A mechanism of lipid accumulation in brown adipose tissue

项目摘要 细胞凋亡相关蛋白锚蛋白-B（AnkB）的人类变异体已被确定为 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缺陷 在代谢组织中，包括白色（WAT）和棕色脂肪组织（BAT）， 肥胖、胰岛素抵抗和葡萄糖处理不当。WAT和BAT中同时存在的AnkB缺陷也导致 BAT中的脂质积累（BAT“美白”）以及能量消耗和氧气消耗的减少。 这些结果表明，AnkB可能作为一个重要的调节脂代谢和全身 通过其在BAT中未探索的作用进行代谢调节。本研究的总体目标是阐明 AnkB在BAT中的细胞自主作用。我们假设AnkB调节BAT中的脂肪生成， 维持BAT的能量和葡萄糖处理能力以应对代谢应激。到 为了回答这些问题，我们提出确定与AnkB结合的分子机制 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缺陷如何调节能量平衡和全身代谢稳态， 代谢应激因素，如衰老和高脂肪饮食（目标2）。完成拟议的研究将提供 AnkB对BAT生理学和代谢稳态的贡献的功能性见解。拟议工作 还将揭示人类AnkB变异体有助于 代谢性疾病

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.