The Role of Relaxin Signaling in Adipose Tissue Fibrosis and Function

松弛素信号传导在脂肪组织纤维化和功能中的作用

• 批准号: 10366393
• 负责人: ROBERT G BENNETT
• 金额: --
• 依托单位: OMAHA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10366393
• 关键词: Adipose tissue; Affect; Age; Aging; Agonist; Biochemical; Brown Fat; Cardiovascular Diseases; Cells; Conjugated Linoleic Acids; Data; Degenerative Disorder; Development; Diabetes Mellitus; Disease model; Elements; Endocrinology; Environment; Fatty acid glycerol esters; Fibrosis; Functional disorder; Goals; Health; Healthcare; Hormones; Hypoxia; Impairment; Inflammation; Injury; Knockout Mice; Leptin; Lipids; Lipolysis; Liver; Liver Cirrhosis; Liver Fibrosis; Liver Regeneration; Liver diseases; Maintenance; Malignant Neoplasms; Metabolic Diseases; Metabolism; Mission; Modeling; Mus; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Obesity associated disease; Organ; Overweight; PPAR gamma; Pathway interactions; Play; Population; Prevalence; Progressive Disease; Proteomics; Relaxin; Research; Risk; Role; Serum; Signal Pathway; Signal Transduction; Testing; Time; Tissues; Veterans; Visceral; Work; adipokines; adiponectin; adult obesity; age related; aged; base; combat; comorbidity; cost; diet-induced obesity; effective therapy; experience; experimental study; improved; in vivo; innovation; insight; liver function; macrophage; military veteran; nanoparticle; negative affect; novel; novel strategies; receptor; relaxin receptor; subcutaneous; targeted delivery; translational approach; uptake

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.

代谢紊乱，例如肥胖，与脂肪组织缺氧、炎症和纤维化有关， 脂质摄取受损，导致其他器官异位脂质摄取，例如肝脏。 脂肪因子谱发生显着变化，抗纤维化因子（例如脂联素）的分泌受损，并且 促纤维化脂肪因子（例如内养蛋白、瘦素）的释放增加，分泌蛋白组的这种变化产生负面影响。 影响其他器官，增加患糖尿病等代谢疾病的风险。 功能障碍是代谢性疾病发生和进展的关键因素。 我们之前的工作重点关注激素松弛素的抗纤维化作用，确定松弛素通过其 受体 RXFP1，减少小鼠已形成的肝纤维化 我们发现松弛素的一种机制。 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)。 小鼠的许多组织都会出现与年龄相关的纤维化，但尚未在脂肪组织中进行研究。 最近的实验表明，RXFP1 基因敲除小鼠的内脏、 皮下和棕色脂肪组织，炎症增加，血清脂联素降低 此外，我们首次确定了 RXFP1 在脂肪组织中表达。 关于松弛素预防脂肪组织纤维化的机制尚不清楚。 考虑到脂肪的重要性，功能受损或脂肪组织分泌改变。 组织在维持新陈代谢中的功能，以及其分泌组在影响其他方面的重要性 器官，靶向松弛素途径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。 我们的长期目标是揭示代谢疾病背后的生化机制，以便开发 我们对该提议的中心假设是松弛素调节脂肪组织和 肝脏功能，从而促进正常功能这一假设是基于松弛素的新发现。 在脂肪纤维化和功能中发挥作用，我们之前的研究结果表明松弛素在肝纤维化和功能中起作用 拟议研究的基本原理是了解松弛素的作用机制。 这些组织中的变化将导致我们在内分泌学和治疗方面的经验的发展。 肝病模型和纳米颗粒的开发将为以下研究提供有利的研究环境： 我们提出了三个具体目标： 1. 确定松弛素在脂肪组织中的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。 3. 开发针对体内脂肪组织纤维化的松弛素受体纳米颗粒。 在目标 1 中，我们将利用具有共轭亚油酸或饮食诱导肥胖的条件性 RXFP1 基因敲除小鼠 目标 2 中，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。 我们将进行蛋白质组学研究，以区分来自条件 RXFP1 敲除的分泌因子 在目标 3 中，我们将开发靶向脂肪组织的纳米颗粒来递送松弛素和选择性 PPARγ。 激动剂治疗脂肪组织功能障碍将为成功完成这些目标提供关键。 深入了解调节脂肪组织纤维化和功能的机制，并将测试一条新途径 这将为对抗当前肥胖相关疾病的增加提供潜力。 合并症，这不仅是广大人群中的一个主要问题，而且尤其是退伍军人群体中的一个主要问题。