Membrane homeostasis in adipose physiology and obesity

脂肪生理学和肥胖中的膜稳态

基本信息

批准号：
10455597
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
项目类别：
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/10455597
关键词：
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 of activation protein Membrane Membrane Lipids Metabolic Metabolic Diseases Mitochondria Modeling Morphology Mus Nutrient Obesity Organelles Pathologic Pathway Analysis 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 genetic manipulation interest loss of function mitochondrial membrane mouse model novel obesity development obesogenic oxidation patch clamp response thermal stress

项目摘要

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一个主要长期目标是描绘控制脂肪细胞的调节机制该提案将解决涉及的新调控途径。脂肪细胞营养感应、脂肪组织生理学和脂肪库特定的能量消耗。拟议的研究重点是了解如何动态调节脂肪细胞膜组成初步数据表明，有助于控制活体动物的全身代谢稳态。磷脂重塑酶 Lpcat3 作为膳食脂肪酸摄入之间的新机制联系，脂肪组织稳态和肥胖易感性该提议建立在我们的初步研究基础上。解决有关膜脂成分与膜脂成分之间关系的重要问题的发现脂肪组织功能与全身生理学和能量平衡我们之前已经表明。 Lpcat3 酶是将 6 多不饱和脂肪酸掺入我们的初步数据表明，脂肪 Lpcat3 表达在寒冷环境下被诱导。此外，选择性缺乏 Lpcat3 的小鼠的初步特征。脂肪组织揭示了两种不同的表型：一种可追溯到白色脂肪组织（WAT），另一种可追溯到白色脂肪组织（WAT）追踪到棕色脂肪组织（BAT），喂养高脂肪饮食的脂肪 Lpcat3 KO 小鼠出现脂肪营养不良。表型无法适当扩大其 WAT，导致异位肝脂质积累和 WAT 中脂肪酸氧化的代偿性上调同时，BAT Lpcat3 KO 小鼠表现出对寒冷挑战的异常反应，其特征是明显的内质网应激。这些 WAT 和 BAT KO 模型是 FGF21 的补偿生产，显然是为了维持我们发现 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，可实现最佳的脂质储存和分解代谢我们将通过以下具体目标来解决这些假设。具体目标 1 是阐明膜磷脂重塑在营养传感和健康中的作用具体目标 2 是确定磷脂重塑在 BAT 功能中的作用。和对热应力的响应。