Membrane homeostasis in adipose physiology and obesity

摘要 我们实验室的一个主要长期目标是描述控制脂肪细胞的调节机制。 发育和系统生理学。该提案将涉及一种新的监管途径，涉及 脂肪细胞营养感知、脂肪组织生理学和脂肪储存库特定能量消耗。这个 拟议的研究集中在了解动态调节脂肪细胞膜成分 有助于控制活体动物的全身代谢动态平衡。初步数据表明 磷脂重塑酶Lpcat3作为新的机制联系膳食脂肪酸摄入量， 脂肪组织动态平衡和肥胖易感性。这项建议建立在我们初步的基础上 解决关于膜脂组成与膜的关系的重要问题 脂肪组织功能与系统生理和能量平衡。我们之前已经表明， Lpcat3酶是将6多不饱和脂肪酸结合到 磷脂。我们的初步数据显示，在寒冷的环境中，脂肪Lpcat3的表达被诱导 暴露或饮食导致的肥胖。此外，选择性缺失Lpcat3的小鼠的初步特征 脂肪组织显示了两种不同的表型：一种是白色脂肪组织(Wat)，另一种是白色脂肪组织 可追溯到棕色脂肪组织(蝙蝠)。喂食高脂饲料的脂肪Lpcat3KO小鼠出现脂肪营养不良 表型不能适当扩大其WAT，导致异位肝脂堆积和 水中脂肪酸氧化的代偿性上调。同时，BAT Lpcat3 KO小鼠表现出 对冷刺激的异常反应，表现为明显的内质网应激。两国之间惊人的共同点 这些WAT和BAT KO车型是FGF21的补偿性产品，显然是为了保持 能量平衡。我们推测，Lpcat3对脂肪组织膜成分的微调 是对寒冷和饮食挑战的关键适应性反应，允许最佳的脂肪储存和分解代谢 在一系列环境中运行。我们将以以下具体目标来解决这些假设。 具体目的1是阐明膜磷脂重构在营养感知和健康中的作用 脂肪组织扩张。具体目的2是确定磷脂重塑在蝙蝠功能中的作用 以及对热应激的反应。

ABSTRACT A major long-term goal of our laboratory is to delineate regulatory mechanisms that control adipocyte development and systemic physiology. This proposal will address a new regulatory pathway involved in adipocyte nutrient sensing, adipose tissue physiology, and adipose depot-specific energy expenditure. The proposed studies are focused on understanding how dynamic regulation adipocyte membrane composition contributes to the control of whole-body metabolic homeostasis in living animals. Preliminary data implicates the phospholipid remodeling enzyme Lpcat3 as novel mechanistic link between dietary fatty acid intake, adipose tissue homeostasis, and susceptibility to obesity. This proposal builds upon our preliminary discoveries to address important questions regarding the relationship of membrane lipid composition to adipose tissue function and systemic physiology and energy balance. We have previously shown that the enzyme Lpcat3 is uniquely required for the incorporation of the 6 polyunsaturated fatty acids into phospholipids. Our preliminary data reveal that adipose Lpcat3 expression is induced in the setting of cold exposure or diet-induced obesity. Moreover, initial characterization of mice lacking Lpcat3 selectively in adipose tissues has revealed two distinct phenotypes: one traced to white adipose tissue (WAT) and one traced to brown adipose tissue (BAT). Adipose Lpcat3 KO mice fed a high-fat diet develop a lipodystrophic phenotype are unable to appropriately expand their WAT, leading to ectopic hepatic lipid accumulation and the compensatory upregulation of fatty acid oxidation in WAT. At the same time, BAT Lpcat3 KO mice show an abnormal response to cold challenge, characterized by marked ER stress. A striking commonality between these WAT and BAT KO models is the compensatory production of FGF21 in an apparent effort to maintain energy homeostasis. We hypothesize that the fine tuning of adipose tissue membrane composition by Lpcat3 is a critical adaptive response to cold and dietary challenge that permits optimal lipid storage and catabolic function in a range of environments. We will address these hypotheses with the following specific aims. Specific Aim 1 is to elucidate the role of membrane phospholipid remodeling in nutrient sensing and healthy adipose tissue expansion. Specific Aim 2 is to determine the role of phospholipid remodeling in BAT function and response to thermal stress.