Lipid storage and utilization in physiology and obesity

生理学和肥胖中的脂质储存和利用

• 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
• 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

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 我们实验室的主要目标是描述控制脂肪细胞开发的监管机制 和肥胖和糖尿病的系统生理学。该提案将解决新的监管途径 参与脂肪组织脂肪特定的能量消耗。了解如何代谢组织 储存和利用脂质与正常生理，肥胖和糖尿病的核心相关。过多的中性脂质 存储在脂质液滴（LDS）中 - 动态细胞器，这些细胞器的扩展和收缩，具体取决于代谢 细胞的需求。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 不完全理解。定义控制组织中燃料利用的分子途径对于 了解系统性稳态和病理脂质积累的根本原因 代谢疾病的设置。我们已经确定了Clstn3，这是一种脂肪组织和肝选择性产品 CLSTN3基因，作为多眼LD形态和功能的关键决定剂。 Clstn3是不可或缺的ER 膜蛋白通过配置的发夹样域定位于ER-LLD接触位点。损失Clstn3 小鼠棕色脂肪组织（BAT）增加LD大小，降低甘油三酸酯的利用，并导致冷 - 诱发体温过低。相反，脂肪细胞中clstn3的依托表达足以降低LD大小 并强制执行多眼LD表型。总的来说，这些最初的发现揭示了以前的 无法识别的分子机制，可最大化LD表面积并促进脂质利用率 热脂肪细胞和潜在的其他细胞。该提议的总体目标是进一步定义 Clstn3作用的机制及其对代谢生理的贡献。特定的目标1将阐明 CLSTN3调节LD结构和功能的机制。具体目标2将调查 clstn3修改白色脂肪细胞功能。具体目标3将定义clstn3在脂质代谢中的作用 其他组织。预计这些研究将提供对调节LD功能的途径的基本见解 并可能建议在代谢疾病的情况下调节脂质利用率。