Membrane homeostasis in adipose physiology and obesity

脂肪生理学和肥胖中的膜稳态

• 批准号: 10611472
• 负责人: PETER J TONTONOZ
• 金额: $ 47.06万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-22 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10611472
• 关键词: Acids; Address; Adipocytes; Adipose tissue; Affect; Animals; Arachidonic Acids; Automobile Driving; Bioenergetics; Brown Fat; Catabolism; Cell Nucleus; Cells; Cellular Morphology; Collaborations; Data; Defect; Diabetes Mellitus; Diet; Dietary Fats; Dietary Fatty Acid; Energy Metabolism; Environment; Enzymes; Equilibrium; Exposure to; FGF21 gene; Gene Expression; Goals; Hepatic; High Fat Diet; Homeostasis; Intake; Knockout Mice; Laboratories; Link; Linoleic Acids; Lipids; Mediator; Membrane; Membrane Lipids; Metabolic; Metabolic Diseases; Mitochondria; Modeling; Morphology; Mus; Nutrient; Obesity; Organelles; Pathologic; Pathway interactions; Phenotype; Phospholipids; Physiological; Physiology; Polyunsaturated Fatty Acids; Population; Predisposition; Process; Production; Publishing; Regulation; Regulatory Pathway; Resistance; Respiration; Role; Signal Transduction; Stress; Testing; Time; Tissue Expansion; Tissue membrane; Tissues; Up-Regulation; adipocyte differentiation; biological adaptation to stress; detection of nutrient; diet-induced obesity; dietary; dietary excess; endoplasmic reticulum stress; energy balance; fatty acid oxidation; fibroblast growth factor 21; genetic manipulation; interest; loss of function; mitochondrial membrane; mouse model; novel; obesity development; obesogenic; oxidation; patch clamp; response; thermal stress

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.

抽象的 我们实验室的主要长期目标是描述控制脂肪细胞的监管机制 开发和系统生理。该提案将解决涉及的新监管途径 脂肪细胞营养感应，脂肪组织生理学和脂肪沉积特异性能量消耗。 拟议的研究重点是了解动态调节脂肪细胞膜组成如何 有助于控制活动物中全身代谢稳态。初步数据含义 磷脂重塑酶LPCAT3作为饮食脂肪酸摄入之间的新机械联系， 脂肪组织体内稳态和对肥胖症的敏感性。该提议建立在我们的初步基础上 发现有关膜脂质成分与与膜脂质成分之间关系的重要问题 脂肪组织功能以及全身生理和能量平衡。我们以前已经表明 LPCAT3的酶是6多不饱和脂肪酸的公司所需的 磷脂。我们的初步数据表明，脂肪LPCAT3表达在冷的情况下诱导 暴露或饮食引起的肥胖症。此外，在有选择性地缺乏LPCAT3的小鼠的初始表征 脂肪组织揭示了两种不同的表型：一种可追溯到白脂肪组织（WAT）和一个 追溯到棕色脂肪组织（蝙蝠）。脂肪lpcat3 ko小鼠喂养高脂饮食，发展脂肪营养不良 表型无法适当扩大其水位，导致生态肝脂质积累和 WAT中脂肪酸氧化的补偿性上调。同时，BAT LPCAT3 KO小鼠显示 对冷挑战的异常反应，其特征是明显的ER应力。罢工共同点 这些WAT和BAT KO模型是FGF21的补偿性生产，以维持 能量稳态。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重要适应性反应，允许最佳脂质储存和分解代谢 在各种环境中的功能。我们将以以下特定目标解决这些假设。 具体目的1是阐明膜磷脂重塑在营养感和健康中的作用 脂肪组织扩张。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。