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

项目总结/摘要 美国人口正在迅速老龄化。据预测，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 对抗代谢疾病和影响心脏功能的组织是棕色脂肪组织（BAT）。布朗 脂肪组织（BAT）是具有高葡萄糖和脂质氧化能力的产热组织， 使BAT成为降低血糖和血脂以及预防肥胖的潜在靶点， 疾病，包括2型糖尿病和心血管疾病（CVD）。增加最佳可得技术的数量， 移植改善了代谢健康、减少了肥胖、并增加了葡萄糖摄取到心脏中。 BAT作为治疗代谢和心血管疾病的治疗靶点具有巨大的潜力，但BAT 随着年龄的增长而减少。因此，我们假设增加BAT可能是一种潜在的治疗方法， 随着年龄的增长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）中可改善代谢和心血管健康。我们 还产生了令人兴奋的数据，显示运动增加了BAT的信号脂质12，13-diHOME 在人类身上。12，13-diHOME在人类和小鼠中均随着年龄的增长而减少，而在老年人中， 群体将12，13-diHOME恢复至与年轻成人受试者相似的浓度。将这种脂质注射到 对小鼠心脏有直接影响，增加左心室压力的发展。总的来说，我们的 令人兴奋的初步数据表明，1）BAT的移植改善了代谢和心血管健康， 老年小鼠; 2）运动训练增加信号脂质12，13-diHOME; 3）12，13-diHOME的浓度。 在人类和小鼠中随着年龄的增长而减少;以及4）在小鼠中直接注射12，13-diHOME 影响心脏功能在这里，我们将测试BAT发挥内分泌作用的新范式， 代谢健康和心脏功能在衰老的三个具体目标：1）确定BAT的作用， 年龄引起的代谢和胰岛素敏感性损伤; 2）确定BAT对年龄的作用， 心功能的损伤;以及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最佳可得技术，特别是 脂质12，13-diHOME，否定了代谢和心血管损伤，发生与衰老， 啮齿动物和人类。拟议的研究有可能阐明一种新的作用， 治疗方法，为BAT否定老化的有害影响。 .

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. .