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.

项目总结 细胞骨架相关蛋白AnkB(AnkB)的人类变异已被确定为高血压的危险因素 代谢紊乱，包括2型糖尿病和肥胖症。携带这些变体的小鼠表现出AnkB缺乏症 在代谢组织中，包括白色脂肪组织(WAT)和棕色脂肪组织(BAT)，并形成年龄和饮食依赖 肥胖、胰岛素抵抗和葡萄糖处理不当。WAT和BAT同时缺乏AnkB也是导致 这与蝙蝠体内脂肪的积累(蝙蝠变白)以及能量消耗和氧气消耗的减少有关。 这些发现表明，AnkB可能作为一种重要的脂代谢和全身调节因子发挥作用。 通过其在蝙蝠中未知的作用来调节代谢。这项研究的首要目标是阐明 AnkB在BAT中的细胞自主作用。我们假设，AnkB调节蝙蝠的脂肪生成，并且是必需的 用于维持蝙蝠的能量和葡萄糖处理能力，以应对代谢应激源。至 回答这些问题，我们提出了确定AnkB结合的分子机制 棕色脂肪细胞中葡萄糖处理和脂肪代谢的调节(目标1)。此外，我们还将定义 BAT中AnkB缺乏如何调节能量平衡和系统代谢动态平衡 代谢应激源，如衰老和高脂肪饮食(目标2)。建议的研究完成后，将提供 对AnkB对蝙蝠生理和代谢动态平衡的贡献的功能洞察。拟议中的工作 也将阐明人类AnkB变异体对 代谢性疾病。