Rev. Med. Chir. Soc. Med. Nat., Iaşi – 2016 – vol. 120, no.

BASIC SCIENCES UPDATES

VITAMIN D AND TISSULAR EXPRESSION OF VITAMIN D RECEPTOR

IN OBESITY

Raluca Haliga1, F. Zugun-Eloae 2, T. Oboroceanu1,

A. Pînzariu 1, Veronica Mocanu1
University of Medicine and Pharmacy “Grigore T. Popa”-Iasi
Faculty of Medicine
Department of Morpho-functional Sciences
* Corresponding author. E-mail: pinzariu_alin@yahoo.com

VITAMIN D AND TISSULAR EXPRESSION OF VITAMIN D RECEPTOR IN OBESITY

(Abstract): Vitamin D (VitD), a lipid-soluble hormone, is able to regulate the transcription of
many genes through vitamin D receptor (vitD receptor - VDR). It has been shown that VitD
deficiency is associated with obesity, characterized by a low degree inflammatory state,
which contribute to the pathogeny of metabolic syndrome and type 2 diabetes mellitus. VitD
deficiency is a public health problem, at the same time the global prevalence of obesity and
cardiovascular diseases is continuously growing. Evidence from recent studies on animal
models suggest that VitD or VDR deficiency promotes cardiomyocyte hypertrophy, which
can be one of the mechanisms for increasing cardiovascular risk. The heart is one of the ta r-
get organs of action for VitD, because VDR is expressed in cardiomyocytes. Also, previous
in vitro studies have shown that VitD is able to inhibit the production of monocyte chemo-
tactic factors (MCP-1) and other pro-inflammatory mediators in human preadipocytes and
mature adipocytes. Inflammation is an important factor in the pathogenesis of atheroscler o-
sis. In obesity there are not known data about correlations between plasma levels of VitD
and VDR expression in the subcutaneous fat tissue, epicardial visceral adipose tissue, and in
particular in myocardium. Also, there are still no studies to test VDR expression in myoca r-
dial cells and to investigate the results of dietary VitD supplementation on the expression of
VDR in the epicardial adipose tissue and myocardium. Keywords: OBESITY, HEART, IN-
FLAMMATION, VITAMIN D RECEPTOR.

VITAMIN D – MORE THAN A
CALCIUM REGULATOR
It has been established in time the vital
role of vitamin D (VitD) in the regulation
of calcium and phosphate homeostasis, a
key nutrient for maintaining the health of
the musculoskeletal system (1). VitD defi-
ciency is a public health problem. Humans
obtain vitD either from exposure to sun-
light or dietary intake, both whole food and
supplementation (2).
The circulating form of Vit D is 25-
hydroxycholecalciferol (25OHD) and the
most active form is 1α,25-
dihydroxyvitamin D (1α,25(OH) 2 D) or
calcitriol. The enzymes responsible for the
activation to 1α,25(OH)2D are vitamin D-
25-hydroxylase (25-OHase) and 25-

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 Vitamin D and tissular expression of vitamin D receptor in obesity
hydroxyvitamin D-1α-hydroxylase (1α-
OHase or CYP27B1). Calcitriol is further
degraded by 24-hydroxylase CYP24A1.
The worldwide prevalence of obesity
has nearly doubled between 1980 and 2008.
According to World Health Organization,
in 2008, 10% of men and 14% of women in
the world were obese (BMI ≥30 kg/m2),
compared with 5% for men and 8% for
women in 1980 , and the prevalence is
rapidly increasing. As a group, obese indi-
viduals have decreased levels of circulating
25(OH)D, and, according to a recently
published meta-analyses, are at a 35 %
higher risk for vitD deficiency across all
age ranges (1).While actually recommend-
ed daily dietary supplementation of vitD
are at least 600 IU for healthy adults aged
19–70 (2), and 800 IU/d for those over 70
years old, these doses reflect adequate
intake for maximal bone health and muscle
function, but for obese populations may be
necessary at least two to three times more
vitD (1,3).
Recent experimental and human studies
demonstrated an inverse correlation be-
tween adiposity and the level of VitD. VitD
deficiency has been showed to be closely
associated with obesity, which is a chronic,
low-grade inflammatory state, and contrib-
ute to the pathogenesis of insulin re-
sistance, metabolic syndrome, and type 2
diabetes mellitus (1).
VitD, a fat-soluble hormone, is able to
regulate the transcription of many genes
through vitD receptor (VDR) (4). The VDR
functions in cells such as osteoblasts, skin
keratinocytes, macrophages, and epithelial
cells and modulates the action of 1,25-
(OH)2 D, and in turn controls transcription
of several genes (1). Adipose tissue is rec-
ognized as a target for VitD actions. In
particular, adipocytes may be directly in-
volved in the local synthesis and degrada-
tion of calcitriol, which is able to affect
adipocyte biology by modulating pre-
adipocyte differentiation, lipid accumula-
tion and mobilization and also adipokine
production (4). There are contradictory
data in the literature regarding the expres-
sion of VDR in subcutaneous or visceral
adipose tissues.
Muscle fat infiltration can be the result
of aberrant trans differentiation of myogen-
ic precursor cells into adipocytes, resulting
in the formation of fat within the intermus-
cular space. Recent studies demonstrated
that myogenic precursor cells have the
potential to transdifferentiate towards the
adipogenic lineage (5) and VitD has potent
effects on both adipogenesis and myogene-
sis (6). Muscle fat infiltration has been
shown to have a direct consequence on
muscle strength and functionality, but it is
also a key independent risk factor for met-
abolic diseases, such as insulin resistance,
obesity and diabetes mellitus (3).
In rats, adipose tissue has been shown
to sequester more vitamin D for signifi-
cantly longer periods of time than other
major tissues or organs. In humans, central
adiposity in obese states is a key marker of
metabolic syndrome, which, along with
type 2 diabetes mellitus, has been identified
to be associated with vitD deficiency. VitD
deficiency may also be associated with
lipid synthesis via action of the VDR. VitD
and VDR also regulate de novo adipogene-
sis since VDR has been shown to be ex-
pressed in preadipocytes (1).
Recent studies reported that calcitriol
induces genomic effects, leading to the
synthesis of new proteins that affect muscle
cell contractility, proliferation and differen-
405
 Raluca Haliga et al.
tiation (7). Furthermore, mice lacking the
vitamin D receptor showed a skeletal mus-
cle phenotype with smaller and variable
muscle fibers and persistence of immature
muscle gene expression during adult life,
suggesting a role of VitD in muscle devel-
opment (8).
VitD deficiency can lead to myopathy,
characterized by muscle hypotonia, weak-
ness and atrophy of skeletal muscle. Mus-
cle biopsies from VitD-deficient adults
demonstrated enlarged interfibrillar spaces,
fibrosis and loss of type II fiber comple-
ment (7). There was also found an increase
in fat infiltration within the muscles (9),
similar effects being observed in elderly
individuals, where progressive loss in mus-
cle mass and strength are seen at the onset
of sarcopenia, associated with an increase
in fat deposition within the tissue. Sarcope-
nia consists of a deterioration in muscles
quantity and quality, a gradual slowing of
movement, a decline in strength and power,
and an increased risk of falls and fall-
related injuries (10).
VITAMIN D, CARDIOVASCULAR
SYSTEM AND INFLAMMATION
Cardiovascular diseases (CVD) are the
most common causes of morbidity and
remain the most important cause of death.
Recent observational and prospective stud-
ies have shown an association between
VitD deficiency and hypertension, diabetes
mellitus, metabolic syndrome, coronary
and peripheral arterial disease (PAD), and
heart failure. Vit D has been shown to exert
many biological activities, including reduc-
tion in blood pressure through down regu-
lation of renine-angiotensin system (RAS),
enhancement in insulin secretion and insu-
lin sensitivity (11), protection against angi-
406
ogenesis and regulation of cellular differen-
tiation and proliferation through locally-
formed calcitriol in tissues (12).
VitD deficiency has been also shown to
impair endothelial function, which may be
a supplementary contributing factor to
increased CVD risk (1). Recent studies
suggested that serum 25(OH)D levels were
inversely associated with coronary lesion
severity established by coronary angi-
ography, but not with arterial stiffness or
peripheral arterial disease (12).
Epicardial adipose tissue (EAT) (epi-
cardial fat) is a metabolically active viscer-
al adipose tissue, which may locally inter-
act with myocardium and coronary arteries
through secretion of various adipokines and
cytokines. Recent reports indicated that
EAT accumulation may be a risk factor for
coronary artery disease (CAD) and altera-
tions in EAT biology, such as increased
thickness, elevated inflammatory infiltrate
and cytokine production, have been ob-
served in CAD patients (6). The secretion
of various epicardial inflammatory adi-
pokines, including tumor necrosis factor
alpha (TNF-α), interleukin-6 (IL-6), adi-
ponectin, and monocyte chemoattractant
protein-1 (MCP-1), contribute to an in-
flammatory milieu and play a significant
role in the development and progression of
atherosclerosis. Subjects with coronary
artery disease (CAD) had elevated inflam-
matory infiltrates in EAT (13).
Evidence from studies on animal mod-
els suggest that vitD or vitD receptor
(VDR) deficiency promotes cardiac hyper-
trophy, which might be also one of the
mechanisms for increased cardiovascular
risk (13). Thus, a recent experimental study
revealed that vitD deficiency was associat-
ed with cardiomyocyte hypertrophy in
 Vitamin D and tissular expression of vitamin D receptor in obesity
hypercholesterolemic miniswine and signif-
icantly decreased expression of VDR was
found in ventricular cardiomyocytes of
vitD-deficient swine (13). The heart is
believed to be one of the target organ of
vitD, because VDR is expressed in cardio-
myocytes (14).
In addition to its well-known role as a
regulator of calcium homeostasis and bone
metabolism, vitamin D may exert other
different functions. In particular, due to its
ability to modulate T-lymphocyte prolifera-
tion and function, vitamin D exert immune-
regulatory effects and suppress the produc-
tion of inflammatory cytokines, thus being
recognized as a potential anti-inflammatory
molecule. Previous in vitro studies showed
that vitD is able to down-regulate the ex-
pression of pro-inflammatory mediators in
human monocytes stimulated with interferon
and to inhibit the production of MCP-1 and
other pro-inflammatory mediators in human
preadipocytes and mature adipocytes (6).
In human adipose tissue, there are few
studies which investigated the potential
anti-inflammatory role of vitamin D. One
study demonstrated that, as 25OHD level
decreases, local EAT expression of both
VDR and proinflammatory cytokines in-
creases (13). In condition of plasma
25OHD deficiency, local vitamin D metab-
olism seemed to be suppressed and associ-
ated to an increased production of inflam-
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In conclusion, besides the vital role of
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the expression of VDR in the myocardial
cells and to investigate and correlate the
results of diet supplementation with VitD
on VDR expression in the visceral epicar-
dial adipose tissue and myocardium.
ACKNOWLEDGEMENTS
This work received financial support
through the project “Program of excellence
in doctoral and postdoctoral research mul-
tidisciplinary chronic diseases”, contract
no. HRD/159/1.5/S/133377, financed from
the European Social Fund through the Sec-
toral Operational Programme Human Re-
sources Development 2007-2013.
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