The applicant's objective is to enhance his training in the field of hormonal mechanisms of cardiovascular disease in obesity. Obesity is a state of high adipose-tissue renin-angiotensin system (RAS) activity, hypoadiponectinemia, and vitamin D deficiency. These intertwined metabolic abnormalities contribute to increased cardiovascular risk in obesity. The applicant's prior data support the hypothesis that vitamin D therapy may be an effective strategy to lower adipose-tissue RAS activity and raise circulating adiponectin in obesity; these favorable metabolic profiles could reduce cardiovascular risk in obesity. The applicant proposes to study 60 obese human subjects in a well-controlled physiologic experimental protocol that is designed to test whether the active vitamin D metabolite, calcitriol, can modulate adipose-tissue RAS activity and influence circulating adiponectin levels in obesity.
The specific aims of this project are designed to test: 1) whether calcitriol interacts with the vitamin D receptor to reduce adipose-tissue renin expression in obesity; and 2) whether calcitriol therapy raises circulating adiponectin in obesity. Although each aim addresses a specific relevant metabolic question, both utilize the same study population and core study design to maximize efficiency and resources. Study subjects will be randomized to calcitriol therapy or placebo for two weeks.
Aim 1 will evaluate adipose-tissue renin expression before and after intervention, and whether the effect of calcitriol is influenced by genetic variation at Fok1: a functional polymorphism of the vitamin D receptor gene.
Aim 2 will assess circulating adiponectin before and after intervention. The demonstration that vitamin D therapy modulates the expression of hormones that mediate vascular disease (the RAS and adiponectin) is crucial to the current medical debate surrounding vitamin D and its potentially therapeutic properties; it would strongly support the role of vitamin D supplementation in obesity. This is particularly relevant since obesity and vitamin D deficiency are epidemics that occur in tandem, and are the focus of large-scale NIH funded prospective randomized trials. In this regard, the applicant's results could serve as an important physiologic mechanism to explain the results of these concurrent trials; an issue of high relevance for the NIH and NHLBI. The applicant has a long track-record of success in academic research, and extensive experience conducting human physiology studies investigating vitamin D, the RAS, and adiponectin biology in obesity. The NIH has awarded him the NIH F32 (NRSA) and Loan Repayment Awards for his related projects. His research and mentoring environment are strongly suited to successfully complete the proposed research, and he has assembled an experienced team of senior investigators to enhance his training plan and support his future endeavor of becoming an independent investigator.
Obesity, excess adipose-tissue renin-angitoensin system (RAS) activity, and the deficiencies of vitamin D and adiponectin are all unfavorable metabolic profiles that aggregate in tandem, and are all associated with increased cardiovascular risk. The applicant's preliminary data support vitamin D therapy as a potential method to reduce adipose-tissue RAS activity and raise circulating adiponectin in obesity; thus, potentially reducing cardiovascular risk. This research plan proposes to conduct a prospective study to evaluate whether vitamin D therapy lowers adipose-tissue RAS activity and raises adiponectin in obese humans; this demonstration would be of major public health relevance, and in line with the missions of the NIH and NHLBI.
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