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.

项目总结： 在美国，肥胖和肥胖相关的心脏代谢性疾病是发病率和死亡率的日益增长的原因。 以及在世界各地。当营养摄入量超过身体的能量需求时，就会发生肥胖，导致 储存过多的卡路里和体重增加。因此，调节身体能量需求的机制 作为治疗肥胖和相关疾病的有吸引力的靶点。棕色脂肪组织(BAT)是人体的重要器官 调节哺乳动物的能量使用。在寒冷中，蝙蝠会激活UCP1，使营养物质解偶联 从ATP生产中消耗，释放能量而不是热量，这一过程被称为生热作用。蝙蝠 生热作用依赖于对各种代谢底物的利用。一种未被开发的代谢底物 蝙蝠产热的背景是乳酸。在基础条件下，乳酸代谢起主导作用 在全身碳流中的作用。然而，目前尚不清楚全身和蝙蝠乳酸代谢是如何变化的。 在冷暴露期间，或乳酸代谢在产热中起什么作用。BAT激活诱导表达 乳酸脱氢酶(LDH)是一种催化乳酸转化为丙酮酸的酶。刺激 BAT还会导致组织乳酸水平下降，这表明乳酸可能在产热过程中被消耗。因此， 我推测，在冷暴露期间，蝙蝠通过乳酸脱氢酶消耗乳酸，这有助于 生热作用。在目标1中，我将利用小鼠的稳定同位素示踪方法来确定寒冷暴露的程度 影响全身和蝙蝠乳酸的通量。此外，我将通过可诱导的UCP1-抑制BAT中的LDH活性- 驱动敲除BAT中主要的LDH亚型LDHA，以测试BAT Net是否消耗或产生 通过测量乳酸脱氢酶抑制后乳酸水平相对于其他底物是上升还是下降。在……里面 目的2，我将利用我的遗传模型通过测量来测试乳酸脱氢酶对蝙蝠产热是否重要 与对照组相比，基因敲除小鼠的耐寒性和β肾上腺素能诱导的BAT激活。这些研究 作为我授予医学博士/博士学位申请者博士前奖学金的基础。我的培训计划 专注于为我的职业生涯做准备，成为一名内科科学家。通过这项高度临床相关的研究， 再加上继续接触临床医学，我将培养成功融合的必要技能 基础科学和临床实践在我的职业生涯中。在佐尔坦·阿兰尼医生的出色指导下- 科学家本人，以及宾夕法尼亚大学著名的医学博士项目的一部分，我是 在完美的环境中追求这一激动人心的事业。