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

肥胖人群运动效果的机制：新型脂肪组织功能的性别特异性调节

• 批准号: 10667772
• 负责人: ROELAND J MIDDELBEEK
• 金额: $ 13.64万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10667772
• 关键词: Address; Adipocytes; Adipose tissue; Aerobic Exercise; Biological Markers; Biology; Clinical Research; Data; Development; Development Plans; Diabetes Mellitus; Disease; Ensure; Environment; Exercise; Exercise Physiology; Female; Functional disorder; Genomics; Goals; Health; High Fat Diet; Human; Impairment; K-Series Research Career Programs; Knowledge; Lead; Mediating; Mediator of activation protein; Mentors; Metabolic; Metabolic Diseases; Metabolism; Molecular; Mus; Muscle; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Overweight; Physical activity; Physicians; Physiology; Play; Prevention; Principal Investigator; Process; Proteins; Proteomics; Rattus; Regulation; Research; Research Personnel; Resources; Rodent; Rodent Model; Role; Scientist; Skeletal Muscle; Stimulus; Thermogenesis; Thinness; Tissues; Training; Transforming Growth Factor Beta 2; Translational Research; United States; Universities; Woman; adipokines; base; blood glucose regulation; career; career development; energy balance; exercise program; exercise training; experimental study; human subject; improved; interest; male; men; multidisciplinary; novel; novel therapeutics; obese person; obesity management; obesity treatment; oxidation; potential biomarker; response; sex; skeletal muscle metabolism; subcutaneous; translational scientist

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.

项目总结/摘要 肥胖是一个重大的健康危机，非常需要为这种疾病开发新的治疗方法。定期 身体活动对于预防和治疗肥胖和2型糖尿病至关重要，但其机制 这些影响背后的原因还不太清楚。虽然运动训练已经被广泛研究， 对改善葡萄糖稳态和骨骼肌代谢的作用，运动训练对 脂肪组织的功能知之甚少。尤其是肥胖的男性和女性。 最近，我们使用啮齿动物模型提供了证据，证明运动训练可以引起适应， 脂肪组织介导了运动对葡萄糖稳态的一些有益作用。其中一些 这些益处可以通过称为脂肪因子的新的脂肪衍生因子来介导。另一个假定的调解人 运动对脂肪组织代谢的影响可能是beiging的诱导作用。米色脂肪细胞具有 增加燃料氧化和产热，使beiging成为一种潜在的治疗肥胖的方法。我们的研究，沿着 与其他人，已经清楚地表明，运动训练导致scWAT beiging在雄性啮齿动物，但我们最近 数据显示，肥胖可能会抵消运动引起的肥胖。此外，我们发现，运动训练只 增加雄性小鼠的beiging，但对雌性小鼠没有影响。关于北京与小说的关系， 运动诱导的脂肪因子。因此，这个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， 肥胖的男女具体目的是：1）阐明肥胖对运动训练的影响- 诱导调节scWAT beiging在人类受试者，并确定是否训练诱导的适应， scWAT具有性别特异性; 2）确定性别特异性运动调节的潜在机制 训练诱导的适应scWAT;和3）表征和发现新的运动调节 脂肪因子，并确定循环因子作为运动诱导的代谢变化的生物标志物， 肥胖的男女该职业发展奖的首席研究员具有很强的 在运动生理学和人类转化研究的背景，但将受益于额外的职业生涯 成为一名成功的独立调查员。指导委员会由一名 强大的多学科团队，由国家认可的运动生理学、脂肪组织生物学 以及具有人类转化生理学专业知识的医学科学家。拟议的职业发展 计划概述了详细的课程，并利用刺激，资源丰富的环境，可通过 乔斯林糖尿病中心和哈佛大学，以确保成功过渡到独立。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，主要研究者将获得专业知识，开始作为一个独立的职业生涯， 翻译研究员阐明运动对健康的益处的机制。