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: 10462920
• 负责人: Marc Bornstein
• 金额: $ 3.42万
• 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/10462920
• 关键词: Acute; Adipose tissue; Adrenergic Agents; Affect; 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.

项目概要： 在美国，肥胖和肥胖相关的心脏代谢疾病是发病率和死亡率不断增长的原因。 和在世界各地.当营养摄入超过身体的能量需求时，肥胖就会发生， 储存多余的卡路里和体重增加。因此，调节身体能量需求的机制 作为治疗肥胖症和相关疾病的有吸引力的靶点。棕色脂肪组织（BAT）是一种重要的器官， 调节哺乳动物的能量使用。在暴露于寒冷中时，BAT激活UCP 1， 消耗ATP的生产，释放能量，而不是作为热量，一个过程称为产热。蝙蝠 产热依赖于多种代谢底物的利用。一种未充分研究的代谢底物， BAT产热的背景是乳酸盐。在基础条件下，乳酸代谢起主导作用， 在全身碳通量中的作用。然而，仍不清楚全身和BAT乳酸代谢如何变化 或者乳酸代谢在产热中扮演什么角色。BAT激活诱导表达 乳酸脱氢酶（LDH）是一种介导乳酸转化为丙酮酸的酶。刺激 BAT还导致组织乳酸水平下降，表明乳酸可能在产热过程中被消耗。因此，在本发明中， 我推测，在冷暴露期间，BAT通过LDH消耗乳酸，这有助于 产热作用在目标1中，我将利用小鼠的稳定同位素示踪方法来确定冷暴露 影响全身和BAT乳酸盐通量。此外，I将通过诱导型UCP 1 - 1抑制BAT中的LDH活性。 驱动敲除LDHA（BAT中的主要LDH同种型），以测试BAT是否净消耗或产生 通过测量LDH抑制后乳酸水平相对于其他底物是否升高或降低来测定乳酸。在 目的2，我将利用我的遗传模型，以测试是否LDH是重要的BAT产热通过测量 与对照组相比，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 作为我的博士前奖学金申请授予医学博士/博士申请者我的训练计划 致力于为我成为一名物理学家兼科学家做准备。通过这项高度临床相关的研究， 再加上继续接触临床医学，我将发展必要的技能，成功地融合 基础科学和临床实践。在佐尔坦·阿拉尼医生的出色指导下，一位内科医生- 科学家自己，作为公认的医学博士的一部分。博士在宾夕法尼亚大学的项目，我是 在完美的环境中追求这一令人兴奋的职业。