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Consequences of low-intensity light at night on cardiovascular and metabolic parameters in spontaneously hypertensive rats

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Canadian Journal of Physiology and Pharmacology
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Circadian rhythms are an inherent property of physiological processes and can be disturbed by irregular environmental 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, Pparα and Pparγ, 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.
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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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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, PPARand 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, PPARpartici-
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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... Several attempts have been made to investigate functional perturbations of exposure to lightat-night (LAN) (Qian et al., 2015;Opperhuizen et al., 2017;McLay et al., 2018;Rumanova et al., 2019;Hong et al., 2020), however, most of the efforts have been widely centered towards shift work and other non-conventional work schedules (Qian et al., 2013;Touitou et al., 2017;Fleury et al., 2020;Hong et al., 2020). While these studies have revealed the implications of exposure to artificial light at night, they lack the strong credibility for extrapolation onto the general populace. ...
... Furthermore, although the average duration of LAN exposure in humans is reportedly 5 hours (Dissi et al., 2019) and not constant exposure to light (Rumanova et al., 2020), most of these studies have chosen to ignore simulating this real-life scenario. Rather, they consistently employed an exposure protocol of 12 hours LAN exposure (Mustonen et al., 2002;Dauchy et al., 2010;Qian et al., 2013;Qian et al., 2015;Maroni et al., 2018;McLay et al., 2018;Rumanova et al., 2019;Hong et al., 2020), thus subjecting the animals to a constant lighting condition, hence, making human extrapolation highly unreliable. Consequently, this study was designed to capture these peculiarities as well as control other variables with the primary aim of assessing the effect of exposure to light at night on haematological and metabolic parameters of sleep restricted adult male Wistar rats. ...
... The utility of TriG index as a marker for insulin resistance has gained wide popularity due to its putative nature of discriminating insulin resistance even among normoglycemic subjects (Du et al., 2014). Although exposure to LAN has been found to impair glucose tolerance and insulin sensitivity (Mustonen et al., 2002;Coomans et al., 2013;Rumanova et al., 2019;Hong et al., 2020), the present study findings of similar TriG index among the groups is indicative that the impairment is unlikely to be insulin-sensitivity mediated. However, it is pertinent to note that LAN-exposure-related impairment in glucose tolerance has been ameliorated by concomitant melatonin supplementation (Xu et al., 2017;Hong et al., 2020), thus reiterating the mechanistic relationship between melatonin disruptive tendencies of LAN and glucose metabolism. ...
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Health implications of shift work could not be completely due to exposure to light-at-night (LAN). This study evaluated metabolic and haematological impacts of LAN exposure on adult male Wistar rats under sleep restriction condition. The animals were grouped into control (n=8) and LAN exposed (n=8) groups. The controls were sleep restricted (SR) by gentle handling. In addition to SR, the LAN exposed group were exposed to LAN during the first five hours of scotophase for six weeks. Body weight, fasting blood glucose, lipid profile, full blood counts, CD4+ cells, malondialdehyde, superoxide dismutase and catalase were all assessed using their respective protocols. Statistical Package for Social Sciences (SPSS Version 20) was used to analyze and Mean±SEM was used to analyze and summarize the data. Intergroup differences were investigated using Student’s t-test and p≤ 0.05 was considered statistically significant. The results have shown that LAN-exposed rats eat less and have gained more body weight than controls. LAN-exposed rats also had higher fasting blood glucose. On the contrary, there is no statistical difference between the two groups for markers of oxidative stress, triglyceride-glucose index, high-density lipoprotein, and atherogenic index of plasma. In conclusion, the present study has shown that LAN exposure could cause metabolic and hematological impairments in sleep-restricted, Wistar rats. Hence, it might predispose exposed subjects to obesity, diabetes mellitus and adverse cardiovascular events.
... Cardiovascular disease remains a leading cause of death, and many cardiovascular variables (e.g., heart rate and arterial blood pressure) have day-night rhythms that cycle with a periodicity of ≈24 h 12 . The impact that light at night has on day-night rhythms in heart rate and blood pressure is only now being understood [13][14][15] . Data suggest that light at night decreases the amplitude of day-night heart rate and blood pressure rhythms in people and small animals but through distinct mechanisms 14 . ...
... The impact of artificial light at night on people and dLAN on male mice differs from that of artificial light at night on male rats housed at room temperature 14 . Light at night in rats appears to decrease the relative sympathetic signaling at night to decrease the amplitude of the 24-hour heart rate and blood pressure rhythms 13,36 . One possible reason for the difference between our studies in male mice and previous studies in rats is that we studied the effects of dLAN in mice housed at thermoneutrality to limit coldinduced sympathetic nervous system activation. ...
... The concept that light at night decreases the amplitude in day-night rhythms of cardiovascular physiology is not new, nor is the concept that it is linked to increased cardiometabolic risk 4,10,[13][14][15] . A limitation of this study is that we did not include an experimental group for nighttime restricted feeding in mice housed in 12-hour light and dark cycles. ...
Article
Background: Light input to the suprachiasmatic nucleus entrains circadian rhythms in physiology and behavior to the day-night cycle. Exposure to light at night in people is associated with cardiometabolic disease. Pre-clinical studies show that artificial light at night, including at very low levels, disrupts day-night rhythms in activity, feeding behavior, heart rate, and blood pressure dipping. Hypothesis: Dim light at night (dLAN) disrupts day-night rhythms in feeding behavior to blunt day-night rhythms in autonomic input to the heart and blood pressure dipping. Methods: Mice (n=5-6/sex) in thermoneutral housing were implanted with telemetry probes to record heart rate, blood pressure, and core body temperature. Autonomic input to the heart was assessed by measuring heart rate and subtracting the temperature-dependent changes in the heart rate after pharmacological inhibition of muscarinic and β-adrenergic receptor activation. Mice were housed in 12 h light: 12 h dark cycles (LD, 200 lux: 0 lux) with ad libitum access to food (LD-ALF), subjected to 12 h light: 12 h dLAN cycles (dLAN-ALF; 200 lux: 5 lux) for two weeks, and then feeding was time-restricted (not calorically restricted) to the dLAN cycle (dLAN-RF). Data were extracted from Ponemah and Clocklab, and statistical analysis was done using GraphPad PRISM software. Results: Compared to LD-ALF mice, dLAN-ALF mice showed reduced amplitudes in day-night activity, feeding, heart rate, and blood pressure rhythms, with males more affected than females (p<0.001). dLAN-ALF male and female mice had decreased amplitudes in the day-night rhythms in autonomic input to the heart. In addition, dLAN-ALF male mice had less blood pressure dipping. dLAN-RF normalized autonomic input to the heart and heart rate in male and female mice (p<0.05, p<0.01, respectively). dLAN-RF also improved blood pressure dipping in male mice (p<0.001). dLAN-RF did not normalize activity rhythms. Conclusion: dLAN disrupts day-night rhythms in activity, feeding, heart rate, and blood pressure dipping in mice, with males being more impacted. Time-restricted feeding to the dLAN cycle normalizes autonomic input to the heart and blood pressure dipping. These data suggest that time-restricted feeding counteracts the light-at-night-induced circadian disruption of cardiovascular function.
... Cardiovascular disease remains a leading cause of death, and many cardiovascular variables (e.g., heart rate and arterial blood pressure) have day-night rhythms that cycle with a periodicity of ≈24 h 12 . The impact that light at night has on day-night rhythms in heart rate and blood pressure is only now being understood [13][14][15] . Data suggest that light at night decreases the amplitude of day-night heart rate and blood pressure rhythms in people and small animals but through distinct mechanisms 14 . ...
... The impact of artificial light at night on people and dLAN on male mice differs from that of artificial light at night on male rats housed at room temperature 14 . Light at night in rats appears to decrease the relative sympathetic signaling at night to decrease the amplitude of the 24-hour heart rate and blood pressure rhythms 13,36 . One possible reason for the difference between our studies in male mice and previous studies in rats is that we studied the effects of dLAN in mice housed at thermoneutrality to limit coldinduced sympathetic nervous system activation. ...
... The concept that light at night decreases the amplitude in day-night rhythms of cardiovascular physiology is not new, nor is the concept that it is linked to increased cardiometabolic risk 4,10,[13][14][15] . A limitation of this study is that we did not include an experimental group for nighttime restricted feeding in mice housed in 12-hour light and dark cycles. ...
Article
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Shift work and artificial light at night disrupt the entrainment of endogenous circadian rhythms in physiology and behavior to the day-night cycle. We hypothesized that exposure to dim light at night (dLAN) disrupts feeding rhythms, leading to sex-specific changes in autonomic signaling and day-night heart rate and blood pressure rhythms. Compared to mice housed in 12-hour light/12-hour dark cycles, mice exposed to dLAN showed reduced amplitudes in day-night feeding, heart rate, and blood pressure rhythms. In female mice, dLAN reduced the amplitude of day-night cardiovascular rhythms by decreasing the relative sympathetic regulation at night, while in male mice, it did so by increasing the relative sympathetic regulation during the daytime. Time-restricted feeding to the dim light cycle reversed these autonomic changes in both sexes. We conclude that dLAN induces sex-specific changes in autonomic regulation of heart rate and blood pressure, and time-restricted feeding may represent a chronotherapeutic strategy to mitigate the cardiovascular impact of light at night.
... The biological clock generates circadian rhythms with an endogenous period of~24-h. Circadian rhythms are observed in behaviour, locomotor activity, metabolism, and many other physiological processes, including the cardiovascular system [1][2][3]. The main synchronisation factor of circadian rhythms is a regular light/dark (LD) cycle. ...
... The observed effects depended on the length of ALAN exposure; the most significant effects were observed after 2 weeks of ALAN. Similar results were observed in the case of decreased systolic blood pressure, heart rate and sympathetic nervous activity in normotensive Wistar rats [1,12,22] but with a delay in spontaneously hypertensive rats [2] and rats exposed to prenatal hypoxia, which have naturally increased sympathetic activity [12]. In the present study, we calculated sympathetic and vagal activity from blood pressure variability and aLF, aHF indices and their ratio. ...
... The circadian rhythm is essential for the correct timing of processes in the cardiovascular system. Experimental and clinical research showed that ALAN not only increases stress sensitivity and vulnerability in both rats [21] and humans [49] but also leads to the development of cardiometabolic diseases [2,50]. In our works, ALAN decreased the robustness and amplitude of the circadian rhythm in the blood pressure and altered protein expression in the aorta, which can represent a risk for the development of cardiometabolic diseases and an attenuated ability to anticipate load. ...
Article
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Artificial light at night (ALAN) disrupts 24-h variability of blood pressure, but the molecular mechanisms underlying these effects are unknown. Therefore, we analysed the daily variability of pulse pressure, the maximum value of acceleration rate of aortic pressure (dP/dt(max)) measured by telemetry and protein expression in the thoracic aorta of normotensive male rats exposed to ALAN (1-2 lx) for 3 weeks. Daily, 24-h variability of pulse pressure and dP/dt(max) was observed during a regular light/dark regimen with higher values during the dark compared to the light phase of the day. ALAN suppressed 24-h variability and enhanced ultradian (<12-h) periods of pulse pressure and dP/dt(max) in duration-dependent manners. From beat-to-beat blood pressure variability, ALAN decreased low-frequency bands (a sympathetic marker) and had minimal effects on high-frequency bands. At the molecular level, ALAN decreased angiotensin II receptor type 1 expression and reduced 24-h variability. ALAN caused the appearance of 12-h oscillations in transforming growth factor β1 and fibulin 4. Expression of sarco/endoplasmic reticulum Ca2+-ATPase type 2 was increased in the middle of the light and dark phase of the day, and ALAN did not affect its daily and 12-h variability. In conclusion, ALAN suppressed 24-h variability of pulse pressure and dP/dt(max), decreased the power of low-frequency bands and differentially affected the expression of specific proteins in the rat thoracic aorta. Suppressed 24-h oscillations by ALAN underline the pulsatility of individual endocrine axes with different periods, disrupting the cardiovascular control of central blood pressure.
... In spontaneously hypertensive rats (18 weeks old), which are characterised by an increased sympathetic nerve activity [47], ALAN (5 weeks; 1-2 lx) attenuated the age-related increase in blood pressure, leaving a daily heart rate variability unaffected. Moreover, significant increases in blood pressure and heart rate during the transitions between the light and dark phases were lost [74]. ALAN (1-2 lx) had the most pronounced effects on blood pressure and heart rate after two weeks of exposure, and day-night variability was partially restored after five weeks of exposure [55,82]. ...
... Studies in spontaneously hypertensive rats [74] and rats exposed prenatally to hypoxia, which experimentally increases sympathetic nerve activity [82], suggest that the sympathetic nervous system is essential in transmitting information from the SCN to the cardiovascular system [83]. The sympathetic nervous system acts on the cardiovascular system through noradrenaline, released from the nerve terminals. ...
Article
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Artificial light at night (ALAN) affects most of the population. Through the retinohypothalamic tract, ALAN modulates the activity of the central circadian oscillator and, consequently, various physiological systems, including the cardiovascular one. We summarised the current knowledge about the effects of ALAN on the cardiovascular system in diurnal and nocturnal animals. Based on published data, ALAN reduces the day-night variability of the blood pressure and heart rate in diurnal and nocturnal animals by increasing the nocturnal values of cardiovascular variables in diurnal animals and decreasing them in nocturnal animals. The effects of ALAN on the cardiovascular system are mainly transmitted through the autonomic nervous system. ALAN is also considered a stress-inducing factor, as glucocorticoid and glucose level changes indicate. Moreover, in nocturnal rats, ALAN increases the pressure response to load. In addition, ALAN induces molecular changes in the heart and blood vessels. Changes in the cardiovascular system significantly depend on the duration of ALAN exposure. To some extent, alterations in physical activity can explain the changes observed in the cardiovascular system after ALAN exposure. Although ALAN acts differently on nocturnal and diurnal animals, we can conclude that both exhibit a weakened circadian coordination among physiological systems, which increases the risk of future cardiovascular complications and reduces the ability to anticipate stress.
... 60,61 Animal experiments established that the expression of metabolic transcription factors Pparα and Pparγ increased in the epididymal fat of the low-dose ALAN group and the expression of Glut4 decreased in the heart. 62 In addition to these harmful factors, the role of protective factors in CVH is also significant, including green spaces and healthy behaviors. These are viewed as potential mechanisms linking human health with the "active component" in nature. ...
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Background Artificial light at night (ALAN) is a common phenomenon and contributes to the severe light pollution suffered by more than 80% of the world's population. This study aimed to evaluate the relationship between outdoor ALAN exposure and cardiovascular health (CVH) in patients with diabetes and the influence of various modifiable factors. Methods A survey method based on the China Diabetes and Risk Factor Monitoring System was adopted. Study data were extracted for 1765 individuals with diabetes in Anhui Province. Outdoor ALAN exposure (nW/cm²/sr) within 1000 m of each participant's residential address was obtained from satellite imagery data, with a resolution of ~1000 m. Health risk behaviors (HRBs) were measured via a standardized questionnaire. A linear regression model was employed to estimate the relationship between outdoor ALAN, HRBs, and CVH. Results Participants' mean age was 59.10 ± 10.0 years. An association was observed between ALAN and CVH in patients with diabetes (β = 0.205) and exercise (β = −1.557), moderated by HRBs, or metabolic metrics. There was an association between ALAN, ALAN, vegetable intake, and CVH. Conclusions Exploring the relationship between ALAN exposure and cardiovascular and metabolic health provides policy data for improving light pollution strategies and reducing the risk of cardiovascular and metabolic disease in patients with diabetes. image
... [11][12][13] Animal experiments have found that rats experiencing LAN showed a loss of light-dark variability in SBP and a gradual increase in SBP over 5 weeks. 14 In a recent study, researchers found that LAN exposure (measured by 7-day actigraphy recording) was associated with a higher prevalence of hypertension (odds ratio [OR] 1.74, 95% CI: 1.21-2.52) among 552 community-dwelling adults aged. ...
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The authors aimed to investigate the association between outdoor light at night (LAN) intensity and blood pressure. The study included 13 507 participants aged 45 and above from the 2011–2012 China Health and Retirement Longitudinal Study baseline survey. Blood pressure measurements were obtained by averaging the last two readings recorded (three measurements with an interval of 45–60 s between each measurement) during the survey. Outdoor LAN intensity was assessed using Defense Meteorological Satellite Program data. The study categorized participants based on quartiles of outdoor LAN intensity and employed statistical methods like linear regression, restricted cubic splines, and logistic models to analyze the connections. After adjusting for potential confounding factors, higher levels of outdoor LAN intensity were associated with increase in systolic blood pressure (0.592 mmHg/interquartile range [IQR], 95% confidence interval [CI]: 0.027,1.157), diastolic blood pressure (0.853 mmHg/IQR, 95% CI: 0.525,1.180) and mean arterial pressure (0.766 mmHg/IQR, 95% CI: 0.385,1.147). Interestingly, the relationship between LAN intensity and odds of hypertension followed a non‐linear pattern, resembling a reverse “L” shape on cubic splines. Participants with the highest quartile of outdoor LAN intensity had 1.31‐fold increased odds of hypertension (95% CI: 1.08–1.58) compared to the lowest quartile. Additionally, there was an observable trend of rising odds for high‐normal blood pressure with higher levels of LAN intensity in the crude model, but no statistically significant differences were observed after adjusting for confounding factors. In conclusion, this study underscores a significant connection between outdoor LAN intensity and the prevalence of hypertension.
Chapter
Life on earth has evolved under a consistent cycle of light and darkness caused by the earth's rotation around its axis. This has led to a 24-hour circadian system in most organisms, ranging all the way from fungi to humans. With the advent of electric light in the 19th century, cycles of light and darkness have drastically changed. Shift workers and others exposed to high levels of light at night are at increased risk of health problems, including metabolic syndrome, depression, sleep disorders, dementia, heart disease, and cancer. This book will describe how the circadian system regulates physiology and behavior and consider the important health repercussions of chronic disruption of the circadian system in our increasingly lit world. The research summarized here will interest students in psychology, biology, neuroscience, immunology, medicine, and ecology.
Article
Background: Epidemiological studies show that outdoor artificial light at night (ALAN) is linked to metabolic hazards, but its association with metabolic syndrome (MetS) remains unclear. We aimed to investigate the association of outdoor ALAN with MetS in middle-aged and elderly Chinese. Methods: From 2017-2020, we conducted a cross-sectional study in a total of 109,452 participants living in ten cities of eastern China. MetS was defined by fasting blood glucose (FG), triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), blood pressure (BP), and waist circumference (WC). In 2021, we followed up 4395 participants without MetS at the baseline. Each participant's five-year average exposure to outdoor ALAN, as well as their exposure to green space type, were measured through matching to their address. Generalized linear models were used to assess the associations of outdoor ALAN with MetS. Stratified analyses were performed by sex, age, region, physical activity, and exposure to green space. Results: In the cross-sectional study, compared to the first quantile (Q1) of outdoor ALAN exposure, the odds ratios (ORs) of MetS were 1.156 [95 % confidence interval (CI): 1.111-1.203] and 1.073 (95 %CI: 1.021-1.128) respectively in the third and fourth quantiles (Q3, Q4) of outdoor ALAN exposure. The follow-up study found that, compared to the first quantile (Q1) of outdoor ALAN exposure, the OR of MetS in Q4 of ALAN exposure was 1.204 (95 %CI: 1.019-1.422). Adverse associations of ALAN with MetS components, including high FG, high TG, and obesity, were also found. Greater associations of ALAN with MetS were found in males, the elderly, urban residents, those with low frequency of physical activity, and those living in areas with low levels of grass cover and tree cover. Conclusions: Outdoor ALAN exposure is associated with an increased MetS risk, especially in males, the elderly, urban residents, those lacking physical activity, and those living in lower levels of grass cover and tree cover.
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Significance Shift workers are affected by circadian misalignment and have an increased risk to develop metabolic diseases such as type 2 diabetes. Here, we show that during simulated short-term night shift work insulin sensitivity at the level of skeletal muscle is decreased in male volunteers, which could contribute to the development of type 2 diabetes in the long term. We also find that the muscle molecular clock does not align rapidly to the new behavioral cycle. Importantly, on the level of the transcriptome, circadian misalignment induced upregulation of fatty acid metabolism pathways, potentially resulting in substrate competition on the cellular level. These findings help to better understand the negative consequences during night shift work.
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Study Objectives Healthy physiology is characterized by fractal regulation (FR) that generates similar structures in the fluctuations of physiological outputs at different time scales. Perturbed FR is associated with aging and age-related pathological conditions. Shift work, involving repeated and chronic exposure to misaligned environmental and behavioral cycles, disrupts circadian coordination. We tested whether night shifts perturb FR in motor activity and whether night shifts affect FR in chronic shift workers and non-shift workers differently. Methods We studied 13 chronic shift workers and 14 non-shift workers as controls using both field and in-laboratory experiments. In the in-laboratory study, simulated night shifts were used to induce a misalignment between the endogenous circadian pacemaker and the sleep–wake cycles (ie, circadian misalignment) while environmental conditions and food intake were controlled. Results In the field study, we found that FR was robust in controls but broke down in shift workers during night shifts, leading to more random activity fluctuations as observed in patients with dementia. The night shift effect was present even 2 days after ending night shifts. The in-laboratory study confirmed that night shifts perturbed FR in chronic shift workers and showed that FR in controls was more resilience to the circadian misalignment. Moreover, FR during real and simulated night shifts was more perturbed in those who started shift work at older ages. Conclusions Chronic shift work causes night shift intolerance, which is probably linked to the degraded plasticity of the circadian control system.
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Aims/hypothesis: Exposure to light at night (LAN) has increased dramatically in recent decades. Animal studies have shown that chronic dim LAN induced obesity and glucose intolerance. Furthermore, several studies in humans have demonstrated that chronic exposure to artificial LAN may have adverse health effects with an increased risk of metabolic disorders, including type 2 diabetes. It is well-known that acute exposure to LAN affects biological clock function, hormone secretion and the activity of the autonomic nervous system, but data on the effects of LAN on glucose homeostasis are lacking. This study aimed to investigate the acute effects of LAN on glucose metabolism. Methods: Male Wistar rats were subjected to i.v. glucose or insulin tolerance tests while exposed to 2?h of LAN in the early or late dark phase. In subsequent experiments, different light intensities and wavelengths were used. Results: LAN exposure early in the dark phase at ZT15 caused increased glucose responses during the first 20?min after glucose infusion (p?<?0.001), whereas LAN exposure at the end of the dark phase, at ZT21, caused increased insulin responses during the first 10?min (p?<?0.01), indicating that LAN immediately induces glucose intolerance in rats. Subsequent experiments demonstrated that the effect of LAN was both intensity- and wavelength-dependent. White light of 50 and 150?lx induced greater glucose responses than 5 and 20?lx, whereas all intensities other than 5?lx reduced locomotor activity. Green light induced glucose intolerance, but red and blue light did not, suggesting the involvement of a specific retina-brain pathway. Conclusions/interpretation: Together, these data show that exposure to LAN has acute adverse effects on glucose metabolism in a time-, intensity- and wavelength-dependent manner.
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Glucose tolerance is lower at night and higher in the morning. Shift workers, who often eat at night and experience circadian misalignment (i.e., misalignment between the central circadian pacemaker and the environmental/behavioral cycle), have an increased risk of type 2 diabetes. To determine the separate and relative impacts of the circadian system, behavioral/environmental cycles, and their interaction (i.e., circadian misalignment) on insulin sensitivity and β‐cell function, we used the oral minimal model to quantitatively assess the major determinants of glucose control in 14 healthy adults, using a randomized, cross‐over design with two 8‐day laboratory protocols. Both protocols involved 3 baseline inpatient days with habitual sleep/wake cycle, followed by 4 inpatient days with same nocturnal bedtime (circadian alignment) or with 12‐h inverted behavioral/environmental cycles (circadian misalignment). Our data showed that circadian phase and circadian misalignment affect glucose tolerance through different mechanisms. While the circadian system reduces glucose tolerance in the biological evening compared to the biological morning mainly by decreasing both dynamic and static β‐cell responsivity, circadian misalignment reduced glucose tolerance mainly by lowering insulin sensitivity, not by affecting β‐cell function. This article is protected by copyright. All rights reserved.
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Physiological variables such as heart rate (HR) and blood pressure (BP) exhibit long-term circadian rhythms, which can be disturbed by shift work. On the other hand, short-term oscillations in HR and BP have a high prognostic value. Therefore, we aimed to determine if the short-term variability, complexity and entropy of HR and BP would be affected by a regular light/dark (LD) cycle and phase delay shifts of the LD cycle, leading to chronodisruption. Telemetry-monitored rats were exposed first to the regular LD cycle and then to shifts in LD for 8 weeks. On the basis of long-term HR and BP recording and evaluation, we found circadian rhythms in HR and BP variability, complexity and entropy under regular LD cycles. Short-term exposure to shifts disturbed circadian rhythms of HR and BP variability, complexity and entropy, indicating chronodisruption. The power of circadian rhythms was suppressed after 8 weeks of phase delay shifts. Long-term exposure to shifts increased variability (p = 0.007), complexity (p < 0.001) and dark-time entropy (p = 0.006) of HR but not BP. This is the first study demonstrating long-term recording and estimation of HR and BP variability, complexity and entropy in conscious rats exposed to irregular lighting conditions. After long-term phase delay shifts, short-term variability of HR was less predictable than in controls. This study suggests that changes in short-term HR and BP oscillations induced by long-term shift work can negatively affect cardiovascular health.
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Exposure to light at night (LAN) is associated with insomnia in humans. Light provides the main input to the master clock in the hypothalamic suprachiasmatic nucleus (SCN) that coordinates the sleep-wake cycle. We aimed to develop a rodent model for the effects of LAN on sleep. Therefore, we exposed male Wistar rats to either a 12 h light (150–200lux):12 h dark (LD) schedule or a 12 h light (150–200 lux):12 h dim white light (5 lux) (LDim) schedule. LDim acutely decreased the amplitude of daily rhythms of REM and NREM sleep, with a further decrease over the following days. LDim diminished the rhythms of 1) the circadian 16–19 Hz frequency domain within the NREM sleep EEG, and 2) SCN clock gene expression. LDim also induced internal desynchronization in locomotor activity by introducing a free running rhythm with a period of ~25 h next to the entrained 24 h rhythm. LDim did not affect body weight or glucose tolerance. In conclusion, we introduce the first rodent model for disturbed circadian control of sleep due to LAN. We show that internal desynchronization is possible in a 24 h L:D cycle which suggests that a similar desynchronization may explain the association between LAN and human insomnia.
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Use of artificial light resulted in relative independence from the natural light–dark (LD) cycle, allowing human subjects to shift the timing of food intake and work to convenient times. However, the increase in artificial light exposure parallels the increase in obesity prevalence. Light is the dominant Zeitgeber for the central circadian clock, which resides within the hypothalamic suprachiasmatic nucleus, and coordinates daily rhythm in feeding behaviour and metabolism. Eating during inappropriate light conditions may result in metabolic disease via changes in the biological clock. In this review, we describe the physiological role of light in the circadian timing system and explore the interaction between the circadian timing system and metabolism. Furthermore, we discuss the acute and chronic effects of artificial light exposure on food intake and energy metabolism in animals and human subjects. We propose that living in synchrony with the natural daily LD cycle promotes metabolic health and increased exposure to artificial light at inappropriate times of day has adverse effects on metabolism, feeding behaviour and body weight regulation. Reducing the negative side effects of the extensive use of artificial light in human subjects might be useful in the prevention of metabolic disease.
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Prenatal stress has been linked to deficits in neurological function including deficient social behavior, alterations in learning and memory, impaired stress regulation, and susceptibility to adult disease. In addition, prenatal environment is known to alter cardiovascular health; however, limited information is available regarding the cerebrovascular consequences of prenatal stress exposure. Vascular disturbances late in life may lead to cerebral hypoperfusion which is linked to a variety of neurodegenerative and psychiatric diseases. The known impact of cerebrovascular compromise on neuronal function and behavior highlights the importance of characterizing the impact of stress on not just neurons and glia, but also cerebrovasculature. Von Willebrand factor has previously been shown to be impacted by prenatal stress and is predictive of cerebrovascular health. Here we assess the impact of prenatal stress on von Willebrand factor and related angiogenic factors. Furthermore, we assess the potential protective effects of concurrent anti-depressant treatment during in utero stress exposure on the assessed cerebrovascular endpoints. Prenatal stress augmented expression of von Willebrand factor which was prevented by concurrent in utero escitalopram treatment. The functional implications of this increase in von Willebrand factor remain elusive, but the presented data demonstrate that although prenatal stress did not independently impact total vascularization, exposure to chronic stress in adulthood decreased blood vessel length. In addition, the current study demonstrates that production of reactive oxygen species in the hippocampus is decreased by prenatal exposure to escitalopram. Collectively, these findings demonstrate that the prenatal experience can cause complex changes in adult cerebral vascular structure and function.