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.

摘要 我们实验室的一个主要目标是描述控制脂肪细胞发育的调控机制。 以及肥胖和糖尿病的系统生理学。这项提案将解决一条新的监管途径。 参与脂肪组织脂肪储存库的特定能量消耗。了解新陈代谢组织如何 储存和利用脂类与正常生理、肥胖和糖尿病密切相关。过量中性脂类 储存在脂滴(LD)中--动态细胞器，根据新陈代谢而膨胀和收缩 细胞的需求。将脂代谢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。确定控制组织中燃料利用的分子途径对 了解全身动态平衡和病理性脂质堆积的根本原因 代谢性疾病的背景。我们已经鉴定出Clstn3，一种脂肪组织和肝脏选择性的产物 Clstn3基因作为多房性LD形态和功能的关键决定因素。Clstn3是一个完整的ER 通过保守的发夹状结构域定位于ER-LD接触部位的膜蛋白。中丢失Clstn3 小鼠棕色脂肪组织(BAT)增加LD大小，降低甘油三酯的利用，并导致感冒 诱导体温过低。相反，在脂肪细胞中异位表达Clstn3足以减少LD大小 并实施多房性LD表型。总体而言，这些初步发现揭示了以前的 未知的分子机制，最大限度地增加LD表面积和促进脂质的利用 产热脂肪细胞和潜在的其他细胞。这项提案的总体目标是进一步定义 Clstn3的作用机制及其对代谢生理学的贡献具体目标1将阐明 Clstn3调节LD结构和功能的机制。《特定目标2》将调查 Clstn3修饰白色脂肪细胞功能。具体目标3将定义Clstn3在脂类代谢中的作用 其他纸巾。这些研究有望为调节LD功能的途径提供基础性的见解 并可能建议在代谢性疾病的背景下调节脂质利用的机会。