Healthy Remodeling of Obese Adipose Tissue

肥胖已达到流行病的程度，导致多种代谢疾病急剧增加，而目前尚无有效的治疗方法。脂肪（AT）是一种动态组织，能够响应大量效应器而显着改变其整体形态（重塑）。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，其中包括纤维化。在人类中，纤维化是肥胖的一个标志，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相一致。多种药理学和天然药物可以诱导 AT 的广泛重塑，其中包括将棕色样脂肪细胞（米色）募集到白色脂肪组织 (WAT)。这种褐变过程被认为是有益的，因为它有助于增加能量消耗，从而减少异位脂肪沉积并增强胰岛素敏感性。最近的研究表明，长期肥胖和纤维化的 WAT 会损害褐变。为了使褐变成为治疗肥胖相关疾病的策略，我们需要能够在肥胖个体中诱导褐变。一种策略是针对抑制纤维化的途径，同时增强肥胖期间米色脂肪细胞的形成。我们最近报道心肌素相关转录因子 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 褐变，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力。 MRTFA 也是其他组织（包括肝脏和心脏）中肌成纤维细胞（ECM 产生细胞）激活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，因此米色脂肪细胞的扩张很可能在 AT 纤维化中直接受到损害。因此，我们建议抑制 AT 中 MRTFA 活性的效应子是开发肥胖疗法的潜在目标。我们的总体假设提出，血管祖细胞中 MRTFA 的缺失将限制纤维化并使肥胖 AT 对褐变效应子敏感。我们提出四个目标来检验这一假设： 1. 确定 WT 和 MRTFA–/– WAT 血管祖细胞对饮食和褐变的反应的命运。 2. MRTFA 的药理学抑制是否调节壁细胞的命运并增强 WAT 褐变？ 3. 确定MRTFA 调节AT 壁细胞命运的机制。 4. 仅在壁祖细胞中缺失 MRTFA 是否会增强 WAT 的褐变并保护小鼠免受肥胖期间饮食诱导的纤维化？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，从而增进我们对如何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.