The Role of MRTFA in Adipose Tissue Remodeling

摘要 肥胖症的流行正在以惊人的速度加速，并导致2型肥胖症的发病率增加。 糖尿病。改变生活方式，如饮食和锻炼，并没有被证明是有效的减肥方法 代谢功能障碍；因此，需要新的疗法来治疗肥胖相关的疾病。据信， 脂肪组织向肝脏和肌肉的“溢出”是胰岛素抵抗的主要原因。 在肥胖方面。大量研究表明，肥胖的受试者表现出纤维化，血管生成减少， 炎症和脂肪细胞肥大，表明细胞外基质(ECM)在 在肥胖症的病理机制中的作用。ECM的功能是提供机械支持，但ECM会累积 在肥胖期纤维化的间质中，限制脂肪细胞的扩张并抑制血管生成 和成脂作用。了解脂肪组织重塑的机制和动力学 调节脂肪储存是一种耐人寻味的治疗策略。此外，鉴定肌成纤维细胞前体细胞 细胞，以减少它们在肥胖诱导的纤维化期间的积聚，可能具有治疗潜力。它 肌钙蛋白相关转录因子A(MRTFA)调节肌成纤维细胞的激活 和组织重塑；然而，它在脂肪组织纤维化中的作用尚不清楚。我们的数据显示MRTFA为空 小鼠免受饮食诱导的胰岛素抵抗，并减少了胶原基因的表达 脂肪组织。我们假设MRTFA介导脂肪组织重塑和纤维化，因此， 抑制MRTFA可能是一个潜在的治疗靶点，以促进脂质储存和健康扩张 脂肪组织。我们提出了以下三个目标来验证我们的假设，即不利的脂肪组织 重塑会导致代谢功能障碍。在目标1中，我们将确定SMA+肌成纤维细胞是否有助于 到脂肪组织纤维化中的富胶原细胞外基质。在目标2中，我们将确定MRTFA在 脂肪间充质干细胞中肌成纤维细胞的激活与脂肪组织重塑 与肥胖相关的纤维化。在目标3中，我们将确定肌成纤维细胞是否起源于血管 应用可诱导谱系示踪技术将祖细胞定位于间质纤维化 区域。对肥胖小鼠模型中脂肪组织重塑的全面研究将提供新的 对肥胖和纤维化进展的洞察。

Abstract The obesity epidemic is accelerating at an alarming rate and contributes to the increased incidence of type 2 diabetes. Lifestyle modifications, like diet and exercise, have not proven effective as methods to attenuate metabolic dysfunction; thus, new therapeutics are needed to treat obesity related disorders. It is believed that the `spillover' of lipids from adipose tissue into the liver and muscle is the primary etiology of insulin resistance in obesity. Numerous studies have shown obese human subjects exhibit fibrosis, decreased vascularization, inflammation, and hypertrophy of adipocytes, suggesting that the extracellular matrix (ECM) plays an important role in the pathology of obesity. The ECM functions to provide mechanical support, however ECM accumulates in the fibrotic interstitial space during obesity, limiting the expansion of adipocytes and inhibiting angiogenesis and adipogenesis. Understanding the mechanics and kinetics of adipose tissue remodeling in order to modulate lipid storage is an intriguing therapeutic strategy. Additionally, identifying myofibroblast progenitor cells in order to attenuate their accumulation during obesity-induced fibrosis may have therapeutic potential. It is well appreciated that myocardin-related transcription factor A (MRTFA) regulates myofibroblast activation and tissue remodeling; however, its role in adipose tissue fibrosis is not clear. Our data show that MRTFA null mice are protected from diet-induced insulin resistance and have decreased expression of collagen genes in adipose tissue. We hypothesize that MRTFA mediates adipose tissue remodeling and fibrosis and hence, inhibition of MRTFA may be a potential therapeutic target to facilitate lipid storage and the healthy expansion of adipose tissue. We propose the following three aims to test our hypothesis that adverse adipose tissue remodeling causes metabolic dysfunction. In Aim 1, we will determine whether SMA+ myofibroblasts contribute to the collagen-rich ECM in adipose tissue fibrosis. In Aim 2, we will determine the role of MRTFA in myofibroblast activation in adipose-derived mesenchymal stem cells and adipose tissue remodeling and fibrosis associated with obesity. In Aim 3, we will determine whether myofibroblasts originate from vascular smooth muscle-like cells using inducible lineage tracing technology to fate-map progenitors to interstitial fibrotic areas. A comprehensive study of adipose tissue remodeling in an obese mouse model will provide new insights into the progression of obesity and fibrosis.