Adipose tissue plasticity in health and disease

摘要 脂肪组织处理养分供应波动的能力，通过动态扩张和 收缩，对生存至关重要。然而，这一过程的失调会导致脂肪营养不良、肥胖 和失调的能量平衡。影响脂肪细胞可塑性的各种因素，包括解剖学上的 位置、邻近的免疫细胞、血管系统和周围的细胞外基质(ECM)。而当 基质金属蛋白酶(MMPs)被认为参与了ECM的重塑，大多数 人们的注意力集中在I型胶原丰富的基质/间质细胞外基质上。然而，成熟的脂肪细胞 周围环绕着一种特殊形式的细胞外基质，称为基底膜，它机械地调节细胞 形状。在不改变基底膜组装或重塑的情况下，脂肪细胞形态和 存储容量将是不可能的。然而，基底膜在调节脂肪中的作用 新陈代谢和功能几乎都被忽视了。这项提案将寻求记录这种动态 MT1-基质金属蛋白酶介导的基底膜重构在生理和病理状态下的变化 同时确定这一过程中涉及的调控途径。目标1将提供以下特征 脂肪炎症、血糖/胰岛素的基底膜重塑及相应改变 动态平衡转录事件。目标2将阐明MT1-基质金属蛋白酶的调控机制，通过 探讨其通过胰岛素转运至细胞膜的情况。目标3将决定生理学的 通过研究脂肪特异性条件性KO研究肥胖状态下脂肪可塑性受损的后果 MT1-MMPs小鼠。本提案中概述的实验旨在探索和扩展对以下方面的见解 基底膜在脂肪组织中的作用和调节。这里提出的工作奠定了 为未来研究脂肪组织中基底膜是如何被修饰的奠定了基础，并具有 有可能帮助开发与肥胖作斗争的治疗目标。

Abstract The ability of adipose tissue to handle fluctuations in nutrient availability, by dynamically expanding and contracting, is critical for survival. However, dysregulation of this process can lead to lipodystrophy, obesity and dysregulated energy homeostasis. Various factors influence adipocyte plasticity, including anatomical location, neighboring immune cells, the vasculature and the surrounding extracellular matrix (ECM). While matrix metalloproteinases (MMPs) have been postulated to participate in the remodeling of the ECM, most attention has focused on the type I collagen-rich stromal/interstitial ECM. However, mature adipocytes are surrounded by a specialized form of ECM, termed the basement membrane, that mechanically regulates cell shape. Without modifying basement membrane assembly or remodeling, changes in adipocyte shape and storage capacity would not be possible. Nevertheless, the role of the basement membrane in regulating fat metabolism and function are almost uniformly overlooked. This proposal will seek to document the dynamic changes in MT1-MMP-mediated basement membrane remodeling in both physiological and pathological states while identifying the regulatory pathways involved in this process. Aim 1 will provide a characterization of basement membrane remodeling and corresponding alterations in adipose inflammation, glucose/insulin homeostasis transcriptional events. Aim 2 will elucidate the mechanism underlying MT1-MMP regulation by exploring its trafficking to the plasma membrane by insulin. Aim 3 will determine the physiological consequence of impaired adipose plasticity in states of obesity by investigating adipose-specific conditional KO mice of MT1-MMP. The experiments outlined in this proposal are designed to explore and expand insights into the role and regulation of the basement membrane in adipose tissue. The work proposed here lays the groundwork for future studies into how the basement membrane is modified in adipose tissue, and has potential to help develop therapeutic targets in the fight against obesity.