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.