Dichotomous Effects of MT1-MMP on Adipose Tissue Remodeling

MT1-MMP 对脂肪组织重塑的二分效应

• 批准号: 10448990
• 负责人: Kai Sun
• 金额: $ 11.7万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-03-01 至 2023-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10448990
• 关键词: Address; Adipocytes; Adipose tissue; Adverse effects; Angiogenic Factor; Cleaved cell; Collagen; Collagen Type VI; Consensus; Data; Development; Diabetes Mellitus; Digestion; Disease; Doxycycline; Endopeptidases; Event; Extracellular Matrix; Extracellular Matrix Proteins; Family; Fatty acid glycerol esters; Fibrosis; Functional disorder; Hypoxia; In Vitro; Inflammation; Inflammatory; Insulin; Insulin Resistance; Link; MMP14 gene; Messenger RNA; Metabolic; Metabolic Diseases; Metalloproteases; Modeling; Molecular; Mus; Obesity; Pathogenesis; Pathologic; Pathologic Processes; Peptide Hydrolases; Physiology; Production; Regulation; Role; Shapes; Site; Stress; Testing; Therapeutic; Tissue Expansion; Tissues; Transgenic Mice; Transgenic Organisms; Up-Regulation; Ursidae Family; Vascular Endothelial Growth Factors; War; angiogenesis; base; collagenase; combat; diet-induced obesity; flexibility; gain of function; in vivo; in vivo Model; insulin sensitivity; loss of function; metabolic phenotype; mouse model; neutralizing antibody; novel; obesity development; obesity treatment; overexpression; pressure; prevent; programs; tool

Abstract In rapidly expanding adipose tissue (AT), pervasive hypoxia stimulates massive induction of Hypoxia Induced Factor 1 α (HIF1α), which in turn initiates fibrosis and local inflammation ultimately leading to insulin resistance. AT responds to the fibrosis by up-regulating MMPs, a family of endopeptidases that cleave collagens. MT1-MMP (MMP14) is the major collagenase in AT that is up-regulated in obese fat pads. How MT1-MMP is up-regulated and what are the functional consequences of the activation of MT1-MMP remain largely unknown. Interestingly, we recently identified a novel collagen 6 digestion product (we refer to it as endotrophin) which stimulates fibrosis and inflammation locally in unhealthy AT. However, the participating MMPs and detailed digesting event still remain largely unknown. Based on the preliminary observations, it is hypothesized that MT1-MMP is responsible for the digestion event to produce endotrophin. MT1-MMP might have dichotomous effects based on different metabolic contexts in obese AT: On the one hand, at early-stage of AT expansion, MT1-MMP cleaves ECM proteins to release the high pressure on fat cells, thus attempting to maintain healthy conditions; On the other hand, at the late-stage of obese AT remodeling, it digests abnormally accumulated collagen 6α3 and produces endotrophin which further enhances fibrosis and inflammation, ultimately leading a microenvironment highly unfavorable for metabolic flexibility. To test the hypothesis, the current study has three specific Aims: 1). To investigate the role of HIF1α in upregulation of MT1-MMP in obese AT; 2). To determine whether MT1-MMP exerts anti-fibrotic and pro-angiogenic activity at early-stage of obesity development; and 3).To determine whether MT1-MMP produces endotrophin by digesting abnormal accumulating collagen 6α3 to shape unhealthy fat pads in late-stage of obesity development. Both gain-of-function and loss-of-function of HIF1α models will be applied to achieve Aim 1. Diet-induced obese and doxycycline (Dox)-inducible AT specific MT1-MMP transgenic mouse models will be used for Aim 2 and 3. Specifically, the overexpression of MT1-MMP will be induced in AT during both “early-stage” and “late-stage” of obesity development. Endotrophin production, fibrosis and inflammation in AT will be detected and metabolic phenotypes in the transgenic mice will be characterized under different metabolic contexts. To further study the role of endotrophin in shaping unhealthy microenvironment, both AT specific endotrophin overexpression and anti-endotrophin neutralizing antibody treated mouse models will be utilized. The molecular mechanism by which endotrophin stimulates the local fibrosis and inflammation will be further investigated in the mice. Findings from the study will enhance the general understanding of the complexity of AT physiology and highlight the central role of MT1-MMP in the dynamics of AT remodeling during obesity development. Therefore, inhibition of MT1-MMP and endotrophin produced by MT1-MMP bears great promise from a therapeutic perspective for obesity and obesity related metabolic disorders.

抽象的 在快速扩张的脂肪组织（AT）中，普遍缺氧刺激了低氧诱导的大量诱导 因子1α（HIF1α）又引起纤维化和局部炎症最终导致胰岛素抵抗。 在对纤维化的反应中，通过上调MMP，这是一个清除胶原蛋白的内肽酶家族。 MT1-MMP （MMP14）是在肥胖脂肪垫中上调的主要胶原酶。 MT1-MMP如何上调 MT1-MMP激活的功能后果是什么，在很大程度上未知。有趣的是， 我们最近确定了一种新型的胶原蛋白6消化产物（我们将其称为内trophin）刺激纤维化 并在本地不健康的炎症。但是，参与的MMP和详细的消化事件仍然 在很大程度上未知。根据初步观察，假设MT1-MMP负责 MT1-MMP可能基于不同的二分法作用 肥胖中的代谢环境：一方面，在扩展的早期，MT1-MMP裂解ECM 蛋白质以释放脂肪细胞的高压，从而试图维持健康的条件；另一方面 手，在重塑时肥胖的后期，它消化了绝对积累的胶原蛋白6α3并产生 内托蛋白进一步增强纤维化和感染，最终导致了微环境 不利于代谢灵活性。为了检验假设，当前的研究具有三个具体目的：1）。 研究HIF1α在肥胖中MT1-MMP上调的作用； 2）。确定MT1-MMP是否 在肥胖发育的早期阶段发挥抗纤维化和促血管生成活性。和3）。确定 MT1-MMP是否通过消化异常积累胶原蛋白6α3产生内to蛋白以塑造不健康 肥胖发育后期的脂肪垫。 HIF1α模型的功能收益和功能丧失都将 应用于达到目标1。饮食引起的肥胖和强力霉素（DOX） - 在特定的MT1-MMP上可诱导 转基因小鼠模型将用于AIM 2和3。具体来说，MT1-MMP的过表达将为 在肥胖发展的“早期”和“晚期”期间诱导了AT。内托蛋白产生，纤维化 并且将检测到AT的炎症，并且会表征转基因小鼠的代谢表型 在不同的代谢环境中。进一步研究内托蛋白在塑造不健康的作用 微环境，无论是在特异性内核蛋白过表达和中和抗体中和抗体 处理的鼠标模型将被使用。内托蛋白刺激局部的分子机制 小鼠将进一步研究纤维化和炎症。 研究结果将增强对AT生理学复杂性和 突出了MT1-MMP在肥胖发育过程中AT重塑动力学中的核心作用。所以， MT1-MMP产生的MT1-MMP和内trophin的抑制作用是疗法的巨大希望 肥胖和肥胖相关的代谢障碍的观点。

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