Lipid storage and utilization in physiology and obesity

生理学和肥胖中的脂质储存和利用

基本信息

批准号：
10663760
负责人：
PETER J TONTONOZ
金额：
$ 55.38万
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：
2023
资助国家：
美国
起止时间：
2023-05-01 至 2027-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10663760
关键词：
Adipocytes Adipose tissue Affect Albumins Area BSCL2 gene Biochemical Biological Brown Fat Cells Characteristics Data Diabetes Mellitus Ectopic Expression Energy Metabolism Fasting Genes Genetic Transcription Goals Hepatocyte Homeostasis In Vitro Insulin Resistance Laboratories Link Lipids Lipolysis Liver Mediating Membrane Proteins Metabolic Metabolic Diseases Metabolism Mitochondria Modeling Molecular Morphology Mus Obesity Organelles Pathologic Pathway interactions Phenotype Physiological Physiology Proteins Regulatory Pathway Role Site Stimulus Structure Surface Testing Thermogenesis Tissues Triglycerides Ubiquitination Work adipocyte differentiation adiponectin cell type diabetes pathogenesis energy balance expression vector fatty acid oxidation gain of function imaging approach in vivo induced hypothermia insight lipid metabolism liver metabolism loss of function novel oxidation response

项目摘要

ABSTRACT A major goal of our laboratory is to delineate regulatory mechanisms that control adipocyte development and systemic physiology in obesity and diabetes. This proposal will address a new regulatory pathway involved in adipose tissue adipose depot-specific energy expenditure. Understanding how metabolic tissues store and utilize lipids is of central relevance to normal physiology, obesity and diabetes. Excess neutral lipids are stored in lipid droplets (LDs)–dynamic organelles that expand and shrink depending on the metabolic needs of the cell. The molecular mechanisms that link lipid LD dynamics and function to tissue metabolism are incompletely understood. Defining the molecular pathways that govern fuel utilization in tissues is important for understanding systemic homeostasis and the underlying causes of pathological lipid accumulation in the setting of metabolic disease. We have identified Clstn3, an adipose tissue- and liver-selective product of the Clstn3 gene, as a key determinant of multilocular LD morphology and function. Clstn3 is an integral ER membrane protein that localizes to ER-LD contact sites via conserved hairpin-like domains. Loss of Clstn3 in mouse brown adipose tissue (BAT) increases LD size, reduces triglyceride utilization, and leads to cold- induced hypothermia. Conversely, ectopic expression of Clstn3 in adipocytes is sufficient to reduce LD size and enforce a multilocular LD phenotype. Collectively, these initial discoveries have revealed a previously unrecognized molecular mechanism that maximizes LD surface area and facilitates lipid utilization in thermogenic adipocytes and potentially other cells. The overall goal of this proposal is to further define the mechanisms of Clstn3 action and its contributions to metabolic physiology. Specific Aim 1 will elucidate mechanisms by which Clstn3 regulates LD structure and function. Specific Aim 2 will investigate the ability of Clstn3 to modify white adipocyte function. Specific Aim 3 will define the role of Clstn3 in lipid metabolism in other tissues. These studies are expected to provide fundamental insight into pathways regulating LD function and may suggest opportunities for modulating lipid utilization in the setting of metabolic disease.

抽象的我们实验室的一个主要目标是描绘控制脂肪细胞发育的调节机制该提案将解决肥胖和糖尿病的系统生理学问题。参与脂肪组织脂肪库特定的能量消耗。储存和利用脂质与正常生理、肥胖和糖尿病密切相关。储存在脂滴 (LD) 中——动态细胞器，根据代谢情况扩张和收缩将脂质 LD 动力学和功能与组织代谢联系起来的分子机制是定义控制组织中燃料利用的分子途径对于这一点很重要。了解全身稳态和病理性脂质积累的根本原因我们已经鉴定出 Clstn3，一种脂肪组织和肝脏选择性产物。 Clstn3 基因作为多房 LD 形态和功能的关键决定因素，是一个完整的 ER。通过丢失 Clstn3 的保守发夹结构域定位到 ER-LD 接触位点的膜蛋白。小鼠棕色脂肪组织 (BAT) 增加 LD 大小，降低甘油三酯利用率，并导致冷- 脂肪细胞中 Clstn3 的离线、异位表达不足以减少 LD 大小总的来说，这些初步发现揭示了先前的多房 LD 表型。最大化 LD 表面积并促进脂质利用的未知分子机制该提案的总体目标是进一步定义产热脂肪细胞和潜在的其他细胞。 Clstn3 的作用机制及其对代谢生理学的贡献将阐明。 Clstn3 调节 LD 结构和功能的机制具体目标 2 将研究 Clstn3 调节 LD 结构和功能的机制。 Clstn3 改变白色脂肪细胞功能。具体目标 3 将定义 Clstn3 在脂质代谢中的作用。这些研究有望为调节 LD 功能的途径提供基础见解。并可能建议在代谢疾病的情况下调节脂质利用的机会。