The Role of Relaxin Signaling in Adipose Tissue Fibrosis and Function

代谢紊乱，如肥胖，与脂肪组织缺氧、炎症和纤维化有关， 以及脂质摄取受损，引起其它器官如肝脏的异位脂质摄取。此外， 脂肪因子谱显著改变，抗纤维化因子（如脂联素）分泌受损， 促纤维化脂肪因子（例如内营养因子、瘦素）的释放升高。分泌蛋白的这种改变 影响其他器官，增加患糖尿病等代谢疾病的风险。因此，脂肪组织 功能障碍是代谢疾病发展和进展的关键因素。 我们以前的工作，集中在激素松弛素的抗纤维化作用，建立了松弛素，通过其 受体RXFP 1，减少小鼠的肝纤维化。我们发现松弛素的一种机制 过氧化物酶体增殖物激活受体γ（peroxisome proliferator-activated receptor γ，PPAR γ）的选择性激活。RXFP1基因敲除 小鼠在许多组织中发生与年龄相关的纤维化，但尚未在脂肪组织中进行研究。我们 最近的实验显示RXFP 1敲除小鼠在内脏中发生了与年龄相关的纤维化， 皮下和棕色脂肪组织，炎症增加，血清脂联素降低 程度.此外，我们首次证实RXFP 1由脂肪组织表达， 巨噬细胞关于松弛素预防脂肪组织纤维化的机制尚不清楚 或功能的损害，或脂肪组织分泌的改变。考虑到脂肪的重要性 在维持新陈代谢中起作用的组织，以及其分泌组在影响其他组织中的重要性。 靶向松弛素通路代表了一种治疗代谢性疾病的新方法， 脂肪组织功能障碍 我们的长期目标是揭示代谢性疾病的生化机制， 有效的治疗。我们对这一建议的中心假设是松弛素既调节脂肪组织， 肝脏功能，从而促进正常运作。这一假设是基于松弛素 在脂肪纤维化和功能中起作用，我们先前的发现暗示松弛素在肝纤维化和 再生这项研究的基本原理是，了解松弛素的作用机制， 在这些组织中将导致开发特定的治疗靶点。我们在内分泌学方面的经验， 肝脏疾病模型和纳米颗粒的开发，将提供一个有利的研究环境， 顺利完成拟议的研究。我们提出三个具体目标： 1.确定松弛素在脂肪组织中抗纤维化作用的机制。 2.确定松弛素途径对脂肪组织分泌组和器官间信号传导的影响， 肝脏 3.松弛素受体靶向纳米粒对脂肪组织纤维化的体内研究。 在目标1中，我们将利用具有共轭亚油酸或饮食诱导的肥胖的条件性RXFP 1敲除小鼠 模型，以确定RXFP 1在不同脂肪组织细胞及其信号通路中的作用。在目标2中， 我们将进行蛋白质组学研究，以区分条件性RXFP1敲除的分泌因子 小鼠在目标3中，我们将开发脂肪组织靶向纳米颗粒，以递送松弛素和选择性PPAR γ 用于治疗脂肪组织功能障碍的激动剂。这些目标的成功实现将提供关键的 深入了解调节脂肪组织纤维化和功能的机制，并将测试一种新的途径， 治疗这将为应对目前与肥胖有关的疾病的增加提供潜力， 合并症，这是一个主要问题，不仅在一般人群中，但特别是在退伍军人群体。

Metabolic disorders, such as obesity, are associated with adipose tissue hypoxia, inflammation and fibrosis, and impaired lipid uptake, causing ectopic lipid uptake other organs, such as the liver. Furthermore, the secreted adipokine profile changes dramatically, with impaired secretion of antifibrotic factors (e.g. adiponectin), and elevated release of profibrotic adipokines (e.g. endotrophin, leptin). This alteration in the secretome negatively affects other organs, elevating the risk of metabolic diseases such as diabetes. Therefore, adipose tissue dysfunction is a crucial element in the development and progression of metabolic disease. Our previous work, focused on the antifibrotic role of the hormone relaxin, established that relaxin, through its receptor RXFP1, reduced established hepatic fibrosis in mice. We discovered that one mechanism for relaxin’s actions is through selective activation of peroxisome proliferator-activated receptor γ (PPARγ). RXFP1-knockout mice develop age-related fibrosis in many tissues, but no studies had been conducted in adipose tissue. Our recent experiments revealed that RXFP1-knockout mice developed age-related fibrosis in the visceral, subcutaneous and brown adipose tissue, and have increased inflammation and decreased serum adiponectin levels. Furthermore, we have established for the first time that RXFP1 is expressed by the adipose tissue macrophages. Nothing is known about the mechanisms by which relaxin protects against adipose tissue fibrosis or the impairments in function, or in alterations in adipose tissue secretion. Given the importance of adipose tissue functioning in the maintenance of metabolism, and the importance of its secretome in affecting other organs, targeting the relaxin pathway represents a novel approach to treating metabolic disease characterized by adipose tissue dysfunction. Our long-term goal is to uncover biochemical mechanisms underlying metabolic disease in order to develop effective treatments. Our central hypothesis for this proposal is that relaxin regulates both adipose tissue and liver function and thereby promotes normal functioning. This hypothesis is based on the new finding that relaxin plays a role in adipose fibrosis and function, and our previous findings implicating relaxin in liver fibrosis and regeneration. The rationale for the proposed studies is that understanding the mechanisms for relaxin’s effects in these tissues will lead to development of specific targets for treatment. Our experience in endocrinology and liver disease models, and nanoparticle development, will provide a conducive research environment to successful completion of the proposed studies. We propose three Specific Aims: 1. Identify the mechanisms for the antifibrotic effects of relaxin in adipose tissue. 2. Determine the effect of the relaxin pathway on the adipose tissue secretome and interorgan signaling to the liver. 3. Develop relaxin receptor-targeting nanoparticles on adipose tissue fibrosis in vivo. In Aim 1, we will utilize conditional RXFP1 knockout mice with conjugated linoleic or diet-induced obesity models to determine the roles of RXFP1 in different adipose tissue cells and their signaling pathways. In Aim 2, we will conduct proteomics studies to distinguish between secreted factors from conditional RXFP1 knockout mice. In Aim 3, we will develop adipose tissue-targeting nanoparticles to deliver relaxin and selective PPARγ agonists for treatment of adipose tissue dysfunction. Successful completion of these Aims will provide critical insights into the mechanisms regulating adipose tissue fibrosis and function, and will test a new avenue for treatment. This would provide the potential to combat the current increase in obesity-related diseases and comorbidities, which is a major issue not only in the population at-large, but particularly in the veteran population.