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

项目摘要/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.衰老伴随着新陈代谢和心血管疾病的增加。一个重要的 对抗代谢性疾病和影响心脏功能的组织是棕色脂肪组织(BAT)。棕色 脂肪组织(BAT)是一种产热组织，具有很高的葡萄糖和脂肪氧化能力， 使BAT成为降低血糖和血脂以及预防肥胖的潜在靶点，它的共同作用是 发病率，包括2型糖尿病和心血管疾病(CVD)。通过以下方式增加BAT数量 移植可以改善代谢健康，减少肥胖，并增加心脏对葡萄糖的摄取。 作为对抗代谢和心血管疾病的治疗靶点，BAT具有巨大的潜力，但 随着年龄的增长而减少。因此，我们假设增加BAT可能是一种潜在的改善治疗方法。 随着年龄增长而出现的新陈代谢和心血管损伤。我们的初步数据表明 将BAT移植到一只老龄小鼠(18个月)可以改善代谢和心血管健康。我们 也产生了令人兴奋的数据，表明运动增加了BAT的信号脂质12，13-diHOME 在人类身上。在人类和小鼠中，12，13-diHOME随着年龄的增长而减少，而老年人运动时 人群将12，13-diHOME的浓度恢复到与年轻受试者相似的浓度。将这种脂类注射到 小鼠对心脏有直接作用，增加左心室内压的发展。总而言之，我们的 令人兴奋的初步数据显示，1)移植BAT改善了人体的代谢和心血管健康 2)运动训练增加信号脂12，13-diHOME；3)12，13-diHOME浓度 人和小鼠的diHOME随年龄增长而降低；4)直接在小鼠体内注射12，13-diHOME 会影响心脏功能。在这里，我们将测试BAT施加内分泌效应的新范例，它可以改善 衰老时的代谢健康和心功能有三个特定的目的：1)确定BAT在 年龄引起的代谢和胰岛素敏感性障碍；2)确定BAT在年龄- 诱发的心脏功能损害；以及3)确定蝙蝠体重和内分泌功能是否与 老年人的新陈代谢或心脏功能。该项目将建立如果增加BAT，特别是 脂质12，13-diHOME，消除衰老所致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一种新的作用和潜力 治疗方法，为BAT否定衰老的有害影响。 。

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. .