Mobilising vitamin D sequestered in adipose tissue in humans

Up to half of people in the UK have low levels of vitamin D in their blood and finding ways to improve vitamin D status is a recognised health priority. Vitamin D is lipophilic (fat-loving) and accumulates in our adipose tissue (fat stores) in large amounts. The entrapment of vitamin D in adipose tissue contributes to low levels of vitamin D in blood. This is very relevant as most people in the UK are overweight and by 2035 almost half the population is predicted to be obese. Thus, a key challenge now and in the future is to find ways to successfully mobilise vitamin D from adipose to help reduce the impact of adipose expansion on the availability of vitamin D.

Our preliminary data indicate that physical activity is an effective way to mobilise vitamin D from adipose tissue - even without weight loss. These preliminary data show that exercise has a powerful effect on the concentration of the important form of vitamin D in blood and that exercise stimulates the release of this form of vitamin D from adipose tissue. Based on these observations, we propose that regular exercise will improve the mobilisation of vitamin D from adipose tissue and that this will increase the amount and availability of the important form of vitamin D in blood.

In this project, we will use a 12-week randomised controlled trial in men and women to examine the impact of exercise (versus control) on vitamin D status and metabolism in obesity. We will assess the impact of exercise on the various forms of vitamin D that are found in blood, and whether these changes lead to an improvement in the function of cells known to be affected by vitamin D status (a type of white blood cell called monocytes). We will use stable isotopes (non-radioactive tracers) to examine how the turnover of vitamin D is affected by exercise. By taking small biopsies of adipose tissue we will be able to examine the impact of exercise on the ability to mobilise vitamin D from adipose. This will also allow us to understand the biological pathways and mechanisms that are involved in vitamin D mobilisation and how they are affected by exercise. We have designed our research to include a lean comparator group so that we can understand the independent effects of obesity and exercise on vitamin D mobilisation, status and metabolism.

This research will help us to understand the impact of exercise on vitamin D status and whether increasing physical activity represents a potentially useful strategy to mobilise vitamin D from adipose tissue. Understanding whether (and how) vitamin D can be mobilised from adipose tissue has been identified by key stakeholders, including agencies that inform the UK government, as an important knowledge gap. Thus, this research will have great potential for translation into policies and guidance related to vitamin D and health. In the future, we envisage that the benefits of exercise can be promoted as an adjunct strategy to improve population and individual vitamin D status alongside complementary strategies such as dietary supplementation. The outcomes from our research will also have implications for policies and guidance around the effects of obesity and physical inactivity on health. In addition to these direct effects on policies and practices, an understanding of the fundamental biological pathways and mechanisms through which physical activity helps to mobilise compounds sequestered in adipose tissue could provide the basis for novel pharmacological and non-pharmacological strategies, interventions and products related to vitamin D and other lipophilic compounds sequestered in adipose.

Sequestration of lipophilic vitamin D in the lipid droplets of adipocytes creates a challenge to the maintenance of systemic 25-hydroxyvitamin D (25(OH)D) concentration. As the prevalence of overweight and obesity increases, it is increasingly important to find successful strategies to mobilise vitamin D from adipose tissue and thus improve the bioavailability of endogenous vitamin D.

Our preliminary data show that regular exercise has a powerful effect on systemic 25(OH)D concentration in humans even without a large reduction in adipose mass. In addition, we show that human adipose releases 25(OH)D for at least several hours after an acute bout of exercise. Chronic (regular) exercise also has a well-characterised positive effect on adipose tissue dysfunction in obesity - which is likely to further enhance the capacity to mobilise vitamin D from adipose. Thus, we hypothesise that regular exercise will improve the mobilisation of vitamin D metabolites from expanded adipose tissue and thus improve serum vitamin D status and bioavailability.

To test this hypothesis, we will examine the impact of increased exercise on whole-body and adipose tissue vitamin D metabolism and the pathways involved in the mobilisation of vitamin D from adipose tissue. We will use a 12-week randomised controlled trial in men and women to determine the impact of exercise (versus control) on vitamin D status and metabolism in obesity. We will assess multiple vitamin D metabolites in serum and 25(OH)D turnover using an established stable isotope technique. We will determine whether the change in serum 25(OH)D has a demonstrable effect on functional measures of bioavailability. In addition, we will combine measures in adipose biopsies and fluxes across adipose tissue (a-v differences) to understand the impact of exercise on the capacity to mobilise vitamin D from adipose tissue and to characterise the biological pathways and mechanisms that are involved in vitamin D mobilisation.

WHO WILL BENEFIT FROM THIS RESEARCH?

This project will impact on multiple sectors and stakeholders - including policy makers, government agencies and departments, non-profit agencies, the general public, healthcare professionals, other research teams, as well as industry (e.g., pharmaceutical).

HOW WILL THEY BENEFIT?

POLICIES & GUIDANCE (VITAMIN D): Knowledge of the factors that influence vitamin D metabolism will directly impact on the work of various stakeholders and key policy makers. The Scientific Advisory Committee for Nutrition (SACN) advises the UK Government including agencies such as Public Health England (PHE). Policies regarding vitamin D are established by PHE and the National Institute for Health & Care Excellence (NICE). In the recent report from SACN, further research into the role of adipose as a store of vitamin D and its metabolites was one of 12 main research recommendations. Understanding the factors that influence vitamin D sequestration and mobilisation was identified as a major knowledge gap. The current research project will directly target this gap and we will provide evidence for the impact of exercise on adipose tissue mobilisation of vitamin D metabolites in humans. We will also characterise the impact of adiposity per se. In addition to helping the work of SACN, PHE and NICE in the UK, this information will provide similar benefit for international agencies such as the World Health Organisation (WHO) and the US National Institutes of Health (Office of Dietary Supplements).

POLICIES & GUIDANCE (LIFESTYLE): Evidence for the impact of physical activity on vitamin D status will help agencies responsible for advice and guidance regarding the effect of lifestyle on health. Agencies such as PHE and NHS Choices in the UK produce guidance and advice aimed at individuals and populations. PHE often communicate via evidence-based marketing campaigns. Up to half the UK population have low circulating concentrations of the important form of vitamin D during the winter months and this occurs at a time when levels of physical activity tend to fall. Of course, these temporal changes could be partly related and, importantly, if our research confirms that physical activity increases the important circulating form of vitamin D by around 30%, this would provide the underpinning evidence for marketing and fact sheets centred on the additional and important benefit of physical activity for vitamin D status as an adjunct to support guidance regarding supplementation.

INDUSTRY: A detailed characterisation and understanding of the pathways involved in vitamin D mobilisation from adipose tissue is potentially commercially exploitable. Even in lean individuals, adipose tissue has the capacity to accumulate enormous amounts of vitamin D. Thus, strategies that enrich adipose with vitamin D and mobilise it at a time of increased demand or poor synthesis could be very useful and effective. Knowledge about the pathways involved in sequestration and mobilisation of vitamin D may extend to other lipophilic compounds. Collectively, this research may open up new routes to impact through the development of new pharmacological or non-pharmacological interventions and strategies to store and then mobilise endogenous lipophilic compounds such as vitamin D.

OTHER RESEARCHERS: We will create the opportunity for other researchers to benefit directly from this research through a novel 'Announcement of Opportunity'. This will enable other researchers to access samples and propose additional measures within a carefully pre-defined framework. This not only increases value-for-money and creates new academic impact - but it also opens up new routes to national and international non-academic impact via the work of other researchers.