Cellular mechanobiology and engineering of active brown adipose tissue

项目总结/摘要 迫切需要新技术来解决肥胖流行病及其相关后果， 包括II型糖尿病。通过扩张和激活棕色脂肪组织增加热量输出 (BAT)燃烧代谢燃料以产生热量，作为一种新的机制， 引发成年人的体重下降。然而，这种方法的技术翻译，包括工程 生物材料平台，以支持BAT在体外和体内，一直受到限制，因为缺乏了解如何 来自物理微环境的线索调节BAT激活。我们的初步数据暗示， 一种意想不到的模型，其中β-肾上腺素能（β-AR）刺激通过肌球蛋白触发BAT激活， 雅普/TAZ依赖性机械传导信号网络，最终增强热传导蛋白的表达。 产生线粒体蛋白UCP 1。这个模型有着深远的意义，因为它表明， 在微环境中结合机械提示可以用来激活BAT 并促进热量输出作为对抗肥胖的策略。因此，该提案的目标是批判性地 检验β-AR和机械传导信号共同刺激BAT激活的假设， 增强细胞呼吸。我们有三个目的：（1）解剖肌动球蛋白的机制， 张力急性激活BAT;（2）确定雅普/TAZ的机械激活如何调节表达 研究雅普/TAZ依赖性信号在白色/米色中的作用 脂肪命运测定。除了对信号事件的详细剖析外，我们的方法还具有 工程材料、机械刺激、先进的小鼠遗传模型 肌球蛋白激活蛋白的诱导表达，以及细胞和组织力学的测量。 这项工作的成功完成将大大推进我们对BAT的机械理解 激活，同时通知材料技术的设计，以刺激BAT激活，以减少肥胖。

PROJECT SUMMARY/ABSTRACT There is a dire need for new technologies to address the obesity epidemic and its associated sequellae, including Type II Diabetes. Increasing caloric output through expansion and activation of brown adipose tissue (BAT), which “burns” metabolic fuels to produce heat, is garnering increasing interest as a novel mechanism to trigger weight loss in adults. However, the technological translation of this approach, including the engineering of biomaterial platforms to support BAT in vitro and in vivo, has been limited by a poor understanding of how cues from the physical microenvironment regulate BAT activation. Our preliminary data hint at a novel and unexpected model in which beta-adrenergic (ß-AR) stimulation triggers BAT activation through a myosin- and YAP/TAZ-dependent mechanotransductive signaling network, ultimately enhancing expression of the heat- generating mitochondrial protein UCP1. This model has profound implications, because it would suggest that incorporation of mechanical cues within the microenvironment could be leveraged to activate BAT and promote caloric output as a strategy to combat obesity. Thus, the goal of this proposal is to critically test the hypothesis that ß-AR and mechanotransductive signaling collude to stimulate BAT activation and enhanced cellular respiration. We have three aims: (1) To dissect the mechanisms through which actomyosin tension acutely activates BAT; (2) To determine how mechanical activation of YAP/TAZ regulates expression of UCP1; and (3) To investigate the role of mechanosensitive YAP/TAZ-dependent signals in white/beige adipose fate determination. In addition to detailed dissection of signaling events, our approach features an innovative combination of engineered materials, mechanical stimulation, advanced mouse genetic models, inducible expression of myosin-activating proteins, and measurements of cell and tissue mechanics. Successful completion of this work would substantially advance our mechanistic understanding of BAT activation while informing the design of materials technologies to stimulate BAT activation to reduce obesity.