Vitamin D control of calorie allocation to muscle

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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.