Vitamin D control of calorie allocation to muscle

维生素 D 控制肌肉的热量分配

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要/摘要肥胖会导致糖尿病，心脏病和癌症比例最大的风险，并且对当前有抵抗力尽管是强烈研究的重点，但治疗方法。肥胖是因为身体存储了剩余卡路里作为脂肪，这又驱动了与肥胖症相关的健康风险6-10。当前的治疗方法通过热量限制和/或运动，肥胖专注于体重减轻，这是无效的。另一种策略将是重定向多余的卡路里来建立肌肉，而不是储存为脂肪。这种方法会减轻肥胖的健康风险，还可以改善日常运作，生活质量和寿命。我们有趣的初步数据表明，高剂量饮食维生素D降低了储存为脂肪的多余卡路里的比例，而是将这些卡路里分配给肌肉。了解这一发现的基础机制将推动迫切需要预防和治疗肥胖的新型治疗方法的发展。此外，我们的初步结果表明，这种对肌肉的热量分配是通过25D介导的维生素D受体发生的（VDR）在非传统VDR结合位点上的转录调节。我们的长期目标是定义维生素D在卡路里分配中的作用，以识别新型治疗肥胖的目标。该项目的具体目标是1）确定哪种饮食中维生素D代谢产物， 25d或1,25d，将卡路里分配给肌肉的信号，以及2）识别肌肉中维生素的机制 D信号传导导致卡路里分配的基因表达变化。使用鼠标，我们有证明高剂量饮食维生素D会增加肌肉质量，横截面面积，强度/面积和瘦肉和肥胖小鼠的肌肉线粒体能力。我们的中心假设是高剂量维生素 D卡路里分配是由25D通过VDR作用的25D介导的，以通过非传统结合改变转录站点。我们的方法使用经过验证的维生素D失衡的基因工程鼠标模型，并连接通过对VDR结合的全基因组分析对转录变化的信号传导。总而言之，该提案描述了一个五年的研究计划，以了解非 - 维生素D对优先将卡路里分配给肌肉而不是脂肪的钙代谢作用，而不是长期为肥胖开发新颖的理性疗法的目标。主要调查员是宾夕法尼亚大学的任期。他是一位致力于询问翻译的早期职业研究员更好地了解维生素D的非钙代谢作用的问题。他已经组装了一个独特的资格和互补的合作团队，以解决此应用程序的目标。成功完成工作将定义25D在介导维生素D肌肉卡路里分配中的作用，并确定相关信号可以治疗的途径优先将多余卡路里分配给肌肉而不是脂肪，从而减少不良影响和肥胖的发生率。