochondrial homeostasis and cristae remodeling in BAs via the identification and characterization of interacting protein partners that enable FAM210A’s regulation of cristae-shaping protein. In Aim 3, we will utilize our unique loss- and gain-of-function mouse models to test whether FAM210A is required and sufficient to increase energy expenditure and systemic metabolism so as to ameliorate diet-induced obesity and metabolic dysfunction. Upon completion of the proposed studies, we expect to establish the functional role of FAM210A as a novel regulator of mitochondrial dynamics and BA thermogenesis, thus identifying a new potential therapeutic target for the obesity epidemic.

项目摘要 肥胖的全球流行病对与慢性风险有关的人类健康面临着巨大的挑战 诸如2型糖尿病和心血管疾病之类的疾病。肥胖是由全身能量盈余驱动的 白色脂肪细胞中的脂肪沉积过多（WAS）。专门从事的棕色脂肪细胞（BAS） 通过非动摇的热发生和增加能量消耗的能量代表 肥胖治疗中的潜在治疗靶点。但是，完全存在批判性的知识差距 了解BA功能的分子机制。因此，我们的长期目标是探索 BAS的新型分子调节，以促进对抗治疗策略的发展 肥胖。通过执行定量线粒体蛋白质组学，我们最近确定了序列的家族 相似性210，成员A（FAM210a），一种未表征的蛋白质，作为热生成的关键调节剂 棕色脂肪组织（蝙蝠）。新兴研究报告了FAM210a在调节骨骼中的潜在作用 肌肉生长和病理心脏重塑，但是FAM210a在热碱中的功能是 完全未知。使用新开发的FAM210A Floxed小鼠，我们提供了强大的初步数据 支持FAM210A在BAT热发生中的重要生理作用。我们表明1）FAM210A是 高度诱导冷诱导，并与冷诱导的线粒体Cristae重塑相结合； 2）特异性脂肪细胞 Fam210a在小鼠中的敲除（KO）导致蝙蝠和冷肠的美白； 3）FAM210A的损失 导致蝙蝠的代谢功能障碍； 4）FAM210A KO诱导线粒体的耗竭和破坏 Cristae建筑。基于这一令人兴奋的发现，这项拟议研究的总体目标是阐明 FAM210A在BAS中起作用以调节生热的机制和分子机制，并 研究脂肪FAM210a在系统性代谢中的身体作用。为了实现这一目标，我们 提案三个具体目标。在AIM 1中，使用脂肪细胞中FAM210a的小鼠和细胞， 我们将评估FAM210a在线粒体代谢，合成和降解中的调节作用 基于体内和体外。采用高分辨率的三维成像系统，我们将剖析 FAM210a在控制冷诱导的Cristae膜重塑方面的功能。在AIM 2中，我们将定义 FAM210A通过的分子机制调节线粒体稳态和CRISTAE重塑 通过识别和表征相互作用的蛋白质伴侣，使FAM210A的相互作用伙伴 调节Cristae形成蛋白。在AIM 3中，我们将利用我们独特的功能损失和功效鼠标 测试FAM210A是否需要且足以增加能量消耗和全身的模型 代谢，以改善饮食诱导的肥胖和代谢功能障碍。完成后 拟议的研究，我们希望建立FAM210a作为线粒体的新调节剂的功能作用 动力学和BA生热发生，从而确定了肥胖流行的新潜在治疗靶标。