A mechanism of lipid accumulation in brown adipose tissue

棕色脂肪组织中脂质积累的机制

• 批准号: 10605981
• 负责人: Ashley Aguillard
• 金额: $ 3.92万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10605981
• 关键词: ANK2 gene; Adipocytes; Adipose tissue; Adrenergic Agents; Age; Aging; Biochemical; Bioenergetics; Biological Assay; Body Composition; Brown Fat; Carbon; Cells; Clathrin; Complex; Consumption; Coupling; Cytoskeleton; Diet; Energy Metabolism; Exhibits; Fatty Acids; Fatty-acid synthase; Fractionation; Gases; Glucose; Glucose Transporter; Goals; Health; High Fat Diet; Homeostasis; Human; Human Genetics; Image Analysis; Impairment; Indirect Calorimetry; Insulin; Insulin Resistance; Isotopes; Knock-in Mouse; Knockout Mice; Knowledge; Lead; Light; Link; Lipids; Magnetic Resonance Imaging; Membrane Proteins; Metabolic; Metabolic Diseases; Metabolic dysfunction; Microscopy; Molecular; Mus; Neonatal; Non obese; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Oxygen Consumption; Peripheral; Physiology; Play; Predisposition; Proteins; Regulation; Reporting; Research Personnel; Risk; Risk Factors; Rodent; Role; Scaffolding Protein; Surface; Testing; Thermogenesis; Tissues; Training; Up-Regulation; Variant; Work; blood glucose regulation; career; cell type; energy balance; fatty acid-binding proteins; genetic variant; glucose metabolism; glucose uptake; in vivo; insight; lipid biosynthesis; lipid metabolism; lipidomics; live cell imaging; obesity development; response; skills; stressor; western diet

PROJECT SUMMARY Human variants in the cytoskeleton-associated protein ankyrin-B (AnkB) have been identified as risk factors for metabolic disorders, including type 2 diabetes and obesity. Mice harboring these variants exhibit AnkB deficiency in metabolic tissues including white (WAT) and brown adipose tissue (BAT), and develop age and diet-dependent adiposity, insulin resistance, and glucose mishandling. Simultaneous AnkB deficiency in WAT and BAT also lead to lipid accumulation in BAT (BAT “whitening”) and to decreases in energy expenditure and oxygen consumption. These findings suggest that AnkB may function as an important regulator of lipid metabolism and systemic metabolic regulation through its unexplored roles in BAT. The overarching goal of this study is to elucidate the cell-autonomous roles of AnkB in BAT. We hypothesize that AnkB regulates lipogenesis in BAT and is required for maintaining the energetic and glucose-handling capacity of BAT in response to metabolic stressors. To answer these questions, we proposed to determine the molecular mechanism of association with AnkB modulation of glucose handling and lipid metabolism in brown adipocytes (aim 1). Additionally, we will define how AnkB deficiency in BAT regulates energy balance and systemic metabolic homeostasis in response to the metabolic stressors, such as aging and high-fat diet (aim 2). Completion of the proposed studies will provide functional insights into AnkB’s contribution to BAT physiology and metabolic homeostasis. The proposed work will also shed light into the pathophysiological mechanism through which human AnkB variants contribute to metabolic diseases.

项目摘要 细胞骨架相关蛋白Ankyrin-B（ANKB）中的人类变体已被确定为危险因素 代谢性疾病，包括2型糖尿病和肥胖症。携带这些变体的老鼠暴露了ANKB缺乏症 在包括白色（WAT）和棕色脂肪组织（BAT）以及发展年龄和饮食依赖性的代谢组织中 肥胖，胰岛素抵抗和葡萄糖不当。 WAT和BAT的同时ANKB缺乏 脂肪在蝙蝠中积累（蝙蝠“美白”），并减少能量消耗和消耗氧气。 这些发现表明，ANKB可能是脂质代谢和系统性的重要调节剂 代谢通过其在BAT中的意外角色进行调节。这项研究的总体目标是阐明 ANKB在蝙蝠中的细胞自主作用。我们假设ANKB调节BAT中的脂肪形成，并且需要 用于响应代谢应激源响应BAT的能量和葡萄糖处理能力。到 回答这些问题，我们提议确定与ANKB关联的分子机制 棕色脂肪细胞中葡萄糖处理和脂质代谢的调节（AIM 1）。此外，我们将定义 BAT中的ANKB缺乏如何调节能量平衡和全身代谢稳态，以应对 代谢压力源，例如衰老和高脂饮食（AIM 2）。拟议研究的完成将提供 对ANKB对BAT生理学和代谢稳态的贡献的功能见解。拟议的工作 还将阐明人类ANKB变体有助于的病理生理机制 代谢疾病。