Vitamin D3: Identification of central nervous system targets using high-technology functional MRI (D-LIGHTFUL)

Obesity rates are at an all-time high, and low levels of calcitriol are
associated with high adiposity. Evidence from animal studies suggests that
dopamine circuits are a novel mechanism by which calcitriol treatment may
beneficially affect food intake and obesity. While altered dopamine signaling
has been implicated in the progression of obesity and addiction (drug abuse,
food addiction), a role for calcitriol in these disease states has not been
experimentally explored.

Primary objective: To examine the effects of calcitriol on the activity of
dopaminergic central nervous system regions involved in the visualization and
regulation of food intake using functional magnetic resonance imaging (fMRI).

Secondary objectives: To examine the satiety-inducing effect of calcitriol and
its association with changes in fMRI responses. To investigate the effect of
calcitriol on the microbiota and its association with changes in fMRI
responses.

Single center, double-blinded, randomized intervention study.

All participants will receive in random order (after the baseline mri) a
single-dose of calcitriol 4µg (= intervention) and 0.9% NaCl (= placebo). These
interventions will be scheduled approximately one week after each other to
allow for sufficient washout of carryover effects.

Participants will be invited for a baseline screening visit at the Academic
Medical Center (brief physical examination, medical history, in- and exclusion
criteria, informed consent, resting energy metabolism, anthropometrics (i.e.,
BOD POD), venipuncture). If eligible for participation, subjects will receive
one-single dose of calcitriol 4.0µg (=intervention) and saline (=placebo).
These interventions will be scheduled approximately one week after each other
to allow for sufficient washout of carryover effects. The total duration of the
study is two weeks and consist of: i) two study days (duration: 1 day each),
and ii) a total of four safety monitoring blood draws (to check calcium levels
in order to minimize the risk of hypercalcemia; duration: 10 min each). During
both study visits, fMRI scans are made and food and eating behavior
questionnaires are filled out. In addition, blood (75 ml in total) and stool
samples are collected.

Risks: (A) Calcitriol: Side-effects of calcitriol are caused by hypercalcemia.
In order to minimize the risks of adverse events, participants will be checked
frequently during treatment. During clinical use of calcitriol, current
practice guidelines recommend check plasma calcium levels every three days. To
ensure safety, we will check calcium blood test 4, 24, and 72 hours after
treatment (see table 1. Study procedures). (B) Venous blood draw: The
venipunctures in our study can be an unpleasant experience for the subjects.
There is a low risk of phlebitis at the needle sites; this is unpleasant, but
not harmful, of temporary nature and self-limiting. (C) MRI: MRI is a
non-invasive imaging modality. All subjects will receive extensive information
about the MRI procedures beforehand. Subjects with contraindication to MR
scanning (e.g. pacemakers, claustrophobia, etc.) will be excluded.

Benefits: There is no direct benefit for subjects participating in this study.
However, if calcitriol indeed increases cognitive control and inhibits
reward-related regions during food visualization, calcitriol could be a
prospective agent in the treatment of obesity. Obesity is associated with an
increased risk of cardiovascular disease, diabetes and cancer, resulting in a
significant economic burden on society. We therefore feel that we do not expose
the participants to an unacceptable risk of side effects.

Group relatedness: Obesity is a growing problem in industrialized countries,
where approximately a third of the population is obese, and was declared a
global epidemic by the World Health Organization in 2003. Obesity has been
associated with a number of health problems, including diabetes, heart disease,
and different types of cancers, as well as decreased life expectancy. As a
universally growing problem, there is a clear need for the development of new
treatments for obesity.