Adipose tissue plasticity in health and disease

健康和疾病中的脂肪组织可塑性

• 批准号: 10617185
• 负责人: ALAN R. SALTIEL
• 金额: $ 59.97万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10617185
• 关键词: Adipocytes; Adipose tissue; Affect; Anatomy; Architecture; Attention; Basement membrane; Cell Count; Cell Line; Cell Shape; Cell Size; Cell membrane; Cell surface; Cells; Collagen Type I; Collagen Type IV; Communication; Complex; Contracts; Cues; Data; Dimensions; Disease; Ensure; Epidemic; Event; Exocytosis; Extracellular Matrix; Famines; Fasting; Fatty acid glycerol esters; Fibrosis; Future; GTP-Binding Proteins; Gene Expression; Gene Expression Profile; Genetic Transcription; Glucose; Glucose Intolerance; Health; Homeostasis; Hormonal; Immune; Impairment; In Vitro; Individual; Infiltration; Inflammation; Inflammatory; Insulin; Insulin Signaling Pathway; Knockout Mice; Laminin; Lipodystrophy; Location; MMP14 gene; Macrophage; Matrix Metalloproteinases; Mechanics; Mediating; Membrane; Metabolic; Metabolic Diseases; Metalloproteases; Molecular; Mus; Non-Insulin-Dependent Diabetes Mellitus; Nutrient; Nutrient availability; Nutritional; Obesity; Organism; Overnutrition; Pathologic; Pathway interactions; Physiological; Process; Regulation; Regulatory Pathway; Role; Shapes; Signal Pathway; Signal Transduction Pathway; Structure; Surface; Testing; Vesicle; Weight Gain; Work; comparison control; design; experimental study; feeding; fighting; glucose tolerance; insight; insulin tolerance; interstitial; lipid metabolism; membrane assembly; mouse model; obesogenic; permissiveness; response; therapeutic target; trafficking; transcriptome sequencing; uptake

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.

摘要 脂肪组织的能力，以处理波动的营养供应，通过动态扩大和 收缩，对生存至关重要。然而，这一过程的失调可导致脂肪代谢障碍、肥胖症 以及能量平衡失调多种因素影响脂肪细胞的可塑性，包括解剖学 位置、邻近的免疫细胞、脉管系统和周围的细胞外基质（ECM）。而 基质金属蛋白酶（MMPs）被假定参与ECM的重塑，大多数 注意力集中在富含I型胶原的基质/间质ECM上。然而，成熟的脂肪细胞 被一种特殊形式的ECM包围，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，脂肪细胞形状和 存储容量是不可能的。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。本提案将设法记录 MT 1-MMP介导的基底膜重塑在生理和病理状态下的变化 同时确定参与这一过程的调节途径。目标1将提供以下特征： 基底膜重塑和脂肪炎症、葡萄糖/胰岛素的相应改变 稳态转录事件。目的2将阐明MT 1-MMP调节的机制， 探索其通过胰岛素向质膜的运输。目标3将确定生理 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 MT 1-MMP小鼠。本提案中概述的实验旨在探索和扩展以下方面的见解 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 为今后研究脂肪组织中基底膜如何被修饰奠定了基础， 有潜力帮助开发对抗肥胖症的治疗靶点。