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ARTICLE
Consequences of low-intensity light at night on cardiovascular
and metabolic parameters in spontaneously hypertensive rats
1
Valentina Sophia Rumanova, Monika Okuliarova, Lubos Molcan, Hana Sutovska, and Michal Zeman
Abstract: Circadian rhythms are an inherent property of physiological processes and can be disturbed by irregular environ-
mental cycles, including artificial light at night (ALAN). Circadian disruption may contribute to many pathologies, such as
hypertension, obesity, and type 2 diabetes, but the underlying mechanisms are not understood. Our study investigated the
consequences of ALAN on cardiovascular and metabolic parameters in spontaneously hypertensive rats, which represent an
animal model of essential hypertension and insulin resistance. Adult males were exposed to a 12 h light − 12 h dark cycle and the
ALAN group experienced dim light at night (1–2 lx), either for 2 or 5 weeks. Rats on ALAN showed a loss of light–dark variability
for systolic blood pressure, but not for heart rate. Moreover, a gradual increase of systolic blood pressure was recorded over
5 weeks of ALAN. Exposure to ALAN increased plasma insulin and hepatic triglyceride levels. An increased expression of
metabolic transcription factors, Ppar
␣
and Ppar
␥
, in the epididymal fat and a decreased expression of Glut4 in the heart was found
in the ALAN group. Our results demonstrate that low-intensity ALAN can disturb blood pressure control and augment insulin
resistance in spontaneously hypertensive rats, and may represent a serious risk factor for cardiometabolic diseases.
Key words: circadian, metabolism, insulin resistance, blood pressure, PPAR.
Résumé : Les rythmes circadiens sont une propriété inhérente aux processus physiologiques, et ils peuvent être perturbés par
des cycles environnementaux irréguliers, y compris l’éclairage artificiel nocturne (ou ALAN pour « artificial light at night »). Les
perturbations circadiennes pourraient contribuer à de nombreuses pathologies, comme l’hypertension, l’obésité, le diabète de
type 2, mais on n’en connaît pas les modes d’action sous-jacents. Notre étude portait sur les conséquences de l’ALAN sur des
paramètres cardiovasculaires et métaboliques chez le rat spontanément hypertendu, lequel correspond à un modèle animal
d’hypertension essentielle et de résistance à l’insuline. Nous avons exposé des rats adultes mâles à des cycles d’éclairage de 12 h
et d’obscurité de 12 h, et le groupe ALAN subissait l’influence d’un éclairage tamisé la nuit (1–2 lux), pendant 2 ou 5 semaines. Les
rats ALAN ont montré une perte de la variabilité éclairage–obscurité de la tension artérielle systolique, mais pas de la fréquence
cardiaque. De plus, nous avons enregistré une augmentation graduelle de la tension artérielle systolique sur les 5 semaines
d’ALAN. L’exposition à l’ALAN entraînait une augmentation des taux d’insuline plasmatique et de triglycérides hépatiques. Dans
le groupe ALAN, nous avons observé une augmentation de l’expression de récepteurs activés par les proliférateurs de per-
oxysomes (Ppar
␣
et de Ppar
␥
; des facteurs de transcription métaboliques) dans le tissu adipeux de l’épididyme, avec une
diminution de l’expression du gène Glut4 dans le cœur. Nos résultats montrent que l’ALAN de faible intensité peut entraîner des
perturbations dans la régulation de la tension artérielle et une augmentation de la résistance à l’insuline chez le rat spontané-
ment hypertendu. Elle pourrait représenter un facteur de risque important pour les maladies cardiométaboliques. [Traduit par
la Rédaction]
Mots-clés : circadien, métabolisme, résistance à l’insuline, tension artérielle, récepteurs activés par les proliférateurs de peroxysomes.
Introduction
The cardiovascular system is characterised by pronounced cir-
cadian rhythmicity, which partly accounts for the 24-hour rhythm
in the incidence of cardiovascular events (Smolensky et al. 2015).
Disturbed environmental cycles arising from shift work, irregular
lifestyle, and exposure to artificial light at night (ALAN) may in-
terfere with endogenous rhythmicity and have negative conse-
quences on the functioning of the cardiovascular system.
The light–dark cycle is the strongest environmental signal,
which synchronises endogenous circadian rhythms with rhyth-
mic changes in the environment; recently, this synchronising role
has become increasingly compromised by increasing light pollu-
tion (Falchi et al. 2016). The circadian system consists of a central
oscillator in the suprachiasmatic nuclei of the hypothalamus and
peripheral oscillators in nearly all cells of the body (Dibner et al.
2010). The disruption of circadian rhythms can have multiple neg-
ative consequences on health. Epidemiological studies suggest
the involvement of chronodisruption in the progression of several
diseases, such as cancer and metabolic and cardiovascular dis-
eases (Stevens et al. 2014).
The physiological mechanisms triggered by chronodisruption
are not understood. Experimental studies confirm that long-term
disturbances of light conditions reduce the plasticity of the circa-
dian system (Li et al. 2017) and increase unpredictability in the
cardiovascular system (Molcan et al. 2014;Molcan and Zeman
Received 24 January 2019. Accepted 3 June 2019.
V.S. Rumanova, M. Okuliarova, L. Molcan, H. Sutovska, and M. Zeman. Department of Animal Physiology and Ethology, Faculty of Natural
Sciences, Comenius University, Bratislava, Slovakia.
Corresponding author: Michal Zeman (email: michal.zeman@uniba.sk).
1
This paper is part of a Special Issue of selected papers from the 5th European Section Meeting of the International Academy of Cardiovascular Sciences held
in Smolenice, Slovakia, on 23–26 May 2018.
Copyright remains with the author(s) or their institution(s). Permission for reuse (free in most cases) can be obtained from RightsLink.
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Can. J. Physiol. Pharmacol. 00: 1–9 (0000) dx.doi.org/10.1139/cjpp-2019-0043 Published at www.nrcresearchpress.com/cjpp on 28 June 2019.
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2017). These disturbances, in combination with other environ-
mental factors, may lead to an increased cardiovascular risk
(Knutsson 2003).
Changes in circadian rhythmicity due to ALAN may lead to
disturbances in metabolic homeostasis and result in metabolic
diseases, especially type 2 diabetes, as has been investigated in
both humans (Qian et al. 2018) and experimental animals (Fonken
and Nelson 2014). All experimental studies deal with healthy ani-
mals and it is not clear whether comorbidities, such as type 2
diabetes or hypertension, can amplify the negative effects of
ALAN on health. In our study, we used spontaneously hyperten-
sive rats (SHR), which represent an accepted animal model of
essential hypertension in humans (Dornas and Silva 2011). More-
over, SHR are also a good model for metabolic studies due to their
insulin resistance (Girard et al. 2005). Elevated insulin levels in
SHR may contribute to greater peripheral resistance and hyper-
tension as a result of impaired vasodilatation (Potenza et al. 2005).
At the molecular level, the link between ALAN and a control
of metabolic processes may involve clock-controlled transcrip-
tion factors, such as peroxisome-proliferator-activated receptors
(PPARs), which are important regulators of lipid and glucose ho-
meostasis (Grygiel-Górniak 2014). They are rhythmically ex-
pressed in the liver and cardiovascular tissues and can coordinate
the circadian rhythms of metabolism and cardiovascular func-
tions (Cui et al. 2011). The heterodimer CLOCK/BMAL1, a key com-
ponent of the circadian transcription–translation feedback loop,
can directly activate transcription of Ppar
␣
via the E-box reach
region in the liver (Oishi et al. 2005). Interestingly, a parallel in-
crease of Bmal1 and Ppar
␣
expression was found in the heart of
SHR during the dark period (Cui et al. 2011). In humans, microar-
ray studies show that PPAR signalling and fatty acid metabolism is
strongly increased after circadian misalignment (Wefers et al.
2018).
In our study, we tested the hypothesis that a genetically in-
creased risk of essential hypertension and insulin resistance can
be exacerbated by exposure to ALAN with negative consequences
on the cardiovascular system and metabolism. Therefore, the aim
of our study was to analyse how the exposure of SHR to ALAN
affects (1) daily rhythms of telemetrically monitored blood pressure
(BP) and heart rate (HR); (2) plasma insulin, leptin, and metabolite
concentrations; and (3) the gene expression of Ppar
␣
,Ppar
␥
, and Ppar-
controlled genes in the liver, adipose tissue, and heart.
Materials and methods
Animals
The male SHR (n= 40, 18 weeks old, 283.0 ± 2.9 g) used in this
experiment were obtained from the breeding station at the Insti-
tute of Experimental Pharmacology and Toxicology, Slovak Acad-
emy of Sciences (Dobrá Voda, Slovak Republic). Animals were
housed in plastic cages in groups of 3 or 4 rats under controlled
conditions (ambient temperature 21.5 ± 1.3 °C, humidity 55%–
65%). Rats were acclimated to the standard light–dark cycle of 12 h
(100–150 lx)–12 h (0 lx) with lights on at 0600, designed as Zeitge-
ber time 0 (ZT0), for 1 month before the experiment started. Light
was emitted from a warm white light bulb (colour temperature
3000 K). Animals had ad libitum access to a standard chow diet
and water.
The experimental procedure was approved by the Ethical Com-
mittee for the Care and Use of Laboratory Animals at the Comen-
ius University in Bratislava, Slovak Republic, and the State
Veterinary Authority of Slovak Republic. Animals were treated in
accordance with Canadian Council on Animal Care guidelines.
Experimental design
Animals were assigned to 2 groups. The control group (CTRL, n=
15) remained on the standard lighting regime, as described above,
Fig. 1. Design of the experiment. During the acclimation phase, animals were synchronised to the 12 h light (12L) – 12 h dark (12D) cycle. Thereafter,
rats were assigned to a control group (CTRL), which remained in the 12L–12D cycle, or an experimental group (ALAN), which was exposed to dim
light at night (12L–12DL). Rats of both groups were sampled 2 and 5 weeks after the beginning of the treatment (bold vertical lines).
Table 1. Primer sequences used to analyse expression of selected genes by real-time PCR.
Gene Accession number Forward primer Reverse primer
Fasn NM_017332.1 5=-GAGTCTGTCTCCCGCTTGAC-3=5=-TTGCCTTGCTCACCTTCGAG-3=
Glut1 NM_138827.1 5=-GCCGCTTCATCATTGGAGTG-3=5=-CGAACACCTGGGCAATAAGGA-3=
Glut4 NM_012751.1 5=-TATGTTGCGGATGCTATGGGT-3=5=-AATGTCCGGCCTCTGGTTTC-3=
Pygl NM_022268.1 5=-ATCCACTCGGACATCGTGAA-3=5=-CCTGGGTTGCAGAGTAAGAG-3=
Hmgcs1 NM_017268.1 5=-ACGGTTCCCTTGCTTCTGTTC-3=5=-GCCAAGCCAGAACCGTAAGAG-3=
Irs2 NM_001168633.1 5=-ACCTACGCAAGCATCGACTT-3=5=-CCCGCAGCACTTTACTCTTTC-3=
Ppar
␣
NM_013196.1 5=-GACTAGCAACAATCCGCCTT-3=5=-GAAGAATCGGACCTCTGCCT-3=
Pppar
␥
NM_001145367.1 5=-TCCAAGAATACCAAAGTGCGA-3=5=-CCATGAGGGAGTTTGAAGGC-3=
Pgc1
␣
NM_031347.1 5=-AACGATGACCCTCCTCACAC-3=5=-GTTGTTGGTTTGGCTTGAGCA-3=
Actb NM_031144.3 5=-GATCAAGATCATTGCTCCTCCTG-3=5=-AGGGTGTAAAACGCAGCTCA-3=
Ppia NM_017101.1 5=-CCCACCGTGTTCTTCGACAT-3=5=-TGCTGTCTTTGGAACTTTGTCTG-3=
Note: Fasn, fatty acid synthase; Glut1, glucose transporter 1; Glut4, glucose transporter 4; Pygl, glycogen phosphorylase L; Hmgcs1,
3-hydroxy-3-methylglutaryl-CoA synthase 1; Irs2, insulin receptor substrate 2; Ppar
␣
, peroxisome proliferator-activated receptor alpha;
Ppar
␥
, peroxisome proliferator-activated receptor gamma; Pgc1
␣
, PPARG coactivator 1 alpha; Actb,-actin; Ppia, peptidylpropyl isomerase A.
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and the experimental group (ALAN, n= 18) was exposed to dim
light (⬃2 lx) throughout the whole dark phase. Some rats in each
group were sacrificed during week 2 (7 CTRL and 8 ALAN) and the
other rats were sacrificed during week 5 (8 CTRL and 10 ALAN)
after the start of treatment. Body mass and food consumption
were recorded once per week (Fig. 1).
Sample collection
Rats were sacrificed by decapitation under isoflurane anaesthe-
sia during the first half of the light phase. Trunk blood was col-
lected into either heparin or EDTA (2 mg/40 L)-containing tubes.
Plasma was separated after centrifugation (2500g, 10 min, 4 °C)
and stored until the analyses of hormones and biochemical pa-
Fig. 2. Systolic blood pressure (SysBP) and heart rate (HR) in telemetrically monitored spontaneously hypertensive rats (SHR) (n= 7) that were
exposed to the control 12 h light – 12 h dark regime for 1 week (week 0) and then to dim light (1–2 lx) during the whole dark phase (ALAN) for
5 weeks. (A, B) Means ± SEM of SysBP and HR calculated for the light and dark phases during week 0, and for the light and dim light phases
during weeks 2 and 5 of the ALAN regime. ***, p< 0.001 for the comparison of light vs. dark and light vs. dim light;
#
, for the comparison of
week 2 vs. week 0 and week 5 vs. week 0. (C, D) One-hour average values for SysBP (C) and HR (D) during weeks 0, 2, and 5. Shaded areas
represent the dark/dim light phases and white areas correspond to the light phases.
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rameters. The liver, left ventricle of the heart, and epididymal fat
were dissected, immediately frozen in liquid nitrogen, and stored
at −76 °C.
BP and HR measurement
To analyse the effects of the ALAN regime on haemodynamic
parameters, 7 SHR were monitored by radiotelemetry (Data Sci-
ence International, St. Paul, Minnesota, USA) for 5 weeks. A pressure
radiotelemetric transmitter (HD-S10; DSI, St. Paul, Minnesota,
USA) was surgically implanted rostrally into the abdominal aorta,
just above its bifurcation. Before implantation, the animals were
anaesthetised with 4% isoflurane in 100% oxygen and during im-
plantation anaesthesia was maintained with 1.5%–2% isoflurane in
100% oxygen. The rats were treated postoperatively with ampicil-
lin (100 mg/kg, s.c.; BB Pharma a.s., Prague, Czech Republic) and
tramadol (15 mg/kg, s.c.; TRAMAL, STADA, Bad Vilbel, Germany).
Rats were housed individually in cages with ad libitum access to a
standard chow and water. They were included in the experiment
2 weeks after the surgery. Telemetry data for systolic BP (SysBP)
and HR were collected over 1 week (week 0) when the rats were in
the CTRL regime and then over 5 weeks in the ALAN regime.
Telemetry data were acquired with a sampling rate of 500 Hz
continuously over a 5-minute record, once per 15 min for 60 h
during weeks 0, 2, and 5.
Biochemical analyses
Hepatic lipids were extracted from 100 mg of tissue using a
chloroform:methanol mixture (2:1), as previously described (Folch
et al. 1957). After evaporation under nitrogen, extracts were recon-
stituted in isopropanol. Triglyceride levels in the liver and concen-
trations of glucose, triglycerides, cholesterol, and low-density
lipoprotein cholesterol in plasma were measured by enzymatic
colorimetric kits BIO-LA-TEST (Erba Lachema, Czech Republic),
according to the manufacturer’s instructions, but the amounts of
samples and reaction solutions were adjusted for 96-well plates.
Hormone analyses
Plasma leptin levels were determined by an enzyme-linked im-
munosorbent assay (ELISA) using the commercial kit Rat Leptin
ELISA (Biovendor, Czech Republic). Plasma insulin levels were de-
termined by a radioimmunoassay using the Insulin Rat
125
I RIA kit
(DRG Instruments GmBH, Germany), according to the manufac-
turer’s instructions.
RNA isolation and real-time PCR
All tissues were homogenised using Fast-Prep 24 (M.P. Biomedi-
cals, USA). Total RNA from the liver and left ventricle was isolated
using TRI reagent (Molecular Research Center, Inc., USA) and total
RNA was isolated from the epididymal fat using an Rneasy Plus
Universal Mini Kit (Qiagen Inc., Germany), according to the man-
ufacturer’s instructions. Concentrations and purity of the isolated
RNA were measured using a NanoDrop One spectrophotometer
(Thermo Fisher Scientific Inc., USA). RNA integrity was verified by
electrophoresis on a 1.2% agarose gel. Complementary DNA was
synthesised using 1000 ng of RNA and a Maxima cDNA synthesis
kit (Thermo Fisher Scientific Inc., USA). Amplification of cDNA
was performed with the CFX Connect real-time PCR detection
system (Bio-Rad Laboratories, USA) with Maxima SYBR Green
qPCR Master Mix (Thermo Fischer Scientific Inc., USA). The expres-
sion of the following target genes was analysed: fatty acid syn-
thase (Fasn), glucose transporter 1 (Glut1), glucose transporter 2
(Glut2), glucose transporter 4 (Glut4), glycogen phosphorylase L
(Pygl), 3-hydroxy-3-methylglutaryl-CoA synthase 1 (Hmgcs1), insulin
receptor substrate 2 (Irs2), peroxisome proliferator-activated re-
ceptor alpha (Ppar
␣
), peroxisome proliferator-activated receptor
gamma (Ppar
␥
), PPARG coactivator 1 alpha (Pgc1
␣
). The relative
expression of the target and reference genes was calculated using
a standard curve method; for normalisation, -actin (Actb) was
used in the liver, peptidylpropyl isomerase A (Ppia) in the epidid-
ymal fat, and the geometric mean of Ppia and hypoxantin guanin
phosphoribosyltransferase 1 (Hprt) was used in the left ventricle of
the heart. Previously published primer sequences were used for
Glut2 (Cailotto et al. 2009) and Hprt (Neigh et al. 2017). Primer
sequences for the other genes are listed in Table 1.
Statistical analyses
Data were checked for a normal distribution using the Kolmogorov–
Smirnov test; for data that did not fit a normal distribution, a
logarithmic (for hepatic triglycerides) or square root transforma-
tion was used (for Ppar
␣
and Irs2 in the liver and Glu4 in the left
ventricle). Weekly changes in body mass and mean daily food
intake in response to the ALAN regime were examined by an
analysis of variance (ANOVA) with repeated measures (within-
group factor: time; between-group factor: regime). Differences in
biochemical parameters, hormone levels and gene expression
were evaluated using a two-way ANOVA (factors: week, regime). In
the case of a significant interaction between factors, differences
between groups were analysed using Fisher least significance dif-
ference post hoc tests. For SysBP and HR, an ANOVA with 2 re-
Fig. 3. Body mass (A) and daily food intake (B) changes in adult
male spontaneously hypertensive rats that were exposed either to
the control light–dark regime (CTRL) or dim light (1–2 lx) during the
whole dark phase (ALAN) for 5 weeks. Data are presented as means ± SEM.
No significant differences between the ALAN and CTRL groups were
recorded.
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peated factors (light–dark phase and week) and Tukey post hoc
tests were used.
Results
In the CTRL regime, telemetrically monitored SysBP and HR
showed the typical circadian variability, with higher levels during
the dark than the light phase (Fig. 2). Exposure to ALAN resulted in
a loss of the light–dark variability for SysBP (for interaction be-
tween week and phase: F
[2,12]
= 7.61, p< 0.01; Fig. 2A) but not for HR
(Fig. 2B). Interestingly, rats exposed to ALAN displayed suppressed
peaks of BP, which occurred at the light–dark and dark–light
transitions on the CTRL regime (Figs. 2C and 2D). Moreover, as
compared with CTRL week 0, SysBP was higher in the ALAN re-
gime during both weeks 2 and 5 (F
[2,12]
= 54.93, p< 0.001) and HR
was lower during week 5 (F
[2,12]
= 10.0, p< 0.01).
For body mass, significant effects of time (F
[6,96]
= 233.82,
p< 0.001) and the interaction between time and regime (F
[6,96]
=
3.91, p< 0.01) were recorded. The body mass of rats exposed to the
ALAN regime did not differ from that of the CTRL rats, although
both groups showed a different pattern of body mass changes over
5 weeks (Fig. 3A). Daily food intake changed over the 5-week ex-
perimental period (F
[6,18]
= 7.70, p< 0.001), but no effects of the
regime (F
[1,3]
= 0.04, p= 0.85) nor the interaction between time and
regime (F
[6,18]
= 1.43, p= 0.26) were found (Fig. 3B).
Plasma levels of glucose, triglycerides, cholesterol, and low-
density lipoprotein cholesterol were not affected in SHR exposed
to ALAN either for 2 or 5 weeks, compared with CTRL rats (Table 2).
A significant interaction between regime and week was found for
hepatic triglycerides, which were higher in rats exposed to ALAN
for 2 weeks, as compared with CTRL rats, while no effect of treat-
ment was found after 5 weeks of ALAN exposure (Table 2). Higher
concentrations of plasma insulin levels were noted in ALAN com-
pared with CTRL rats (Table 2). No differences between groups
were found for plasma leptin levels (Table 2).
In the liver, the expression of Ppar
␥
increased in rats exposed to
ALAN for 5 weeks compared with the CTRL group, as was indi-
cated by the significant interaction between regime and week
(Table 3;Fig. 4). Moreover, the hepatic expression of Glut2,Fasn,
and Hmgcs1 showed a tendency towards higher levels in ALAN
than in CTRL rats (Table 3;Fig. 4). No significant differences in the
expression levels of other genes were found in the liver (Table 3).
In the epididymal fat, rats in the ALAN regime displayed a signif-
icantly higher gene expression of Ppar
␣
and Ppar
␥
than CTRL rats,
whereas no differences between groups were detected for Glut4
and Fasn (Table 3;Fig. 5). In the left ventricle of the heart, exposure
of rats to the ALAN regime resulted in a decreased expression of
Glut4 and a tendency towards lower expression levels of Pgc1a,as
compared with CTRL rats (Table 3;Fig. 6). ALAN did not affect the
gene expression of Ppar
␣
and Ppar
␥
in the heart (Table 3).
Discussion
In the present study, we investigated the consequences of ALAN
exposure on cardiovascular and metabolic parameters in SHR,
which are considered an animal model of essential hypertension
and insulin resistance in humans. Exposure to ALAN led to in-
creased plasma insulin, as well as hepatic triglyceride levels, al-
Table 2. Plasma and hepatic biochemical parameters and plasma metabolic hormone levels in adult male spontaneously hypertensive rats that
were exposed either to the control light–dark regime (CTRL) or dim light (1–2 lx) during the whole dark phase (ALAN) for 2 and 5 weeks.
CTRL ALAN Factors of ANOVA
Week 2 Week 5 Week 2 Week 5 Regime Week Interaction
Plasma glucose (mmol/L) 6.97±0.24 7.44±0.14 7.60±0.27 7.29±0.22 ns ns p= 0.096
Plasma triglycerides (mmol/L) 0.83±0.09 0.75±0.06 0.81±0.12 0.76±0.05 ns ns ns
Hepatic triglycerides (mg/g) 1.89±0.11 1.98±0.17 2.75±0.36* 1.61±0.08 ns p< 0.05 p< 0.01
Plasma cholesterol (mmol/L) 1.58±0.05 1.65±0.08 1.70±0.03 1.63±0.06 ns ns ns
Plasma LDL-cholesterol (mmol/L) 0.73±0.04 0.72±0.02 0.78±0.04 0.72±0.03 ns ns ns
Plasma leptin (ng/mL) 3.13±0.32 3.03±0.27 3.44±0.41 3.58±0.36 ns ns ns
Plasma insulin (ng/mL) 2.38±0.33 2.71±0.35 2.93±0.31 3.58±0.36 p= 0.052 ns ns
Note: Data represent means ± SEM. The sample size was n= 7–8 in CTRL and n= 8–10 in ALAN groups. Results of two-way ANOVA are given as pvalues for each of
the factors: Regime, Week, and Interaction (Regime × Week). *, p< 0.05 for the comparison of CTRL and ALAN group on week 2; ns, not significant. LDL, low-density
lipoprotein.
Table 3. Statistical analysis of the expression of metabolic genes in the liver, epididymal fat, and left ventricle of the heart in spontaneously
hypertensive rats that were exposed either to the control light–dark regime or dim light (1–2 lx) during the whole dark phase for 2 and 5 weeks.
Genes in the liver
Factor Ppar
␣
Ppar
␥
Fasn Hmgcs1 Pygl Glut1 Glut2 Irs2
Regime F
[1,28]
= 0.39 F
[1,29]
= 0.81 F
[1,29]
= 3.50 F
[1,29]
= 3.18 F
[1,29]
= 0.06 F
[1,29]
= 0.34 F
[1,29]
= 3.56 F
[1,28]
= 0.11
p= 0.536 p= 0.376 p= 0.072 p= 0.085 p= 0.803 p= 0.563 p= 0.69 p= 0.743
Week F
[1,28]
= 0.97 F
[1,29]
= 1.43 F
[1,29]
= 6.95 F
[1,29]
= 1.07 F
[1,29]
=0 F
[1,29]
= 0.34 F
[1,29]
= 0.81 F
[1,28]
= 0.80
p= 0.334 p= 0.241 p< 0.05 p= 0.310 p= 0.993 p= 0.564 p= 0.375 p= 0.379
Regime × Week F
[1,28]
= 0.14 F
[1,29]
= 4.86 F
[1,29]
= 1.55 F
[1,29]
= 1.84 F
[1,29]
= 2.44 F
[1,29]
= 0.56 F
[1,29]
=0 F
[1,28]
= 0.21
p= 0.710 p< 0.05 p= 0.223 p= 0.185 p= 0.129 p= 0.462 p= 0.979 p= 0.650
Genes in the epididymal fat Genes in the left ventricle of the heart
Factor Ppar
␣
Ppar
␥
Glut4 Fasn Ppar
␣
Ppar
␥
Glut4 Pgc1a
Regime F
[1,29]
= 5.92 F
[1,29]
= 8.32 F
[1,29]
= 0.94 F
[1,29]
=0 F
[1,28]
= 0.16 F
[1,28]
= 0.54 F
[1,28]
= 5.90 F
[1,28]
= 3.03
p< 0.05 p< 0.01 p= 0.339 p= 0.975 p= 0.696 p= 0.467 p< 0.05 p= 0.092
Week F
[1,29]
= 2.69 F
[1,29]
= 5.13 F
[1,29]
= 6.46 F
[1,29]
= 1.05 F
[1,28]
= 0.94 F
[1,28]
= 4.45 F
[1,28]
= 6.59 F
[1,28]
= 0.36
p= 0.112 p< 0.05 p< 0.05 p= 0.313 p= 0.341 p< 0.05 p< 0.05 p= 0.553
Regime × Week F
[1,29]
= 0.06 F
[1,29]
= 0.2 F
[1,29]
= 1.55 F
[1,29]
= 0.02 F
[1,28]
=0 F
[1,28]
=1 F
[1,28]
= 1.68 F
[1,28]
= 0.13
p= 0.804 p= 0.658 p= 0.223 p= 0.894 p= 0.975 p= 0.327 p= 0.205 p= 0.724
Note: Ppar
␣
, peroxisome proliferator-activated receptor alpha; Ppar
␥
, peroxisome proliferator-activated receptor gamma; Fasn, fatty acid synthase; Hmgcs1,
3-hydroxy-3-methylglutaryl-CoA synthase 1; Pygl, glycogen phosphorylase L; Glut1, glucose transporter 1; Glut2, glucose transporter 2; Irs2, insulin receptor substrate 2;
Glut4, glucose transporter 4; Pgc1
␣
, PPARG coactivator 1 alpha.
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though triglycerides were higher only in the group exposed to
ALAN for 2 weeks, compared with the CTRL group. Altered meta-
bolic signalling due to ALAN was documented by the increased
gene expression of metabolic transcription factors, Ppar
␣
and
Ppar
␥
, in the epididymal fat and decreased Glut4 expression in the
left ventricle of the heart. In the liver, the expression of Ppar
␥
was
elevated only in the group exposed to ALAN for 5 weeks, but the
downstream PPAR-controlled genes (Hmgcs1,Fasn, and Glut2) showed
a tendency for upregulation in the ALAN group.
We found the expected circadian rhythms in SysBP and HR
under CTRL conditions; ALAN exposure resulted in a loss of this
light–dark variability in BP, but not HR. Moreover, we identified
2 peaks of BP associated with the light–dark and dark–light tran-
sitions, and these peaks were either suppressed or absent in
animals exposed to ALAN. Similar peaks had been previously dem-
onstrated in SHR (van den Buuse 1994) and it was hypothesised
that they were related to increased sympathetic activity and the
release of vasoactive hormones, as well as increased feeding,
grooming, and other behavioural displays. It is possible that these
variables were suppressed by ALAN and, therefore, the peaks were
not evident in the experimental regime. Future studies should
reveal whether these peaks are a part of ultradian rhythmicity
and how they relate to circadian rhythms and the underlying
behavioural activities after ALAN exposure. In our previous study,
we found more prominent ultradian rhythmicity on the expense
of circadian rhythms after circadian desynchronisation induced
by chronic phase shifts of the light–dark regimen (Molcan et al.
2013). Indeed, in the present study, circadian rhythmicity was also
suppressed after exposure to ALAN. However, in contrast to our
previous data, here, we recorded changes mainly in BP and not
HR. The suppressed circadian control of BP may have negative
consequences on the cardiovascular system. This phenomenon is
well known in non-dippers (a nocturnal BP drop of less than 10%),
who are at a higher risk of cardiovascular events than hyperten-
sive patients, who are expected to have a 10%–20% decrease in BP
during the night (Knutsson 2003).
Systolic BP was higher 2 and 5 weeks after ALAN exposure,
compared with the beginning of the experiment. This is an impor-
tant finding because increased SysBP is a major predictor of car-
diovascular diseases, such as ischemic heart disease, stroke, and
myocardial infarction (Kannel et al. 1972). However, we must in-
terpret this finding with caution because the increase may reflect,
to some extent, a developmental increase of BP in SHR. Systolic BP
starts to increase after the age of 5 weeks and reaches a plateau
after week 15 in SHR when measured by plethysmography
(Dickhout and Lee 1998). Our rats were 18 weeks old at the begin-
ning of the experiment and the BP values corresponded with data
measured in 18-week-old SHR (Kren et al. 1997), which had a mean
SysBP of around 185 mm Hg. However, because the BP increase in
our study was derived from the comparison of values before and
after ALAN exposure in the same animals, and we did not have a
group tracing the developmental changes, the BP increase cannot
be exclusively explained by ALAN exposure.
Fig. 4. Expression of metabolic genes in the liver of adult male spontaneously hypertensive rats that were exposed either to the control
light–dark regime (CTRL, white bars) or dim light (1–2 lx) during the whole dark phase (ALAN, grey bars) for 2 and 5 weeks. Data are presented
as means ± SEM. pvalues for the ALAN factor are shown when differences between the CTRL and ALAN groups were significant or when there
was a nonsignificant trend (p< 0.1). *, p< 0.05.
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Body mass and daily food intake did not differ between the
CTRL and ALAN rats. Increased body mass after ALAN exposure
has been mostly reported in mice (Fonken et al. 2010), but not in
rats (Stenvers et al. 2016); therefore, interspecies and strain differ-
ences in susceptibility to ALAN may exist. One of the main behav-
ioural consequences of ALAN is the consumption of food at an
inappropriate time of the 24-hour cycle (Versteeg et al. 2016). How-
ever, SHR are known to consume more food during the daytime
than Wistar rats (Cui et al. 2011;Polidarova et al. 2013) and, there-
fore, the consequences of ALAN on food intake and body mass
gain may be less obvious in SHR than Wistar rats.
Circulating concentrations of glucose, triglycerides, choles-
terol, and low-density lipoprotein cholesterol were not affected by
ALAN, compared with the CTRL regime. On the other hand, ALAN
resulted in higher plasma insulin levels in SHR than CTRL rats.
SHR are known for their insulin insensitivity (Bursztyn et al. 1992)
and ALAN has been reported to deteriorate insulin resistance in
both humans (Stenvers et al. 2019) and experimental animals
(Opperhuizen et al. 2017). Our findings are important in this con-
text because they suggest that ALAN can attenuate insulin sensi-
tivity and, therefore, diabetic patients might be more sensitive to
ALAN than healthy individuals. Because high BP and type 2 diabe-
tes affect over 1 billion people worldwide, and the 2 conditions
frequently co-exist (Vos et al. 2015), the problem also requires
more attention in relation to ALAN exposure.
Because the regulation of cardiovascular and metabolic pro-
cesses is mutually coordinated by the circadian system and can be
affected by the disruption of lighting regimes (Rüger and Scheer
2009), in our study, we examined the effects of ALAN on the gene
expression of 2 members of the PPAR family, PPAR␣and PPAR␥,in
metabolically active and cardiac tissues. We found that SHR on
the ALAN regime showed an increased expression of both Ppar
␣
and Ppar
␥
in their epididymal fat, compared with CTRL rats. Sim-
ilarly, in the liver, an upregulated expression of Ppar
␥
was de-
tected in the group exposed to ALAN for 5 weeks. PPARs represent
important metabolic transcription factors, which transactivate a
number of genes that are involved in lipid and carbohydrate me-
tabolism (Grygiel-Górniak 2014;Rakhshandehroo et al. 2010).
Daily variation in gene expression was reported for both Ppar
␣
and Ppar
␥
in the liver, adipose, and cardiovascular tissues (Cui
et al. 2011;Yang et al. 2006) and was higher in SHR than normo-
tensive rats (Cui et al. 2011). Our results indicate that ALAN expo-
sure can further potentiate the expression levels of these
metabolic transcription factors in SHR, especially in epididymal
fat. One possible explanation involves a direct link between the
circadian clock and PPARs, because the heterodimer CLOCK/
BMAL1 has been identified as an upstream regulator of Ppar
␣
ex-
pression in the liver (Oishi et al. 2005). However, further studies
analysing the whole 24-hour profile of these genes under ALAN
conditions are needed to reveal whether the increased expression
Fig. 5. Expression of metabolic genes in the epididymal fat of adult
male spontaneously hypertensive rats that were exposed either to
the control light–dark regime (CTRL, white bars) or dim light (1–2 lx)
during the whole dark phase (ALAN, grey bars) for 2 and 5 weeks.
Data are presented as means ± SEM. pvalues for the ALAN factor are
shown when differences between the CTRL and ALAN groups were
significant.
Fig. 6. Expression of metabolic genes in the left ventricle of the
heart of adult male spontaneously hypertensive rats that were
exposed either to the control light–dark regime (CTRL, white bars)
or dim light (1–2 lx) during the whole dark phase (ALAN, grey bars)
for 2 and 5 weeks. Data are presented as means ± SEM. pvalues for
the ALAN factor are shown when differences between the CTRL and
ALAN groups were significant or when there was a nonsignificant
trend (p< 0.1).
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of Ppar
␣
and Ppar
␥
in our study can be explained by impaired
circadian rhythmicity.
In our study, the expression of PPAR-controlled metabolic genes
was only marginally affected by ALAN. A tendency towards higher
expression levels in the liver of ALAN compared with CTRL rats
was found for the gene encoding the key cholesterol-synthesising
enzyme, Hmgcs1, the gene encoding the rate-limiting enzyme for
de novo fatty acids synthesis, Fasn, and the gene encoding the
main hepatic glucose transporter, Glut2. Although these changes
were not significant, they can imply an imbalance in energy
homeostasis. Because the liver orchestrates rhythms in energy
homeostasis and buffers the fluctuations of metabolite levels,
originated by behavioural and feeding–fasting cycles, observed
changes can be important for control of metabolism and should
be further studied in the circadian context.
Interestingly, we recorded decreased Glut4 expression in the
heart of rats on the ALAN regime, compared with the CTRL
group. Cardiac insulin resistance in association with a reduced
rate of glucose uptake and decreased Glut4 expression has been
demonstrated in SHR (Paternostro et al. 1995). Moreover, the
daily rhythmicity of Glut4 expression was markedly attenuated
in hypertrophied hearts, indicating the importance of cardiac
metabolic rhythms, which can be controlled by neurohumoral
signals, local peripheral clocks, or both (Young et al. 2001). There-
fore, our data may suggest that cardiac glucose uptake can be
further deteriorated in insulin-resistant individuals and may have
negative consequences on the heart, especially after long-term
exposure to ALAN. In a broader clinical context, our results un-
derlay an urgent need to explore consequences of chronodisrup-
tion in hypertensive and diabetic patients, because they might be
more vulnerable than a standard population, which is usually
investigated.
We found an increased lipid content in the liver after 2 weeks,
but not after 5 weeks on the ALAN regime. This can be related to
the opposite pattern of the expression of Ppar
␥
, which increased
after 5 weeks, but not 2 weeks of ALAN because hepatic Ppar
␥
expression was reported to negatively correlate with lipid levels in
the liver (Chechi et al. 2010). We found both Ppar
␣
and Ppar
␥
to be
upregulated in epididymal fat after ALAN exposure. In adipose
tissue, they control fatty acid storage and, in this way, they can
protect non-adipose tissue against an excessive lipid overload
(Lecarpentier et al. 2014). Moreover, in adipocytes, PPAR␥partici-
pates in leptin production, which was not altered in our study.
Stabile leptin concentrations, in spite of increased Ppar
␥
after
ALAN, might be related to unchanged body mass and reflect the
resistance of SHR, or rats in general, to ALAN-induced obesity.
To summarise, 2- and 5-week exposure of SHR to low-intensity
ALAN resulted in the suppression of daily rhythm and an increase
of systolic BP. Circulating insulin concentrations were augmented
and the expression of insulin-dependent Glut4 in the heart was
decreased, indicating that ALAN can deepen insulin resistance.
Because SHR are the most widely used animal model of essential
hypertension and exhibit insulin insensitivity, the results demon-
strate that low-intensity ALAN occurring in urban areas can
worsen genetically determined predisposition to cardiometabolic
diseases. Because hypertension is frequently associated with dia-
betes and their incidence is increasing in industrial countries,
chronodisruption should be considered as a potent risk factor.
Acknowledgements
The study was supported by the Slovak Research and Develop-
ment Agency APVV-17-0178 and the Scientific Grant Agency of the
Ministry of Education of the Slovak Republic VEGA 1/0492/19.
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