Mechanisms of exercise effects in obese humans: sex-specific regulation of novel adipose tissue function

项目摘要/摘要 肥胖是一种重大的健康危机，非常需要为这种疾病开发新的治疗方法。常规 体力活动对于预防和治疗肥胖症和2型糖尿病至关重要，但其机制 这些影响背后的原因还没有得到很好的理解。虽然运动训练已经被广泛研究，因为它 运动训练对改善血糖稳态和骨骼肌代谢的影响 人们对脂肪组织的功能知之甚少。对于肥胖的男性和女性来说尤其如此。 最近，我们使用啮齿动物模型提供了证据，证明运动训练可以导致适应 脂肪组织，调节运动对葡萄糖稳态的一些有益影响。其中一些 益处可能是由称为脂肪因子的新型脂肪衍生因子介导的。另一位可能的调解人 运动对脂肪组织代谢的影响可能是对褐变的诱导。米色脂肪细胞 燃料氧化和生热作用增加，使米色成为治疗肥胖症的潜在疗法。我们的研究，沿着 已经清楚地表明，运动训练会导致雄性啮齿类动物出现褐变，但我们最近的研究 数据显示，肥胖可能会抵消运动引起的褐变。此外，我们发现只有运动训练 增加雄性小鼠的褐变，但不增加雌性小鼠的褐变。关于米色和小说的研究很有限，或者根本没有。 运动诱导的人类脂肪因子。因此，这一职业发展奖的研究重点是 确定运动训练是否调节新的脂肪因子生理学、循环因子和褐变 肥胖的女性和男性。具体目的是：1)阐明肥胖对运动训练的影响- 人类受试者对scWAT的诱导调节，并确定训练诱导的适应是否 SCWAT是性别特异性的；2)确定运动的性别特异性调节的潜在机制 训练诱导的对scwat的适应；以及3)表征和发现新的运动调节 脂肪因子，并确定循环因素作为运动诱导的瘦肉和脂肪代谢变化的生物标志物。 肥胖的男人和女人。这一职业发展奖的首席调查者有很强的 运动生理学和人类翻译研究背景，但将受益于额外的职业 发展转变为一个成功的、独立的调查者。指导委员会由一个 由国家公认的运动生理学、脂肪组织生物学领域的领导者组成的强大的多学科团队 以及内科医生--在人类翻译生理学方面有专长的科学家。拟议的职业发展 计划概述了详细的课程安排，并利用了可通过 乔斯林糖尿病中心和哈佛大学合作，确保向独立的成功过渡。通过 进行这些研究，与指导委员会密切合作，并完成教育 目标，首席调查员将获得开始独立职业生涯的专业知识 解释运动对健康益处的潜在机制的翻译调查者。

Project Summary/Abstract Obesity is a major health crisis and there is a great need to develop new treatments for this disease. Regular physical activity is crucial for the prevention and treatment of obesity and type 2 diabetes, but the mechanisms that underlie these effects are not well understood. While exercise training has been extensively studied for its effect on improving glucose homeostasis and skeletal muscle metabolism, the effects of exercise training on adipose tissue function are only poorly understood. This is especially the case for obese men and women. Recently, we have provided evidence using rodent models that exercise training can cause adaptations to adipose tissue that mediate some of the beneficial effects on exercise on glucose homeostasis. Some of these benefits may be mediated by novel adipose-derived factors called adipokines. Another putative mediator of the effects of exercise on adipose tissue metabolism may be the induction of beiging. Beige adipocytes have increased fuel oxidation and thermogenesis, making beiging a potential therapy for obesity. Our research, along with others, has clearly shown that exercise training causes scWAT beiging in male rodents, but our more recent data show that obesity may negate exercise-induced beiging. In addition, we find that exercise training only increases beiging in male, but not female mice. There have only been limited, or no studies of beiging and novel exercise-induced adipokines in humans. Thus, the research focus of this career development award is to determine whether exercise training regulates novel adipokine physiology, circulating factors, and beiging in obese women and men. The Specific Aims are: 1) To elucidate the effects of obesity on exercise training- induced regulation of scWAT beiging in human subjects, and to determine if training-induced adaptations to scWAT are sex-specific; 2) To determine the underlying mechanisms of sex-specific regulation of exercise training-induced adaptations to scWAT; and 3) To characterize and discover novel exercise-regulated adipokines, and to identify circulating factors as biomarkers of exercise-induced metabolic changes in lean and obese men and women. The Principal Investigator on this Career Development Award has a strong background in exercise physiology and human translational research, but will benefit from additional career development to transform into a successful, independent investigator. The mentoring committee consists of a strong multi-disciplinary team of nationally recognized leaders in exercise physiology, adipose tissue biology and physician-scientists with expertise in human translational physiology. The proposed career development plan outlines detailed coursework and utilizes the stimulating, resource-rich environments available through the Joslin Diabetes Center and Harvard University to ensure a successful transition toward independence. By conducting these studies, working closely with the mentoring committee, and completing the educational objectives, the Principal Investigator will acquire the expertise to embark upon a career as an independent translational investigator elucidating the mechanisms underlying the benefits of exercise on health.