Regulation of Mitochondrial Remodeling in Adipose Thermogenesis

项目摘要 肥胖症的全球流行对与慢性疾病风险相关的人类健康构成了巨大挑战。 如2型糖尿病和心血管疾病。肥胖是由系统性能量过剩驱动的 在白色脂肪细胞（WA）中存在过量脂肪沉积。棕色脂肪细胞（BAs）专门用于 通过非颤抖性产热和增加能量消耗来消耗能量， 肥胖症治疗的潜在治疗靶点。然而，在充分利用知识方面存在着严重的知识差距。 了解BA功能的分子机制。因此，我们的长期目标是探索 BAs的新分子调控，以促进治疗策略的发展， 肥胖通过进行定量线粒体蛋白质组学，我们最近确定了具有序列的家族， 相似性210，成员A（FAM 210 A），一种未表征的蛋白质，作为产热的关键调节因子， 棕色脂肪组织（BAT）。新的研究报道了FAM 210 A在调节骨骼肌中的潜在作用。 肌肉生长和病理性心脏重塑，然而FAM 210 A在产热性BA中的功能是 完全未知使用新开发的Fam 210 a floxed小鼠，我们提供了强有力的初步数据， 支持FAM 210 A在BAT产热中的重要生理作用。我们发现，1）FAM 210 A是 冷诱导的线粒体嵴重构; 2）脂肪细胞特异性 Fam 210 a基因敲除（KO）导致BAT白化和耐寒; 3）Fam 210 a基因缺失 导致BAT的代谢功能障碍; 4）Fam 210 a KO诱导线粒体的消耗和线粒体的破坏。 嵴状结构基于这一令人兴奋的发现，这项研究的总体目标是阐明 FAM 210 A在BA中发挥作用以调节产热的细胞和分子机制，以及 研究脂肪FAM 210 A在全身代谢中的生理作用。为了实现这一目标，我们 提出三个具体目标。在目的1中，使用小鼠和脂肪细胞中Fam 210 a可诱导缺失的细胞， 我们将评估FAM 210 A在线粒体代谢、合成和降解中的调节作用， 体内和体外BA。采用高分辨率三维成像系统，我们将解剖 FAM 210 A在控制冷诱导的嵴膜重塑中的功能。在目标2中，我们将定义 FAM 210 A调节线粒体稳态和嵴重塑的分子机制 通过鉴定和表征相互作用的蛋白质伴侣， 嵴形成蛋白的调节。在目标3中，我们将使用我们独特的功能丧失和功能获得鼠标 模型，以测试是否需要FAM 210 A，并足以增加能量消耗和系统 从而改善饮食诱导的肥胖和代谢功能障碍。完成后 通过这些研究，我们希望建立FAM 210 A作为线粒体膜电位的一种新的调节因子的功能作用。 动力学和BA产热，从而确定了肥胖流行病的新的潜在治疗靶点。

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.