Vitamin D control of calorie allocation to muscle

维生素 D 控制肌肉的热量分配

• 批准号: 10567569
• 负责人: Jeffrey David Roizen
• 金额: $ 54.41万
• 依托单位: CHILDREN'S HOSP OF PHILADELPHIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-02-15 至 2028-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10567569
• 关键词: Area; Binding; Binding Sites; Biological Assay; Body Weight decreased; Calcifediol; Calcitriol; Calcium; Caloric Restriction; Calories; Cell Culture Techniques; DNA Binding; Data; Dedications; Development; Diabetes Mellitus; Disease; Dose; Elements; Enzymes; Exercise; Fatty acid glycerol esters; Gene Expression; Generations; Genes; Genetic Transcription; Genetically Engineered Mouse; Goals; Hand Strength; Health; Heart Diseases; Hydroxylation; In Vitro; Incidence; Knock-out; Knockout Mice; Longevity; Malignant Neoplasms; Maps; Measures; Mediating; Metabolism; Mitochondria; Mixed Function Oxygenases; Modeling; Mus; Muscle; Muscle Mitochondria; Muscle function; Obese Mice; Obesity; Output; Oxidative Phosphorylation; Pathway interactions; Pennsylvania; Qualifying; Quality of life; Receptor Signaling; Research; Research Personnel; Resistance; Risk; Role; Running; Serum; Signal Pathway; Signal Transduction; Testing; Therapeutic; Thinness; Time; Transcriptional Regulation; Universities; Vitamin D; Vitamin D Response Element; Vitamin D3 Receptor; Work; career; daily functioning; diabetes risk; dietary; genome-wide; genome-wide analysis; improved; in vivo; mouse model; muscle form; muscle physiology; new therapeutic target; novel; novel therapeutic intervention; obesity risk; obesity treatment; prevent; professor; receptor binding; response; side effect; targeted treatment; tenure track; transcriptome; transcriptome sequencing; treadmill

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.

项目总结/摘要 肥胖导致糖尿病、心脏病和癌症的最大比例风险， 治疗，尽管它是一个密集的研究的焦点。肥胖的发生是因为身体储存了多余的卡路里 作为脂肪，这反过来又推动了与肥胖相关的健康风险6 -10。目前的治疗方法， 肥胖症集中于通过热量限制和/或锻炼来减轻体重，这是无效的。另一种策略 将多余的卡路里转化为肌肉，而不是储存为脂肪。这种方法将减轻 肥胖的健康风险，并改善日常功能，生活质量和长寿。我们有趣的初步调查 数据显示，高剂量的膳食维生素D减少了多余的卡路里以脂肪形式储存的比例， 将这些热量分配给肌肉。了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治疗方法。此外，我们的 初步结果表明，这种热量分配给肌肉是通过25 D介导的维生素D受体发生的 (VDR)在非典型VDR结合位点的转录调控。 我们的长期目标是确定维生素D在卡路里分配中的作用，以确定新的治疗方法。 肥胖的目标。该项目的具体目标是：1）确定哪些膳食维生素D代谢物， 25 D或1，25 D，信号分配卡路里的肌肉，和2）确定机制，在肌肉中，维生素 D信号导致基因表达的变化，这些变化是热量分配的基础。使用小鼠模型，我们有 证明高剂量的膳食维生素D增加肌肉质量，横截面积，强度/面积， 肌肉线粒体的能力。我们的核心假设是高剂量维生素 25 D通过VDR作用，通过非典型结合改变转录，从而介导D卡路里分配 网站.我们的方法使用了经过验证的维生素D不平衡的基因工程小鼠模型， 通过VDR结合的全基因组分析， 总之，该提案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，优先分配热量给肌肉，而不是脂肪，长期 目的是开发新的合理的肥胖疗法。主要研究者是一名助理教授， 宾夕法尼亚大学的终身教职他是一个早期的职业研究人员，致力于问翻译 问题，以更好地了解维生素D的非钙代谢作用。他召集了一个独一无二的 和互补的协作团队来解决这个应用程序的目标。成功完成本 这项工作将确定25 D在介导维生素D肌肉卡路里分配中的作用，并将确定相关的信号传导 这些途径可以在治疗上有针对性地优先将多余的卡路里分配给肌肉， 脂肪，从而减少不必要的影响和肥胖的发生率。