Healthy Remodeling of Obese Adipose Tissue

肥胖已经达到了流行病的比例，导致几种代谢疾病的急剧增加，对此没有有效的治疗方法。脂肪（AT）是一种动态的组织，能够显着改变其整体形态（重塑），以响应主机的效应。这些动态事件可以重塑组织，使其既有益又有害。肥胖AT经历广泛的重塑，包括纤维化。在人类中，纤维化是肥胖的标志，与炎症密切相关。AT的重塑也可能是有益的，并且与增强胰岛素敏感性和减少炎症的条件一致。多种药理学和天然试剂可诱导AT的广泛重塑，包括棕色样脂肪细胞（米色）向白色脂肪组织（WAT）的募集。这种布朗宁过程被认为是有益的，因为它有助于增加能量消耗，导致异位脂肪沉积减少和胰岛素敏感性增强。最近的研究表明，布朗宁在慢性肥胖和纤维化WAT中受到损害。为了使布朗宁成为治疗肥胖相关疾病的一种策略，我们需要能够在肥胖个体中诱导它。一种策略是靶向抑制纤维化的途径，同时增强肥胖期间米色脂肪细胞的形成。我们最近报道了心肌蛋白相关转录因子A（MRTFA）调节血管祖细胞向米色脂肪细胞的转化。事实上，我们报道了MRTFA整体缺失的小鼠具有广泛的WAT布朗宁，并且对短期饮食诱导的肥胖（DIO）及其相关的胰岛素抵抗具有抵抗性。MRTFA也是包括肝脏和心脏在内的其他组织中肌成纤维细胞（ECM产生细胞）活化和纤维化的已知调节剂。由于MRTFA似乎调节血管祖细胞向米色脂肪细胞和肌成纤维细胞的命运，因此米色脂肪细胞扩增很可能在AT纤维化中直接受损。因此，我们认为抑制AT中MRTFA活性的效应物是开发肥胖治疗剂的潜在靶点。我们的总体假设是，血管祖细胞中MRTFA的缺失将限制纤维化并使肥胖AT对布朗宁效应物敏感。我们提出了四个目标来检验这一假设：1。确定WT和MRTFA-/- WAT血管祖细胞响应饮食和布朗宁的命运。2.药物抑制MRTFA是否调节壁细胞的命运并增强WAT布朗宁？3.确定MRTFA调节AT壁细胞命运的机制。4.在壁祖细胞中缺失MRTFA是否会增强WAT的布朗宁并保护小鼠在肥胖期间免受饮食诱导的纤维化？这些目标的成功完成将为调节米色AT形成的途径提供新的见解，从而推进我们对如何治疗性靶向脂肪组织治疗人类肥胖症的理解。

Obesity has reached pandemic proportions contributing to the dramatic increases in several metabolic diseases, for which there is no effective therapy. Adipose (AT) is a dynamic tissue capable of dramatically changing its overall morphology (remodeling) in response to a host of effectors. These dynamic events can remodel the tissue to be both beneficial as well as harmful. Obese AT undergoes extensive remodeling, which includes fibrosis. In humans, fibrosis is a hallmark of obesity that is tightly associated with inflammation. Remodeling of AT can also be beneficial and coincide with conditions that enhance insulin sensitivity and reduce inflammation. A variety of pharmacological and natural agents can induce extensive remodeling of AT, which include recruitment of brown-like adipocytes (beige) to white adipose tissues (WAT). This browning process is considered to be beneficial because it contributes to an increase in energy expenditure resulting in decreased ectopic fat deposition and enhanced insulin sensitivity. Recent studies suggest that browning is compromised in chronically obese and fibrotic WAT. For browning to be a strategy to treat obesity-associated disorders, we need to be able to induce it in obese individuals. A strategy is to target pathways that inhibit fibrosis while enhancing beige adipocyte formation during obesity. We recently reported that myocardin related transcription factor A (MRTFA), regulates conversion of vascular progenitors to beige adipocytes. In fact, we reported that mice with a global deletion of MRTFA have extensive WAT browning and are resistant to short-term diet-induced obesity (DIO) and its associated insulin resistance. MRTFA is also a known regulator of myofibroblast (ECM producing cells) activation and fibrosis in other tissues including liver and heart. Since MRTFA appears to regulate the fate of vascular progenitors to beige adipocytes and myofibroblasts, it is very possible that beige adipocyte expansion is directly compromised in AT fibrosis. We suggest, therefore, that effectors that suppress MRTFA activity in AT are potential targets for development of obesity therapeutics. Our overall hypothesis proposes that deletion of MRTFA in vascular progenitors will limit fibrosis and sensitize obese AT to browning effectors. We propose four aims to test this hypothesis: 1. Determine the fate of WT and MRTFA–/– WAT vascular progenitors in response to diet and browning. 2. Does pharmacological inhibition of MRTFA regulate the fate of mural cells and enhance WAT browning? 3. Identify the mechanisms by which MRTFA regulates the fate of AT mural cells. 4. Does deletion of MRTFA exclusively in mural progenitors enhance browning of WAT and protect mice from diet-induced fibrosis during obesity? The successful completion of these aims will provide novel insights into pathways that regulate beige AT formation, thus advancing our understanding of how to therapeutically target adipose tissues for the treatment of human obesity.