Exploring the role of lactate in adipose tissue thermogenesis

探索乳酸在脂肪组织产热中的作用

• 批准号: 10843713
• 负责人: Marc Bornstein
• 金额: $ 3.51万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-05-01 至 2025-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10843713
• 关键词: Acute; Adipose tissue; Adrenergic Agents; Affect; Anesthesia procedures; Automobile Driving; Award; Basic Science; Body Temperature; Brown Fat; Calories; Carbon; Cardiometabolic Disease; Citric Acid Cycle; Clinical; Clinical Medicine; Consumption; Data; Development; Disease; Doctor of Medicine; Doctor of Philosophy; Energy Metabolism; Environment; Enzymes; Evolution; Exposure to; Fatty acid glycerol esters; Feeds; Fellowship; Future; Gene Expression; Generations; Genetic Models; Glucose; Healthcare; Impairment; Infusion procedures; Intake; Knock-out; Knockout Mice; Label; Lactate Dehydrogenase; Learning; Mammals; Measures; Mediating; Mentorship; Metabolic; Metabolic Diseases; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Morbidity - disease rate; Mus; NADH; Norepinephrine; Nutrient; Obesity; Obesity associated disease; Organ; Oxygen Consumption; Pathogenesis; Pennsylvania; Pentobarbital; Physicians; Plasma; Play; Process; Production; Protein Isoforms; Protons; Public Health; Pyruvate; Ramp; Research; Research Personnel; Role; Scientist; Source; Subcutaneous Injections; Techniques; Testing; Thermogenesis; Tissues; Training; United States; Universities; Weight Gain; Wild Type Mouse; Work; career; clinical practice; clinically relevant; falls; fatty acid oxidation; improved; in vivo; insight; interest; mitochondrial membrane; mortality; novel therapeutics; obesity treatment; optogenetics; oxidation; pre-doctoral; programs; pyruvate carrier; response; skills; stable isotope; targeted treatment; uncoupling protein 1

PROJECT SUMMARY: Obesity and obesity-related cardiometabolic diseases are growing causes of morbidity and mortality in the U.S. and around the world. Obesity develops when nutrient intake exceeds the body's energy demands, leading to storage of excess calories and weight gain. As such, mechanisms regulating the body's energy demands serve as attractive targets for treating obesity and related diseases. Brown adipose tissue (BAT) is an important organ regulating energy use in mammals. During exposure to cold, BAT activates UCP1, which uncouples nutrient consumption from ATP production, releasing the energy instead as heat, a process called thermogenesis. BAT thermogenesis relies on utilization of a variety of metabolic substrates. An underexplored metabolic substrate in the context of BAT thermogenesis is lactate. Under basal conditions, lactate metabolism plays a predominant role in whole-body carbon flux. However, it remains unknown how systemic and BAT lactate metabolism changes during cold exposure or what role lactate metabolism plays in thermogenesis. BAT activation induces expression of lactate dehydrogenase (LDH), the enzyme mediating interconversion of lactate to pyruvate. Stimulation of BAT also causes tissue lactate levels to fall, suggesting lactate may be consumed during thermogenesis. Thus, I hypothesize that during cold exposure, BAT consumes lactate via LDH and that this contributes to thermogenesis. In Aim 1, I will utilize stable isotope tracing approaches in mice to determine how cold exposure affects systemic and BAT lactate fluxes. Further, I will inhibit LDH activity in BAT via an inducible UCP1- driven knockout of LDHA, the primary LDH isoform in BAT, to test whether BAT net consumes or produces lactate by measuring whether lactate levels rise or fall relative to other substrates following LDH inhibition. In Aim 2, I will utilize my genetic model to test whether LDH is important for BAT thermogenesis by measuring cold tolerance and β adrenergic-induced BAT activation in the knockout mice relative to controls. These studies serve as the basis for my pre-doctoral fellowship application awarded to M.D./Ph.D. applicants. My training plan is focused on preparing me for a career as a physician-scientist. Through this highly clinically relevant research, combined with continued exposure to clinical medicine, I will develop the skills necessary to successfully blend basic science and clinical practice in my career. Under the excellent mentorship of Dr. Zoltan Arany, a physician- scientist himself, and as part of the well-established M.D./Ph.D. program at the University of Pennsylvania, I am in the perfect environment to pursue this exciting career.

项目摘要： 肥胖和与肥胖相关的心脏代谢疾病在美国越来越多的发病率和死亡率原因 和世界各地。当营养摄入超过人体的能量需求时，肥胖就会发展 储存多余的卡路里和体重增加。因此，调节人体能量需求的机制服务 作为治疗肥胖和相关疾病的有吸引力的靶标。棕色脂肪组织（BAT）是重要器官 调节哺乳动物的能源使用。在暴露于冷的过程中，BAT激活UCP1，这使ucp1无法养成营养 从ATP生产中消耗的消耗，将能量作为热量释放，这是一种称为热生成的过程。蝙蝠 热发生依赖于多种代谢底物的利用。未经充实的代谢基质 蝙蝠热发生的上下文是缝隙。在基本条件下，新陈代谢占主导地位 在全身碳通量中的作用。但是，尚不清楚系统性和蝙蝠的新陈代谢如何变化 在冷暴露期间，或在热发生中涉及代谢的作用。 BAT激活诱导表达 葡萄酸盐脱氢酶（LDH）的酶，介导裂解酸盐的酶介导向丙酮酸。刺激 BAT还会导致组织乳酸水平下降，这表明在热发生过程中可能会消耗乳酸。那， 我假设在冷暴露期间，蝙蝠会通过LDH消耗鞋底，这有助于 热发生。在AIM 1中，我将利用小鼠中稳定的同位素跟踪方法来确定暴露的暴露方式 影响系统性和蝙蝠插入通量。此外，我将通过诱导的UCP1-抑制BAT中的LDH活性 LDHA的驱动淘汰赛是BAT中的主要LDH同工型，以测试BAT净消耗还是产生蝙蝠 通过测量LDH抑制后相对于其他底物的鞋底水平是否上升还是下降来进行磨损。在 AIM 2，我将利用我的遗传模型来测量LDH是否对BAT的热发生很重要 相对于对照组，敲除小鼠中的冷耐受性和β肾上腺素诱导的蝙蝠激活。这些研究 作为我授予M.D./ph.d的博士前奖学金申请的基础。申请。我的培训计划 专注于为我作为身体科学家的职业做好准备。通过这项高度临床相关的研究， 结合持续接触临床医学，我将发展成功融合所需的技能 我职业生涯的基础科学和临床实践。在Zoltan Arany博士的出色心态下， 科学家本人，也是公认的M.D./ph.d的一部分。我是宾夕法尼亚大学的课程 在完美的环境中，追求这一激动人心的职业。