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节机制 以及肥胖和糖尿病的全身生理学。该提案将提出一条新的监管途径 参与脂肪组织脂肪库特定的能量消耗。了解代谢组织如何 储存和利用脂质与正常生理、肥胖症和糖尿病具有中心相关性。中性脂质过多 储存在脂滴（LDs）中，脂滴是一种动态细胞器，根据代谢水平的不同而膨胀和收缩。 细胞的需要。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。确定控制组织中燃料利用的分子途径对以下方面很重要： 了解全身稳态和病理性脂质蓄积的根本原因， 代谢性疾病的设置。我们已经鉴定了Clstn 3 β，一种脂肪组织和肝脏选择性产物， Clstn 3基因是决定多房LD形态和功能的关键基因。Clstn 3是一个积分ER 通过保守的发夹样结构域定位于ER-LD接触位点的膜蛋白。Clstn 3丢失 小鼠棕色脂肪组织（BAT）增加LD大小，减少甘油三酯利用，并导致冷- 诱导性体温过低相反，脂肪细胞中Clstn 3 β的异位表达足以减少LD大小， 并形成多房LD表型。总的来说，这些最初的发现揭示了一个以前 未被认识的分子机制，最大限度地提高LD表面积和促进脂质利用， 产热脂肪细胞和潜在的其它细胞。本提案的总体目标是进一步界定 Clstn 3的作用机制及其对代谢生理学的贡献。具体目标1将阐明 Clstn 3 β调节LD结构和功能的机制。具体目标2将调查的能力， Clstn 3修饰白色脂肪细胞功能。具体目标3将定义Clstn 3 β在脂质代谢中的作用， 其他组织。这些研究有望为LD功能的调控途径提供基本的见解 并可能表明在代谢疾病背景下调节脂质利用的机会。