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， 并损害脂肪摄取，导致异位脂肪摄取其他器官，如肝脏。此外，隐秘的 脂肪因子谱显著改变，抗纤维化因子(如脂联素)分泌受损，以及 促肝纤维化脂肪因子(如内营养素、瘦素)的释放增加。分泌体中的这种变化是负面的 影响其他器官，增加患糖尿病等代谢性疾病的风险。因此，脂肪组织 功能障碍是代谢性疾病发生和发展的关键因素。 我们之前的工作集中在松弛素激素的抗纤维化作用上，证实松弛素通过其 受体RXFP1，减少小鼠已建立的肝纤维化。我们发现松弛素的一种机制 其作用是通过选择性激活过氧化物酶体增殖物激活受体γ(PPARγ)实现的。RXFP1-淘汰型 小鼠在许多组织中出现与年龄相关的纤维化，但尚未对脂肪组织进行研究。我们的 最近的实验表明，RXFP1基因敲除小鼠的内脏出现了与年龄相关的纤维化， 皮下和棕色脂肪组织，并有增加炎症和降低血清脂联素 级别。此外，我们还首次证实RXFP1在脂肪组织中表达。 巨噬细胞。松弛素抗脂肪组织纤维化的机制尚不清楚。 或功能障碍，或脂肪组织分泌的改变。鉴于脂肪的重要性 组织在维持新陈代谢中的作用及其分泌体在影响其他组织中的重要性 靶向松弛素途径的器官代表了一种治疗代谢性疾病的新方法 由脂肪组织功能障碍引起。 我们的长期目标是发现代谢性疾病背后的生化机制，以便开发 有效的治疗方法。我们对这一提议的中心假设是，松弛素能调节脂肪组织和 肝功能，从而促进正常功能。这一假说是基于一项新的发现，即放松 在脂肪纤维化和功能中起作用，我们之前的发现表明松弛素与肝纤维化和 再生。这项拟议研究的基本原理是，了解松弛素的作用机制 将导致特定的治疗靶点的形成。我们在内分泌学和 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 圆满完成拟议的研究。我们提出三个具体目标： 1.明确松弛素在脂肪组织中的抗纤维化作用机制。 2.确定松弛素途径对脂肪组织分泌组和器官间信号转导的影响。 肝脏。 3.体内开发松弛素受体靶向脂肪组织纤维化纳米粒。 在目标1中，我们将利用共轭亚油酸或饮食诱导肥胖的条件性RXFP1基因敲除小鼠 确定RXFP1在不同脂肪组织细胞中的作用及其信号通路的模型。在目标2中， 我们将进行蛋白质组学研究，以区分条件RXFP1敲除和分泌因子 老鼠。在目标3中，我们将开发脂肪组织靶向纳米颗粒来传递松弛素和选择性PPARγ 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至关重要的 对调节脂肪组织纤维化和功能的机制的洞察，并将测试一条新的途径 治疗。这将为抗击目前肥胖相关疾病的增加提供潜力， 合并症，这不仅是整个人口的一个主要问题，而且特别是在退伍军人群体中。

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.