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， 脂肪细胞营养感测、脂肪组织生理学和脂肪库特异性能量消耗。的 建议的研究集中在了解如何动态调节脂肪细胞膜组成 有助于控制活体动物的全身代谢稳态。初步数据显示 磷脂重塑酶Lpcat 3作为膳食脂肪酸摄入之间的新机制联系， 脂肪组织稳态和对肥胖的易感性。这一建议建立在我们初步的 解决有关膜脂组成与 脂肪组织功能和全身生理和能量平衡。我们之前已经证明， 酶Lpcat 3是将β 6多不饱和脂肪酸掺入到 磷脂我们的初步数据显示，脂肪Lpcat3表达在寒冷环境中被诱导， 暴露或饮食引起的肥胖。此外，选择性缺乏Lpcat 3的小鼠的初步特征 脂肪组织揭示了两种不同的表型：一种追溯到白色脂肪组织（WAT）， 棕色脂肪组织（BAT）。高脂饮食喂养的脂肪Lpcat3 KO小鼠发生脂肪营养不良 表型不能适当地扩大他们的WAT，导致异位肝脂质积聚， WAT中脂肪酸氧化的补偿性上调。与此同时，BAT Lpcat3 KO小鼠显示出 对冷刺激的异常反应，以显著的ER应激为特征。一个惊人的共同点， 这些WAT和BAT KO模型是FGF21的补偿性生产，显然是为了维持 能量平衡我们假设Lpcat3对脂肪组织膜组成的微调 是对寒冷和饮食挑战的关键适应性反应，允许最佳的脂质储存和分解代谢 在一系列环境中发挥作用。我们将讨论这些假设与以下具体目标。 具体目标1是阐明膜磷脂重塑在营养感受和健康中的作用。 脂肪组织扩张术具体目标2是确定磷脂重塑在BAT功能中的作用 和对热应力的反应。

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.