The effect of noise exposure on insulin sensitivity in mice may be mediated by the JNK/IRS1 pathway
Liu et al. Environmental Health and Preventive Medicine
The effect of noise exposure on insulin sensitivity in mice may be mediated by the JNK/IRS1 pathway
Lijie Liu 0
Cong Fang 1
Jing Yang 1
Hongyu Zhang 1
Yi Huang 1
Chuanying Xuan 1
Yongfang Wang 0
Shengwei Li 0
Jun Sha 0
Mingming Zha 0
Min Guo 0
0 Medical College, Southeast University , No.87, Dingjiaqiao Street, Gulou, Nanjing , China
1 Institute of Life Sciences, Southeast University , Nanjing , China
Background: Epidemiological studies have suggested that noise exposure may increase the risk of type 2 diabetes mellitus (T2DM), and experimental studies have demonstrated that noise exposure can induce insulin resistance in rodents. The aim of the present study was to explore noise-induced processes underlying impaired insulin sensitivity in mice. Methods: Male ICR mice were randomly divided into four groups: a control group without noise exposure and three noise groups exposed to white noise at a 95-dB sound pressure level for 4 h/day for 1, 10, or 20 days (N1D, N10D, and N20D, respectively). Systemic insulin sensitivity was evaluated at 1 day, 1 week, and 1 month post-noise exposure (1DPN, 1WPN, and 1MPN) via insulin tolerance tests (ITTs). Several insulin-related processes, including the phosphorylation of Akt, IRS1, and JNK in the animals' skeletal muscles, were examined using standard immunoblots. Biomarkers of inflammation (circulating levels of TNF-α and IL-6) and oxidative stress (SOD and CAT activities and MDA levels in skeletal muscles) were measured via chemical analyses. Results: The data obtained in this study showed the following: (1) The impairment of systemic insulin sensitivity was transient in the N1D group but prolonged in the N10D and N20D groups. (2) Noise exposure led to enhanced JNK phosphorylation and IRS1 serine phosphorylation as well as reduced Akt phosphorylation in skeletal muscles in response to exogenous insulin stimulation. (3) Plasma levels of TNF-α and IL-6, CAT activity, and MDA concentrations in skeletal muscles were elevated after 20 days of noise exposure. Conclusions: Impaired insulin sensitivity in noise-exposed mice might be mediated by an enhancement of the JNK/IRS1 pathway. Inflammation and oxidative stress might contribute to insulin resistance after chronic noise exposure.
Noise exposure; Insulin sensitivity; JNK/IRS1 pathway; Inflammation; Oxidative stress
Noise, one of the most widespread sources of
environmental pollution, is considered not only an environmental
nuisance but also a threat to public health [
]. Beyond the
well-recognized problem of hearing impairment,
increasing attention is being paid to the cumulative adverse
effects of noise exposure on extra-auditory systems [
a more than 10-year prospective epidemiological study
conducted by Sorensen et al. in a Danish cohort, each
10dB increase in average road traffic noise at the current
residence was found to be associated with a statistically
significant 11% increased risk of incident diabetes; this risk
increased to 14% when road traffic noise was estimated
for all the places in which an individual had lived during
the previous 5 years [
]. Their study raised concern about
noise as a risk factor of diabetes, particularly given the
global epidemic of this disease and the increasingly
widespread pattern of noise pollution [
]. A previous study
by our group indicated that noise exposure at a 95-dB
sound pressure level (dB SPL) induces insulin resistance
in mice . More recently, another experimental study
reported abnormalities in glucose regulation and insulin
sensitivity in rats that were chronically exposed to noise at
a 100-dB SPL [
]. Because insulin resistance is well known
to be a key contributor to type 2 diabetes mellitus
(T2DM) and a key pathological feature of T2DM, these
experimental studies together suggested a contributory
role of noise exposure to increasing the risk of T2DM.
Considering the alarming global epidemic of T2DM [
and the global prevalence of noise pollution [
], it is
imperative to explore the mechanisms underlying the
impairment of insulin sensitivity after noise exposure.
We previously examined circulatory corticosterone
levels in mice subjected to noise exposure at a 95-dB
SPL at 4 h/day for 1, 10, and 20 days. The collected data
showed that at 1 day after the cessation of noise
exposure, the levels of plasma corticosterone in all three noise
groups were significantly increased compared to those in
matched control groups [
]. This result was consistent
with other reports indicating that noise is a source of
environmental stress [
]. Furthermore, these data
illustrated a sustained stress response to chronic noise
and support the notion that the animals did not adapt to
the noise, even after prolonged exposure [
Persistently elevated cortisol levels have been proposed
to be associated with the development of insulin
]. Positive associations between excess stress
hormones, oxidative stress, and insulin resistance have
been widely reported [
]. It is also well documented
that the release of inflammatory cytokines, such as
tumor necrosis factor-α (TNF-α) and interleukin-6
(IL6), which are often cited as crucial cytokines that
mediate insulin resistance [
], can be induced by chronic
]. The protein c-Jun N-terminal kinase
(JNK) has been increasingly recognized as an important
mediator of insulin resistance that is associated with
inflammation and oxidative stress [
] through the
phosphorylation of serine residues in insulin receptor
substrate-1 (IRS-1) [
]. Considering these facts, we
postulated that the adverse effects of noise exposure on
insulin sensitivity might be mediated, at least in part,
through complex interactions between inflammation,
oxidative stress, and the JNK/IRS1 pathway. Thus, in the
present study, we evaluated the influence of noise
exposure (95 dB SPL, 4 h/day for 1, 10, or 20 consecutive
days) on systemic insulin sensitivity, the JNK/IRS1/Akt
pathway, and markers of inflammation and oxidative
stress in ICR mice.
Animals and experimental protocol
Five-week-old wild-type male ICR mice were obtained
from the Qinglongshan Animal Center (Nanjing, China,
SCXK(SU)2012-0008). In total, 144 mice were used in this
study. The mice were housed in conventional cages with a
12-h light/dark cycle (lights on at 7 am) and had free
access to food (standard rodent chow, SHOOBREE,
Xietong Organism, Jiangsu, China) and water. After a
1week acclimation period, the animals were randomly
assigned into one control group or into one of three
noise-exposure groups. The animals in the noise-exposure
groups were exposed to broadband noise at a 95-dB SPL
for 4 h/day between 8:00 am and 12:00 pm for 1 day (the
N1D group), 10 days (the N10D group), or 20 days (the
N20D group). The animals in each of the noise-exposure
groups were further subdivided into three subgroups
according to the times at which the assessments were
performed: at 1 day, 1 week, or 1 month after the final noise
exposure (1DPN, 1WPN, and 1MPN, respectively) (Fig. 1).
The mice in the control group were also subdivided into
the same subgroups according to the assessment time
points and served as age-matched controls. The animals
were treated humanely and with regard for the alleviation
of suffering. Food consumption per cage was measured
every 3 or 4 days by subtracting the amount of the food
left from the initial amount of food supplied. To avoid
circadian rhythm-induced variations, the insulin tolerance
test (ITT) was always initiated at 9:00 am, and tissue and
blood samples used for further studies were collected
between 2:00 pm and 3:00 pm. All of the animal
procedures were approved by the University Committee for
Laboratory Animals of Southeast University, China
(reference number: 20130307-004).
The animals were exposed to noise as described previously
]. Briefly, after acclimatization to the noise-exposure
setting for 30 min, awake and unrestrained mice were
placed separately into metal net cages that were 50 cm
below the horns of two loudspeakers. Electrical Gaussian
noise generated by a System III processor from
TuckerDavis-Technologies (TDT, Alachua, FL, USA) was delivered
to speakers after power amplification. In consistent with
our previous studies, the acoustic spectrum of the sound
was distributed mainly between 1 and 20 kHz [
noise level was monitored using a 1/4-in. microphone
linked to a sound level meter (Larson Davis 824, Depew,
NY, USA), and the sound intensity was maintained at a 95
± 1 dB SPL.
Insulin tolerance test
The insulin tolerance test (ITT) on 4-h-fasted mice was
initiated at 9:00 am to avoid circadian rhythm-induced
variation. Blood samples were obtained from the tail vein
of awake mice just prior to (0 min) and at 30, 60, and
90 min after an intraperitoneal injection of insulin
(Humulin, 0.75 U/kg body wt). Blood glucose levels were
measured using a portable glucose monitor (Bayer
Contour, Bayer HealthCare LLC, Whippany, NJ) and test
strips. The time course of absolute blood glucose recorded
during the ITT and the areas under the blood glucose
curves (AUC) were used to evaluate insulin sensitivity.
After completion of the test, the mice were returned to
their home cage and given free access to food and water.
Western blot analysis
Three to 4 h after completion of the ITT (i.e., 2:00–
3:00 pm), the mice were decapitated 20 min after an
intraperitoneal injection of insulin (Humulin, 0.75 U/kg body
wt), and their gastrocnemius muscles were dissected and
homogenized in ice-cold RIPA buffer (Beyotime P0013C,
China) supplemented with a complete protease inhibitor
cocktail (Roche, Germany) and PhosSTOP (Roche,
Germany). The protein extracts (40 μg) for each
preparation were separated using 10% SDS-PAGE and
electrotransferred onto PVDF membranes (Millipore, Bedford,
MA, USA). After blocking with Tris-buffered saline, 0.1%
Tween 20, and 5% nonfat dry milk, the membranes were
incubated with primary antibodies overnight at 4 °C. The
following antibodies were used: anti-IRS1 (Cell Signaling
Technology, Cat no. #2382, Beverly, MA, USA),
antiphospho-IRS1 (Ser307) (Cell Signaling Technology, Cat
no. #2381, Beverly, MA, USA), anti-JNK (Cell Signaling
Technology, Cat no. #9252, Beverly, MA, USA),
antiphospho-JNK (Thr183/Tyr185) (Cell Signaling
Technology, Cat no. #9251, Beverly, MA, USA), anti-Akt (Cell
Signaling Technology, Cat no. #4685, Beverly, MA, USA),
anti-phospho-Akt (Ser473) (Cell Signaling Technology,
Cat no. #4058, Beverly, MA, USA), and anti-phospho-Akt
(Thr308) (Cell Signaling Technology, Cat no. #4056). The
protein bands were visualized using an ECL Kit
(WBKLS0050; Millipore, Billerica, MA, USA), and a
densitometry analysis was performed using ImageJ.
Because insulin can influence the production of
inflammatory cytokines and the oxidative stress response [
separate groups of mice were used in the biochemical analyses.
Blood was collected immediately from the trunk into dry
tubes after the mice were decapitated without the
preadministration of insulin. Gastrocnemius muscles were
then harvested, weighed, and homogenized to evaluate
oxidative stress according to the protocols provided with
assay kits for superoxide dismutase (SOD, a powerful
endogenous enzymatic antioxidant) (STA-340, Cell Biolabs,
Inc.), catalase (CAT, an important endogenous enzymatic
antioxidant) (Cell Biolabs, STA-341, USA), and
malondialdehyde (MDA, a major secondary oxidation product) (Cell
Biolabs, STA-832, USA). Following centrifugation at 4 °C,
plasma was separated from each sample, and plasma
concentrations of TNF-a and IL-6 (Cat#EMC102a and
Cat#EMC004, NeoBioscience, Shenzhen, China) were
determined using enzyme-linked immunosorbent assay kits
according to the manufacturer’s instructions and guidelines.
The data are expressed as means ± standard errors (SE).
Depending on the type of measurement, two-way or
one-way ANOVAs were performed with a focus on the
effect of noise exposure (grouping). Post hoc pairwise
comparisons between each noise group and the control
group were performed (Tukey’s method) if a significant
effect of noise exposure was detected. Significance was
assumed at p < 0.05.
Effect of noise exposure on systemic insulin sensitivity in mice
The food intake and the bodyweight of all groups tested
at the three time points were similar (Fig. 2, inserts). At
1DPN, all noise groups exhibited blunted glucose
responses to insulin challenge, as indicated by
significantly higher blood glucose level(s) at one or more time
point(s) during the ITT and larger AUC values (which
were significant for N10D and N20D) compared with
the control values (Fig. 2a, d). At 1WPN, the N1D group
showed similar insulin sensitivity to that of the control
group, and the N10D group only exhibited a significantly
high blood glucose level at 30 min after insulin
injections. However, the N20D group displayed not only
significantly higher glucose levels at all three test points
after insulin injections but also a significantly higher
value of AUC (Fig. 2b, e). No differences were observed
between any of the groups at 1MPN (Fig. 2c, f ).
Effect of noise exposure on the JNK/IRS1/Akt pathway in the gastrocnemius muscle
As demonstrated in Fig. 3, at 1DPN, the phosphorylation
of JNK at Thr183/Thr185 and IRS1 at Ser307 were
significantly elevated in all three noise-exposed groups, while
the Akt phosphorylation at Thr308 and Ser473 induced by
exogenous insulin stimulation exhibited decreases in all
three noise-exposed groups, which reached significance
in the N20D group for Thr308 phosphorylation and in
the N10D and N20D groups for Ser473 phosphorylation.
At 1WPN, significantly elevated phosphorylation of JNK
was observed in the N10D and N20D groups, while the
significantly elevated IRS1 phosphorylation and blunted
Akt phosphorylation were only shown in the N20D
group. No significant difference in phosphorylation
levels from the controls was identified in any of the
noise-exposed groups at 1MPN.
Effect of noise exposure on the levels of inflammatory and oxidative stress markers
To explore whether inflammation and/or oxidative stress
might be involved in the influence of noise exposure on
insulin sensitivity, we examined the circulating levels of
inflammatory cytokines (TNF-α and IL-6) and the tissue
levels of oxidative stress markers (SOD and CAT
activities and MDA concentrations) in mice subjected to
1 day and 20 days of noise exposure. Since no significant
difference in the ITT and Western blotting assay was
revealed between the groups at 1MPN, we did not perform
these biochemical assays at 1MPN.
As illustrated by Fig. 4, the levels of the tested
cytokines and oxidative stress markers were all comparable
between the control and N1D groups at both 1DPN and
1WPN. However, the N20D group exhibited significantly
higher plasma TNF-α and IL-6 levels at 1DPN and
significantly elevated CAT activity and MDA
concentrations in their skeletal muscles at both 1DPN and 1WPN,
suggesting a transient elevation in systemic
inflammatory responses and a prolonged oxidative imbalance in
the skeletal muscle of the animals that were chronically
subjected to repeated noise.
As in our previous work, the animals in this study were
exposed to broadband noises presented at 95 dB for 4 h/
day, which is equivalent to 90 dBA for 8 h (dBA is the
sound pressure level when an “A” contour filter is used
according to the sensitivity of the human ear). The
recommended exposure limit in workplaces according to
the Occupational Safety and Health Administration
(OSHA) is 90 dBA for 8 h. Therefore, the exposure
setting used in this study is not higher than the
occupational safety allowance. Similar to our previous
observations, the blunted glucose response observed during the
ITT was shown in all noise-exposed groups at 1DPN
and was also evident at 1WPN in the N10D and N20D
groups in this study, indicating a trend towards insulin
resistance with prolonged noise exposure.
Skeletal muscles are the most important insulin-targeted
tissue involved in maintaining whole-body glucose
homeostasis under insulin-stimulated conditions and are major
sites of insulin resistance in T2DM subjects. In skeletal
muscle, insulin binds to a surface receptor and triggers a
cascade of signaling events involving IRS-1 and Akt that
induces the translocation of the glucose transporter from
its intracellular depot(s) to the cell surface, where these
transport proteins mediate the uptake of glucose into the
cell. Defects in these signaling pathways are considered the
major pathogenic disturbances underlying the development
and progression of insulin resistance [
]. Decreased Akt
phosphorylation at the insulin-responsive active site (Ser473
and Thr308) following insulin stimulation have been well
documented in insulin resistance [
]. In the present study,
noise-exposed animals exhibited a blunted glucose response
to insulin injection, which was accompanied by decreased
Akt phosphorylation in the skeletal muscle, indicating an
impairment of skeletal muscle insulin sensitivity.
Noise has long been classified as an environmental
stress. Several studies (including the two studies
illustrating the development of insulin resistance in animals
subjected to chronic noise) have reported significant increases
in plasma stress hormone levels during and after various
4, 5, 10
]. In our previous study, increased plasma
corticosterone levels were observed at 1 day after noise
exposure for 1, 10, and 20 days, suggesting a sustained
stress response throughout the noise exposure in the
N20D group [
]. Persistently elevated cortisol levels have
been proposed to be an etiological factor of insulin
11, 13, 23
]. Therefore, we have proposed that stress
responses might contribute to the development of insulin
resistance in noise-exposed animals [
]. c-Jun N-terminal
kinase (JNK) is an evolutionarily conserved stress-activated
protein kinase (SAPK) that is activated primarily by
inflammatory cytokines and exposure to environmental stress
]. Recent studies have identified JNK as a crucial link
between environmental challenges and metabolic
]. Activated JNK can phosphorylate IRS-1 at the
inhibitory site Ser307 and therefore suppress insulin signal
]. The results of the present study indicated
that systemic insulin resistance in the noise-exposed groups
was accompanied by an increased activation of JNK with a
corresponding increase in IRS-1 Ser307 phosphorylation in
skeletal muscle tissue. Although our data do not allow us to
rule out the contribution of other cellular serine kinases to
the altered phosphorylation state of muscle IRS-1, it is
highly plausible that JNK might serve as a candidate for the
link between noise exposure and insulin resistance.
Accumulating evidence supports the notion that
inflammatory markers can be induced after various stresses [
Inflammatory cytokines, including TNF-α and IL-6, are
thought to contribute to the development of insulin
resistance through the activation of several stress kinases, such
as JNK [
]. As noise has long been realized as an
environmental stress, we wondered whether inflammation
might be involved in the adverse effect of noise exposure
on insulin sensitivity. The data collected in this study
show that the plasma concentrations of both TNF-α and
IL-6 were comparable between the N1D and control
group at both 1DPN and 1WPN, indicating that no
inflammatory response was caused by the 1-day noise
exposure. These inflammatory cytokines were significantly
increased in the N20D group at 1DPN but not at 1WPN,
suggesting that a temporary inflammatory response
occurred in the animals that were subjected to chronic
noise exposure. The recovery of inflammatory cytokine
levels occurred earlier than that of insulin sensitivity,
indicated by the same-as-control blood concentrations of
TNF-α and IL-6 and the significantly blunted glucose
response during ITT at 1WPN. The time courses of the
inflammatory response, JNK activation, and the impaired
insulin sensitivity in the N20D group suggest that the
inflammation might be an event that links noise exposure
with insulin resistance rather than a consequence of
abnormal insulin sensitivity. Thus, consistent with the
findings of Cui et al. in rat [
], our results provide more
evidence that inflammation might contribute to the
increased diabetes risk after chronic noise exposure.
Oxidative stress, defined as a disturbance in the balance
between the production of reactive oxygen species and
antioxidant defenses, has been proposed as a contributor
to both the onset and the progression of insulin resistance
]. As one of the major secondary oxidation products,
MDA level has been regarded as reflecting the level of
tissue damage caused by oxidative stress [
]. In the
present work, the N20D group exhibited significant
increases in MDA levels in skeletal muscles at both 1DPN
and 1WPN, indicating enhanced oxidative stress. SOD
and CAT are powerful endogenous enzymatic antioxidants
that are responsible for protecting cells from oxidative
]. In the present work, no differences in SOD
activity were shown, whereas significant increases in CAT
activity in skeletal muscle were exhibited in the N20D
group at both 1DPN and 1WPN, suggesting an
insufficient compensatory response to oxidative stress. Although
the cross-sectional design of the present study does not
permit us to determine the exact relationship between the
insulin resistance, inflammatory cytokine levels and
oxidative stress exhibited in the N20D group at both 1DPN and
1WPN, these data provide some information regarding
the possible molecular mechanism underlying the
nonauditory effects of noise pollution.
We observed that insulin sensitivity impairment in
noiseexposed animals was accompanied by an increase in JNK
activation with a corresponding increase in IRS-1 serine
phosphorylation in skeletal muscle tissue. Consistent with
the possible causal role of inflammation and oxidative stress
in JNK activation, we observed that the levels of circulatory
inflammatory cytokines and oxidative stress markers in
skeletal muscle were increased in animals that were
exposed to noise for 20 days. These results suggest that the
JNK/IRS pathway might mediate the adverse effect of noise
exposure on skeletal muscle insulin sensitivity and that
inflammatory response and oxidative stress are involved in
the onset and/or development of insulin resistance after
chronic noise exposure. Additional and more
comprehensive methods (e.g., inhibiting JNK activity using JNK
inhibitors) are required to reveal the exact relationships between
these factors and their individual contributions to insulin
resistance after noise exposure. The influence of noise
exposure on the insulin sensitivity of liver and adipose
tissue, the other two main types of insulin-sensitive tissues,
should also be further investigated in future studies.
1DPN: 1-day post-noise exposure; 1MPN: 1-month post-noise exposure;
1WPN: 1-week post-noise exposure; Akt: Protein kinase B; AUC: Area under the
curve; CAT: Catalase; dB SPL: Decibel sound pressure level; IL-6: Interleukin-6;
IRS-1: Insulin receptor substrate-1; ITT: Insulin tolerance test; JNK: c-Jun
N-terminal kinase; MDA: Malondialdehyde; N10D: Noise exposure for
10 days; N1D: Noise exposure for 1 day; N20D: Noise exposure for 20 days;
SOD: Superoxide dismutase; TNF-α: Tumor necrosis factor-α
Thanks to Prof. Jian Wang for the writing assistance of the manuscript.
This work was supported by the National Natural Science Foundation of
China (81670935, 81520108015, 81100548, and 81271086) and the
Fundamental Research Fund of Southeast University (2242016K40073).
Availability of data and materials
Please contact the author for data requests.
LL and CF designed the experiments. CF, JY, HZ, YH, CX, YW, SL, JS, MZ, and
MG performed the experiments. LL and CF performed the statistical analysis.
LL and CF interpreted the data and wrote the paper. All authors read and
approved the final manuscript.
All experimental procedures were conducted in accordance with relevant
guidelines for the care of experimental animals and were approved by the
University Committee for Laboratory Animals of Southeast University, China
(approval no. 20130307-004).
Consent for publication
The authors declare that they have no competing interests.
Springer Nature remains neutral with regard to jurisdictional claims in
published maps and institutional affiliations.
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