Vitamin D control of calorie allocation to muscle

项目摘要/摘要 肥胖导致糖尿病、心脏病和癌症的比例最大，而且对目前的 尽管治疗是紧张研究的重点。肥胖是因为身体储存了多余的卡路里 作为脂肪，这反过来又导致与肥胖相关的健康风险6-10。目前的治疗方法是 肥胖侧重于通过限制卡路里和/或锻炼来减肥，但这些都是无效的。另一种策略 就是把多余的卡路里用来锻炼肌肉，而不是储存脂肪。这种方法将缓解 它不仅可以降低肥胖的健康风险，还可以改善日常功能、生活质量和寿命。我们引人入胜的预赛 数据显示，高剂量的饮食维生素D反而减少了储存在脂肪中的多余卡路里比例 将这些卡路里分配给肌肉。理解这一发现背后的机制将推动 开发预防和治疗肥胖症迫切需要的新的治疗方法。此外，我们的 初步结果表明，这种热量分配到肌肉是通过25D介导的维生素D受体实现的 (VDR)非规范VDR结合位点的转录调控。 我们的长期目标是确定维生素D在热量分配中的作用，以确定新的治疗方法 肥胖的目标。该项目的具体目标是：1)确定饮食中的维生素D代谢物， 25d或1，25d，发出信号将卡路里分配给肌肉，以及2)确定肌肉中维生素 D信号导致热量分配相关基因表达的变化。使用鼠标模型，我们有 研究表明，高剂量的膳食维生素D增加肌肉质量、横截面积、力量/面积和 瘦小鼠和肥胖小鼠的肌肉线粒体能力。我们的中心假设是高剂量的维生素 D卡路里的分配是由25D通过VDR起作用，通过非正则结合改变转录来调节的 网站。我们的方法使用了经过验证的维生素D失衡的基因工程小鼠模型，并将 通过全基因组分析VDR结合来发出转录变化的信号。 总而言之，这项建议描述了一个五年研究计划，以了解非 维生素D的钙代谢作用长期优先将热量分配给肌肉而不是脂肪 开发合理的肥胖症新疗法的目标。首席调查员是一名助理教授 在宾夕法尼亚大学获得终身教职。他是一名早期职业研究人员，致力于询问翻译 更好地了解维生素D的非钙代谢作用的问题他已经组装了一种唯一合格的 和互为补充的协作团队，以实现此应用程序的目标。成功完成这项工作 研究工作将确定25D在调节维生素D肌肉卡路里分配中的作用，并将确定相关信号 治疗上可以有针对性的途径，优先将多余的卡路里分配给肌肉，而不是 脂肪，从而减少不必要的影响和肥胖率。

PROJECT SUMMARY/ABSTRACT Obesity causes the greatest proportional risk for diabetes, heart disease, and cancer and is resistant to current treatments despite being a focus of intense research. Obesity occurs because the body stores surplus calories as fat, which in turn drives the health risks associated with obesity6-10. The current therapeutic approaches to obesity focus on weight loss, via caloric restriction and/or exercise, which are not effective. An alternate strategy would be to redirect surplus calories to build muscle instead of storage as fat. This approach would mitigate the health risks of obesity and also improve daily functioning, quality of life, and longevity. Our intriguing preliminary data reveal that high-dose dietary vitamin D decreases the proportion of excess calories stored as fat, instead allocating these calories to muscle. Understanding the mechanisms underlying this finding will drive the development of novel therapeutic approaches desperately needed to prevent and treat obesity. Further, our preliminary results suggest that this calorie allocation to muscle occurs via 25D mediated vitamin D receptor (VDR) transcriptional regulation at non-canonical VDR binding sites. Our long term goal is to define the roles of vitamin D in calorie allocation in order to identify novel therapeutic targets in obesity. The specific objectives of this project are 1) to determine which dietary vitamin D metabolite, 25D or 1,25D, signals to allocate calories to muscle, and 2) to identify the mechanisms in muscle whereby vitamin D signaling leads to changes in gene expression underlying calorie allocation. Using mouse models, we have demonstrated that high-dose dietary vitamin D increases muscle mass, cross sectional area, strength/area, and muscle mitochondrial capacity in both lean and obese mice. Our central hypothesis is that high-dose vitamin D calorie allocation is mediated by 25D acting via the VDR to alter transcription through non-canonical binding sites. Our approach uses validated genetically engineered mouse models of vitamin D imbalance, and connects signaling to transcriptional changes by genome-wide analysis of VDR binding. In sum, this proposal describes a five-year research plan to understand the mechanisms underlying non- calciometabolic actions of vitamin D to preferentially allocate calories to muscle instead of fat with the long-term goal of developing novel rational therapies for obesity. The primary investigator is an Assistant Professor on the tenure track at the University of Pennsylvania. He is an early career researcher dedicated to asking translational questions to better understand non-calciometabolic actions of vitamin D. He has assembled a uniquely qualified and complementary collaborative team to tackle the objectives of this application. Successful completion of this work will define the role of 25D in mediating vitamin D muscle calorie allocation and will identify relevant signaling pathways that could be targeted therapeutically to preferentially allocate surplus calories to muscle instead of fat, thereby decreasing both unwanted effects and incidence of obesity.