BAT as a therapeutic for the metabolic and cardiac dysfunction with senescence.

BAT 作为治疗衰老代谢和心脏功能障碍的药物。

• 批准号: 10355418
• 负责人: Paul Martin Coen
• 金额: $ 60.19万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-05-15 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10355418
• 关键词: Ablation; Acute; Address; Adult; Affect; Age; Aging; Area; Body Composition; Body mass index; Brown Fat; Cardiovascular Diseases; Cardiovascular Physiology; Cardiovascular system; Chemicals; Chronic; Clinical Data; Collaborations; Data; Development; Disease; Echocardiography; Educational Intervention; Elderly; Endocrine; Energy Metabolism; Excision; Exercise; Fatty Acids; Genetic; Glucose; Goals; Health; Healthcare; Heart; Human; Impairment; Injections; Left; Link; Lipids; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Mitochondria; Mus; Myocardial dysfunction; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Performance; Peripheral; Phenotype; Physiologic intraventricular pressure; Plasma; Play; Population; Process; Pump; Research Proposals; Risk Factors; Rodent; Role; Signal Transduction; Testing; Therapeutic; Tissue Transplantation; Tissues; Transplantation; VO2max; age effect; aged; aging population; cardiovascular health; combat; comorbidity; disorder risk; exercise training; experimental study; fatty acid metabolism; glucose uptake; heart function; improved; in vivo; innovation; insulin sensitivity; mortality; novel; novel therapeutic intervention; oxidation; pre-clinical; pressure; respiratory; response; sedentary; senescence; therapeutic target; tool; uptake; young adult

PROJECT SUMMARY/ABSTRACT The US population is rapidly aging. It is projected that by 2030, more than 20% of the population will be over 65 years of age1. Aging is accompanied by increased metabolic and cardiovascular disease. An important tissue to combat metabolic disease and influence heart function is brown adipose tissue (BAT). Brown adipose tissue (BAT) is a thermogenic tissue that has a high capacity for both glucose and lipid oxidation, making BAT a potential target to decrease plasma glucose and lipids and to protect against obesity and it's co- morbidities, including type 2 diabetes and cardiovascular disease (CVD). Increasing the amount of BAT by transplantation improves metabolic health, reduces adiposity, and increases glucose uptake into the heart. BAT has great potential as a therapeutic target to combat both metabolic and cardiovascular disease, but BAT decreases with age. Thus, we hypothesized that increasing BAT could be a potential therapeutic to improve the metabolic and cardiovascular impairments that occur with aging. Our preliminary data demonstrate that transplantation of BAT into an aged mouse (18 months) improves metabolic and cardiovascular health. We have also generated exciting data showing that exercise increases the signaling lipid 12,13-diHOME from BAT in humans. 12,13-diHOME is decreased with age in both humans and mice, while exercise in an elderly population restores 12,13-diHOME to concentrations similar to young adult subjects. Injection of this lipid into mice has a direct effect on the heart, increasing left ventricular pressure development. Taken together, our exciting preliminary data show that 1) transplantation of BAT improves metabolic and cardiovascular health in an aged mouse; 2) exercise-training increases the signaling lipid 12,13-diHOME; 3) concentrations of 12,13- diHOME are decreased with age in humans and mice; and 4) injection of 12,13-diHOME in mice directly affects heart function. Here, we will test the novel paradigm that BAT exerts endocrine effects that improves metabolic health and cardiac function in senescence with three specific aims: 1) Determine the role of BAT on age-induced impairments in metabolism and insulin sensitivity; 2) Determine the role of BAT on the age- induced impairments in cardiac function; and 3) Determine if BAT mass and endocrine function is linked with metabolism or cardiac function in older adults. This project will establish if increasing BAT, and specifically the lipid 12,13-diHOME, negates the metabolic and cardiovascular impairments that occur with senescence in rodents and humans. The proposed studies have the potential to elucidate a novel role, and potential therapeutic approach, for BAT to negate the detrimental effects of aging. .

项目概要/摘要 美国人口正在迅速老龄化。预计到2030年，超过20%的人口将超过 65岁1.衰老伴随着代谢和心血管疾病的增加。一个重要的 对抗代谢疾病和影响心脏功能的组织是棕色脂肪组织（BAT）。棕色的 脂肪组织（BAT）是一种产热组织，具有较高的葡萄糖和脂质氧化能力， 使 BAT 成为降低血浆葡萄糖和血脂并预防肥胖的潜在目标，并且它的共同作用 疾病，包括 2 型糖尿病和心血管疾病 (CVD)。增加 BAT 的数量 移植改善代谢健康，减少肥胖，并增加心脏对葡萄糖的摄取。 BAT 作为对抗代谢和心血管疾病的治疗靶点具有巨大潜力，但 BAT 随着年龄的增长而减少。因此，我们假设增加 BAT 可能是改善病情的潜在疗法。 随着衰老而发生的代谢和心血管损伤。我们的初步数据表明 将 BAT 移植到老年小鼠（18 个月）体内可改善代谢和心血管健康。我们 还产生了令人兴奋的数据，表明运动会增加 BAT 的信号脂质 12,13-diHOME 在人类中。在人类和小鼠中，12,13-diHOME 都会随着年龄的增长而减少，而老年人运动时 人群将 12,13-diHOME 恢复到与年轻成人受试者相似的浓度。将这种脂质注射到 对小鼠心脏有直接作用，增加左心室压力的发展。综合起来，我们的 令人兴奋的初步数据表明 1) BAT 移植可改善代谢和心血管健康 一只老老鼠； 2) 运动训练增加信号脂质12,13-diHOME； 3) 12,13-浓度 在人类和小鼠中，diHOME 随着年龄的增长而减少； 4) 直接给小鼠注射12,13-diHOME 影响心脏功能。在这里，我们将测试 BAT 发挥内分泌作用改善内分泌的新范例 衰老过程中的代谢健康和心脏功能，具有三个具体目标：1) 确定 BAT 对衰老的作用 年龄引起的新陈代谢和胰岛素敏感性受损； 2) 确定 BAT 对年龄的作用- 诱发心脏功能受损； 3) 确定 BAT 质量和内分泌功能是否与 老年人的新陈代谢或心脏功能。该项目将确定是否增加 BAT，特别是 脂质 12,13-diHOME，消除衰老过程中发生的代谢和心血管损伤 啮齿动物和人类。拟议的研究有可能阐明新的作用，并且有潜力 BAT 的治疗方法可以消除衰老的不利影响。 。