PPARα suppresses low-intensity-noise-induced body weight gain in mice: the aggravation of fatty liver is covered up

doi:10.21203/rs.3.rs-3175396/v1

Download PDF

Article

PPARα suppresses low-intensity-noise-induced body weight gain in mice: the aggravation of fatty liver is covered up

https://doi.org/10.21203/rs.3.rs-3175396/v1

This work is licensed under a CC BY 4.0 License

Journal Publication

published 20 Jun, 2024

Read the published version in International Journal of Obesity →

You are reading this latest preprint version

Background

As the second risky environmental pollution, noise imposes threats to human health. Exposure to high-intensity noise causes hearing impairment, psychotic disorders, endocrine modifications. However, the relationship among low-intensity noise, obesity and lipid-regulating nuclear factor PPARα is not yet clear.

Methods

In this study, wild-type (WT) and Pparα-null (KO) mice on a high-fat diet (HFD) were exposed to 75 dB noise for 12 weeks to explore the effect of low-intensity noise on obesity development and the role of PPARα. 3T3-L1 cells were treated with dexamethasone (DEX) to verify the down-stream effect of hypothalamic-pituitary-adrenal (HPA) axis activation on the adipose tissues.

Results

The average body weight gain (BWG) of WT mice on HFD exposed to noise was inhibited by 34.6%, which was not observed in KO mice. The mass and adipocyte size of adipose tissues accounted for the above difference of BWG tendency. In WT mice on HFD, the adrenocorticotropic hormone level was increased by the noise challenge. The aggravation of fatty liver by noise exposure occurred in both mouse lines, and the transport of hepatic redundant lipid to adipose tissues were similar. The lipid metabolism in adipose tissue driven by HPA axis accorded with the BWG inhibition, validated in 3T3-L1 adipogenic stem cell model.

Conclusion

Chronic exposure to low-intensity noise aggravated fatty liver in both WT and KO mice. BWG inhibition was observed only in WT mice, which covered up the aggravation of fatty liver by noise exposure. Lipid metabolism in adipose tissues driven by HPA axis activation contributed to the disassociation of BWG and fatty liver development in WT mice.

Health sciences/Diseases/Endocrine system and metabolic diseases/Obesity

Health sciences/Health care/Disease prevention/Preventive medicine

PPARα

body weight gain

low-intensity noise

lipid metabolism

HPA axis

Metabolic syndrome (Mets) is a clinical syndrome characterized by concurrence of 3 or more symptoms, including obesity, elevated blood pressure, insulin (INS) resistance, high serum triglyceride (TG) and low serum high-density lipoprotein cholesterol [1]. Presently, Mets is widespread with a prevalence of 10–40% in the world and 13–35% in European countries [2, 3]. It is well accepted that Mets is associated with abdominal obesity, dyslipidemia, inflammation, INS resistance and diabetes. As a key etiological manifestation of Mets, abdominal obesity marks the dysfunction of adipose metabolism, which contributes most in Mets development [1].

Non-alcoholic fatty liver disease (NAFLD) is a pandemic chronic liver disease, and its increasing prevalence parallels the global rise in diabetes and obesity [4]. NAFLD is considered as a typical hepatic symptom of Mets, and obesity is a key factor driving the development of NAFLD [5]. According to epidemiological statistical analysis, 75% of obese people develop NAFLD and only 16% weigh normal with NAFLD. Thus the prevalence rate of NAFLD in obese patients is 4.6 times higher than that those with normal body weight [6]. So NAFLD can occur in subjects of normal weight (lean) or overweight, called lean NAFLD or non-obese NAFLD [7]. Due to the absence of obesity as a risk factor, the diagnosis and evaluation of non-obese NAFLD are often ignored, leading to the loss of early treatment opportunities. Therefore, NAFLD development in abscence of obesity deserves clinical vigilance.

Noise includes sound of different frequencies or intensities in daily life and working environments, which makes people uncomfortable [8, 9]. In European countries, 56 million people (54%) were exposed to an average of 55 decibels of road traffic noise [10]. As the 2nd risky environmental pollution, noise imposes threats to human health and well-being. The magnitude and intensity of noise were expected to increase due to population growth, urbanization, and the use of powerful, diverse and highly mobile noise sources [11]. The most ordinary source of anthropogenic noise was traffic, such as cars, airplanes and ships [12]. The most general threat to the human body caused by noise is hearing impairment [13]. Exposure to noise also caused damages to the human nervous system, endocrine system, cardiovascular system, digestive system and so on [14]. However, the relationship between noise exposure and metabolic disorders is not fully understood.

Studies reported the effect of noise on body weight, but the conclusions were contradictory. In female rats, 17 days of noise treatment (65 to 100 dB) increased their body weight by 123% [15]. In a detailed study, male mice were exposed to 95 dB noise for 4 hours per day for 1, 10, and 20 days. One week and one month after the end of exposure, the body weight gain (BWG) of these mice were increased by 1.05, 1.07, 1.09-fold and 1.12, 1.16, 1.23-fold respectively [16]. Data from the 2014 US National Health Interview Survey showed that exposure to high levels of occupational noise for 15 years or longer increased the risk of obesity by 46% [17]. In contrast, noise exposure was also reported to suppress the BWG. After 30-day exposure to 90 dB noise, the body weight of mice in the noise-exposed group was reduced by 10% [16]. In line with this study, 2-week exposure to noise of 85 dB hindered obesity development by 30% in high-fat diet (HFD)-treated mice [18]. All of the above data reported the obesogenic effect of high-intensity noise. Nevertheless, how long-term low-intensity noise exposure affects BWG is not known, neither is the underlying mechanism.

Peroxisome proliferator-activated receptor alpha (PPARα) belongs to the nuclear receptor family, which is mainly expressed in tissues with rapid fatty acid metabolism. It is known to be protective in the development of Mets. The increase of body weight, adipose tissue, serum TG and impaired glucose tolerance were attenuated, when the HFD-treated mice were dosed PPARα agonists gemfibrozil and fenofibrate [19]. PPARα was reported to mediate BWG in HFD-treated mice exposed to light pollution [20]. Besides the involvement in regulating fatty acid metabolism, new functions of PPARα were reported to be involved in neuroscience in the past few years [21–23]. In Parkinson's disease rats, PPARα inhibited Caspase-3 activation, alleviated dopaminergic neuron degeneration and striatal dopamine loss. PPARα also reduced depression-like behavior and cognitive dysfunction in mice [24]. In Alzheimer's disease, activated PPARα played a neuroprotective role by attenuating Aβ42-induced DNA damage and neuronal apoptosis [25]. However, as a nuclear receptor, regulation of obesity development by the PPARα in the central nervous system was not known.

In this study, wild type (WT) and Pparα-null (KO) mice on HFD were exposed to 75 dB noise for 12 weeks to investigate the effect of low-intensity noise on development of NAFLD and obesity, as well as the role of PPARα in this process. The endocrine system and lipid metabolism/transport were analyzed to explore the underlying mechanism.

Materials and reagents

High-fat diet (45% fat, 35% carbohydrate, 19.4% protein) and normal diet (4% fat, 78% carbohydrate, 18% protein) were obtained from Nantong Trophy Feed Technology, China. Kits for the detection of total cholesterol (TC) and triglyceride (TG) were purchased from Meikang Biotechnology, China. Foetal bovine serum was gained from Pan Seratech, Germany. Ready-for-use penicillin-streptomycin was purchased from Beyotime Biotechnology, China. 3-isobutyl-1-methylxanthine and dexamethasone were bought from Aladdin, China. Dexamethasone sodium phosphate (DEX) was product by Shiyao Silver Lake Pharmaceutical Company, China. INS was from Novo Nordisk, Denmark. The ELISA kit for apolipoprotein B (ApoB) was from DEVELOP, China. The ELISA kits for adrenocorticotropic hormone (ACTH), INS and growth hormone (GH) were obtained from Qiaodu Biotechnology, China.

Animals and treatments

The wild type (WT) and mice Pparα-null (KO) mice with same genetic background were gifted by Frank J Gonzalez at National Cancer Institute [26]. The mice were housed in independent ventilation cages with humidity (60 ± 5%), temperature (24 ± 1℃) and 12/12-h dark-light cycle. Mice were treated in accordance with the Institute of Laboratory Animal Resource guidelines under protocols approved by the Animal Care and Use Committee of Ningbo University.

Male 4-6-week WT and KO mice were divided into 4 groups randomly (n = 5): Con group; HFD group; Noise group (exposed to noise only) and H + N group (co-exposed to HFD and noise). After 12 weeks of treatment, blood was collected via tail bleeding every 4 hours for 24 hours. All mice were sacrificed at 8:30 after 3 days of recovery. Plasma samples was centrifuged and the supernatants were stored at -20℃ pending analysis. The liver and fat tissue weight of mice were recorded, then halves of the biggest liver lobes were cut off and fixed in 10% neutral formalin buffer. The rest of the liver tissues were preserved at -80℃.

Noise exposure

The background noise was 30–45 dB during the noise-free period. Noise group and H + N group were exposed to varied noise at an average of 75 dB for 12 h everyday between 08:30 and 20:30 for 3 months. To avoid habituation, the noise changed in a random order of white noise, music, radio, traffic and other types of sound. The frequency of the sound ranged from 20 to 20 000 Hz.

Cell culture of 3T3-L1

3T3-L1 adipocytes were cultured in high glucose (4.5 g/L) DMEM supplemented with 10% foetal bovine serum and 1% penicillin-streptomycin. In adipogenic differentiation, 3T3-L1 preadipocytes were firstly cultured for 2 days post-confluence. And then the medium was switched to DMEM containing 0.5 mM 3-isobutyl-1-methylxanthine, 0.1 uM dexamethasone sodium phosphate, and 10 ug/mL INS for 2 days. Then the medium was changed to DMEM containing 10 ug/mL INS for 2 days. Cells were then cultured in a growth medium for an additional 2–4 days before collection. Dexamethasone (DEX, 0, 0.05, 0.5, 5 nM,) was added to the above growth medium 24 h before collection, to explore the action of DEX on lipid accumulation and cell proliferation. The lipid accumulation was demonstrated by oil red O staining. Then the cell lysates were collected for analysis of lipid level. In order to achieve 80–90% degree of fusion after 24 h of DEX treatment, different concentrations of DEX were used to stimulate the cells at confluence of 50%. The cell proliferation was determined using CCK-8 kit.

Measurement of TC and TG

The contents of total cholesterol (TC) and triglyceride (TG) in plasma and liver tissues were determined using TC and TG detection assay kits. Liver tissues were weighted and 9-fold saline was added for homogenization. Supernatants were collected after centrifuging at a speed of 12 000 rpm for 20 min at 4℃. The procedure and calculation of TC and TG contents analysis followed the protocol strictly, using end-point method suggested in the manufacturer’s instructions.

Assay of APOB, ACTH, INS and GH

Plasma apolipoprotein B (APOB), concentrations of adrenocorticotropic hormone (ACTH), INS and GH were determined by ELISA kits. Content of each indicator were assayed according to the manufacturer’s procedure. Considering the natural circadian rhythm of ACTH, its concentration was measured at 4:30, 8:30, 12:30, 16:30, 20:30 and 0:30 to draw the rhythmic profile.

Histopathological analysis

Freshly isolated fat and liver tissues were fixed in 10% formalin for around 24 hours. These tissues were firstly dehydrated in a gradient of 70%, 80%, 90% and 100% ethanol. After transparentization with xylene, the tissues were immersed and embedded in paraffin. Serial 4 micrometer sections were cut followed by hematoxylin and eosin staining. The sections were imaged using light microscope (Olympus BX43, Japan). The size of fat cells was evaluated using Image J 1.8.0.

Oil red O staining

The collected 3T3-L1 cells were bathed twice in PBS and fixed in 10% formalin neutral fixative for 30 min in the refrigerator at 4℃. Cells were stained in the fresh oil red O working solution for 30 min, and then they were soaked with 60% isopropyl alcohol for 10 seconds until the stroma was clear. Cell lipid accumulation was photographed using inverted light microscope (Olympus CKX41, Japan).

Q-PCR analysis

RNA extraction from liver and fat tissues and qPCR analysis were performed as described previously [20]. The specific primer sequences were listed in supplemental table 1. Using 18S rRNA as internal standard, 2^–ΔΔCt was used to calculate the transcriptional expression of the target gene. Messenger RNA levels in vehicle-treated control mice were arbitrarily set as 1 and results were expressed as relative abundance.

Statistical Analysis

The data were represented as the mean ± SD. Student’s t test was used when two groups were compared to difference examination. And one-way ANOVA was used when multiple groups were compared. post hoc analysis of individual group differences were performed using Bonferroni test. P < 0.05 was statistically significant, and statistical analysis was performed using SPSS 22.0.

Chronic noise exposure inhibited BWG and the adipocyte enlargement

Noise exposure did not affect the BWG of the mice on normal diet in WT and KO mice. The body weight of WT-HFD and KO-HFD groups increased by an average of 4.6 g and 5.4 g, compared with Con group after 12-week treatment (P < 0.05). However, BWG was inhibited 34.6% in H + N group compared with HFD group of WT mice (P < 0.05). And there was no significant difference between H + N group and HFD group of KO mice (Fig. 1A, B). Agreeing with the tendency of BWG, adipose weight/body weight (AW/BW) did not change in noise-challenged groups on normal diet but increased in HFD group in both WT and KO mice (P < 0.05). As expected, AW/BW was inhibited in WT mice but not modified in KO mice by noise exposure under HFD treatment (Fig. 1C). Liver weight/body weight (LW/BW) did not differ between groups in either WT or KO mice (Fig. 1D).

In histopathology analysis, adipose tissue showed the adipocytes in WT-Con group were of the same size as those in the WT-Noise group. In the WT-HFD group, the adipocyte size was increased by 2.3-fold (P < 0.05). But the size was reduced by nearly 77% in the WT-H + N group (P < 0.05) (Fig. 2A-D, I). The size of adipocytes in KO mice on normal diet was similar as those of WT mice. But for the mice in the KO- HFD and KO-H + N groups, the adipocyte size both increased around 2.3-fold (P < 0.05) (Fig. 2E-H, J). This tendency of adipocyte enlargement supported the tendency of adipose weight, as well as BWG under the different treatments.

Fatty liver was aggravated by the noise challenge in two mouse lines

Noise exposure did not affect the lipid homeostasis for the mice on normal diet in WT and KO mice. The liver TG of HFD group in two mouse lines respectively increased by 1.3-fold and 4.7-fold compared with Con group after the 12-week treatment (P < 0.05). Noise combined with HFD exposure increased liver TG of WT and KO mice by 50% and 20% compared with their HFD groups (P < 0.05) (Fig. 3A). The liver TC of KO mice in H + N group was 60% higher than that in HFD group (P < 0.05) (Fig. 3B).

In the liver, compared with the Con group, both the WT and KO mice on HFD showed steatosis. And in both mouse lines fed HFD, noise exacerbated hepatic steatosis. But between WT and KO mice, steatosis was severer in the latter, whether on HFD alone or HFD combined with noise exposure (Fig. 3C-J). And these pathological differences accorded with the tendency of TG and TC levels in the liver.

Lipid transport and ACTH activation laid basis for BWG

In ELISA analysis, plasma ApoB levels in HFD groups of two mouse lines increased significantly. Although it decreased in H + N group of KO mice (P < 0.05), there was no significant change in the plasma ApoB level of WT mice in H + N group compared with HFD group (Fig. 4A). The plasma TC of HFD groups in two mouse lines increased compared with their Con groups after 12-week treatment (P < 0.05) (Fig. 4B). For the plasma TG, there were no significant differences among these groups except that H + N groups showed decreases compared with noise-challenged groups (P < 0.05) (Fig. 4C). Combining these data, it was supposed that lipid transport from the liver to the adipose tissues were both up-related in two mouse lines.

Of the endocrinic biomarkers monitored, plasma ACTH at 8:30 a.m. increased compared with Con group (P < 0.05). And it was up-regulated more in the WT mice than that in the KO mice. Different from the KO mice, the 24-hour profile of plasma ACTH level of WT H + N group was disturbed more than that of the HFD group (P < 0.05) (Fig. 4D-F). For plasma INS and GH, they were not modified in either mouse line by the noise exposure. Thus they were not supposed to contribute to the modification of BWG (Fig. 4G, H).

Lipid metabolism modification in WT mice supported the BWG inhibition

The mRNA levels of 16 genes related to lipid synthesis, clean and transport in the adipose tissues were analyzed (Fig. 5A). In the WT-HFD group and KO-HFD group, the average mRNA level of Scd1 (lipid synthesis gene) were up-regulated (by 2.7-fold in WT and by 1.9-fold in KO) (P < 0.05). However, the average mRNA level of Scd1 in the WT-H + N group decreased by 54% (P < 0.05). For lipid transporter genes, the Fabp1 and Fabp4 mRNA levels were increased both in WT-HFD and KO-HFD group (P < 0.05). But the expression levels of the above genes were down-regulated in the WT H + N group compared with WT-HFD group (P < 0.05). In contrast, these genes were not modified in KO mice (Fig. 5B-D). These modifications accorded with the BWG and adipocyte enlargement in HFD-treated WT and KO mice.

To validate the above action of ACTH activation which inhibited the BWG and adipocyte enlargement, 3T3-L1 cells were used for in vitro experiments. Different concentrations of DEX were added to differentiated mature 3T3-L1 cells. The results of oil Red O staining showed that the lipid accumulation of adipocytes was weakened with the increase of DEX concentration (Fig. 5E-H). Similarly, the TG content of adipocytes was decreased after DEX treatment (Fig. 5I) (P < 0.05). Furthermore, in undifferentiated 3T3-L1 cells, DEX inhibited cell proliferation to some extent (Fig. 5J) (P < 0.05). These results indicated that DEX could inhibit the proliferation and lipid accumulation of adipocytes, supporting the BWG inhibition in H + N group of WT mice.

Noise, air pollution, water pollution and solid waste pollution are listed as the 4 kinds of major pollution around the world. Among them, noise pollution is usually overlooked since it is invisible and its effect is chronic. Exposure to harmful level of noise affected the auditory system, cardiovascular system, and endocrine system [27]. Nevertheless, the evidence supporting the association between noise and obesity is not well established. Diverse effects on body weight by different levels and frequencies of noise pollution were reported [28]. It is not known how chronic exposure to low-intensity noise affects the BWG in mouse model. In this study, after challenge by 75 dB noise for 12 weeks, the average BWG of WT mice on a HFD and exposed to noise was decreased by 34.6% compared with the WT mice on a HFD without noise exposure, which accorded with the previous studies [29, 30]. However, there was a dangerous fact that the fatty liver was exacerbated by noise exposure. And in WT mice, this was covered up by the inhibition of BWG. This should be alerted because it was different from the perspective that body weight correlates with Mets symptom fatty liver.

PPARα regulates lipid metabolism and its agonists are the drug of choice for dyslipidemia in the clinic [31–33]. In Pparα-null (KO) mice, HFD treatment increased body weight, adipose tissue, serum TG and impaired glucose tolerance. These phenotypes were attenuated after stimulated with gemfibrozil and fenofibrate (PPARα agonists). The STAT3 pathway was activated in adipose and hepatic tissues in positive control, but inhibited in groups treated with gemfibrozil and fenofibrate [19]. Also, PPARα promoted the BWG of HFD-treated mice by 61% under exposure to night neon light [20]. However, the role of PPARα in the action of noise pollution on BWG is not clear. In the present study, the BWG of WT mice on HFD exposed to noise for 12 weeks were significantly suppressed. The tendency of epididymal visceral adipose tissue weight correlated well to the BWG. However, the BWG of KO mice was quite normal under the same noise challenge. Thus PPARα was supposed to mediate the suppressive action of chronic noise exposure on BWG in mouse model.

To explore how noise exposure inhibits BWG, lipid homeostasis in the liver and in the circulation was firstly examined. Under noise challenge, fatty liver was aggravated in both mice lines fed HFD. But the KO mice developed severer fatty liver than WT mice after HFD treatment, which was consistent with previous studies [34]. In the ELISA analysis, the plasma APOB level in H + N group was lower than that in HFD group in KO mice. Combining the lipid level and APOB level tendencies, it was supposed that lipid transport from the liver to the adipose tissues only provided source materials. The lipid metabolism in the adipocytes was more important to suppress the BWG in WT mice.

As a member of the nuclear receptor family, PPARα was deeply involved in many disorders originating from central nervous system. PPARα was found to be helpful in the treatment of central nervous lesions in neurodegenerative disease [35, 36]. The underlying mechanism might be that PPARα played a neuroprotective role by promoting nerve repair and functional recovery, attenuating inflammatory response, reducing cell death and mitochondrial dysfunction [24, 27]. Clinically, Mets is related to the activation of hypothalamic–pituitary–adrenal (HPA) axis. In physiological state, endocrine system and metabolism in peripheral tissues are well coordinated, but the stresses can disrupt the coordination among them. In this study, only Only plasma ACTH was significantly changed in WT mice, but not in KO mice. So PPARα was involved in the production of ACTH driven by noise exposure. Considering the substantial role of PPARα in central nervous system, it was reasonable to suppose that the increase of ACTH level was regulated by PPARα in the brain tissues.

The effects of GCs on lipid metabolism were different, depending on their levels, treatment time and experimental models. GCs caused the increase of fat tissues in mouse, and 3T3-L1 adipocytes, by up-regulating genes involved in lipid synthesis and decomposition [37]. Long-term high-dose GCs treatment was reported to speed up the circulation of TG and FFA in adipose tissue, increasing lipid metabolism [38]. Some reports tended to suggest that oral GCs induce obesity in mice, while corticosterone sustained-release tablets or peritoneal injection of GC led to body weight loss in mice [39–43]. In this study, DEX, the most prevalent GC, was administered to 3T3-L1 adipocytes. With the increase of DEX concentration, the cellular lipid accumulation decreased continuously. Additionally, the cell proliferation was inhibited in undifferentiated 3T3-L1 cells. In this study, the lipid synthesis was increased and the lipid transport was decreased in the adipose tissues of WT H + N group, supporting the BWG inhibition by noise in the WT mice. So the decrease of visceral adipose in WT mice under noise challenge was the adipocyte response in downstream of the HPA axis activation driven by the PPARα in the central nervous system.

Conclusively, in the present study, chronic exposure to low-intensity noise aggravated fatty liver in mice on HFD. But it was covered up by BWG inhibition in WT mice. PPARα in the central nervous system played a critical role in original activation of the HPA axis. As a down-stream response of glucocorticoid, lipid metabolism modification in the adipose tissues driven by HPA axis activation contributed to the BWG inhibition by noise exposure in the WT mice.

Competing Interests

The authors declared no competing interests.

Author contributions

Zheng Yan: Writing-Original Draft, Formal analysis, Investigation. Jia Luo: Investigation, Methodology, investigation. Manyun Dai: Supervision, Project administration. Mingli Su: Validation, Data Curation. Lei Jiang: Histopathological analysis. Julin Yang and Aiming Liu: Conceptualization, Writing-Review and Editing, Funding acquisition. All authors read and approved the manuscript.

Acknowledgments

Dr. Frank J Gonzalez at NCI NIH was greatly appreciated for gift of PPARα transgenic mice. The authors thank the technical support group at the core facility platform of Ningbo University School of Medicine.

The Graphic abstract was partly generated using Servier Medical Art, provided by Servier, licensed under a Creative Commons Attribution 3.0 unported license.

Funding

This work was supported by Natural Science Foundation of Zhejiang Province (LY20H030001), Ningbo Public Welfare Project (202002N3160), Natural Science Foundation of Ningbo (2018A610253) and the K.C. Wong Magna Fund in Ningbo University.

Despres JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature. 2006;444(7121):881-7.
Grundy SM. Metabolic syndrome pandemic. Arterioscler Thromb Vasc Biol. 2008;28(4):629-36.
Haverinen E, Fernandez MF, Mustieles V, Tolonen H. Metabolic Syndrome and Endocrine Disrupting Chemicals: An Overview of Exposure and Health Effects. Int J Environ Res Public Health. 2021;18(24).
Vancells Lujan P, Vinas Esmel E, Sacanella Meseguer E. Overview of Non-Alcoholic Fatty Liver Disease (NAFLD) and the Role of Sugary Food Consumption and Other Dietary Components in Its Development. Nutrients. 2021;13(5).
Piche ME, Tchernof A, Despres JP. Obesity Phenotypes, Diabetes, and Cardiovascular Diseases. Circ Res. 2020;126(11):1477-500.
Fan JG, Kim SU, Wong VW. New trends on obesity and NAFLD in Asia. J Hepatol. 2017;67(4):862-73.
Kim D, Kim WR. Nonobese Fatty Liver Disease. Clin Gastroenterol Hepatol. 2017;15(4):474-85.
Imam L, Hannan SA. Noise-induced hearing loss: a modern epidemic? Br J Hosp Med (Lond). 2017;78(5):286-90.
Tikka C, Verbeek JH, Kateman E, Morata TC, Dreschler WA, Ferrite S. Interventions to prevent occupational noise-induced hearing loss. Cochrane Database Syst Rev. 2017;7(7):CD006396.
Basner M, Babisch W, Davis A, Brink M, Clark C, Janssen S, et al. Auditory and non-auditory effects of noise on health. Lancet. 2014;383(9925):1325-32.
Goines L, Hagler L. Noise pollution: a modem plague. South Med J. 2007;100(3):287-94.
Slabbekoorn H. Noise pollution. Curr Biol. 2019;29(19):R957-R60.
Xia G, Gao W, Ji K, Liu S, Wan B, Luo J, et al. Single nucleotide polymorphisms analysis of noise-induced hearing loss using three-dimensional polyacrylamide gel-based microarray method. J Biomed Nanotechnol. 2011;7(6):807-12.
Domingo-Pueyo A, Sanz-Valero J, Wanden-Berghe C. Disorders induced by direct occupational exposure to noise: Systematic review. Noise Health. 2016;18(84):229-39.
Coborn JE, Lessie RE, Sinton CM, Rance NE, Perez-Leighton CE, Teske JA. Noise-induced sleep disruption increases weight gain and decreases energy metabolism in female rats. Int J Obes (Lond). 2019;43(9):1759-68.
Liu L, Wang F, Lu H, Cao S, Du Z, Wang Y, et al. Effects of Noise Exposure on Systemic and Tissue-Level Markers of Glucose Homeostasis and Insulin Resistance in Male Mice. Environ Health Perspect. 2016;124(9):1390-8.
Paoin K, Ueda K, Ingviya T, Buya S, Phosri A, Seposo XT, et al. Long-term air pollution exposure and self-reported morbidity: A longitudinal analysis from the Thai cohort study (TCS). Environ Res. 2021;192:110330.
Liu L, Huang Y, Fang C, Zhang H, Yang J, Xuan C, et al. Chronic noise-exposure exacerbates insulin resistance and promotes the manifestations of the type 2 diabetes in a high-fat diet mouse model. PLoS One. 2018;13(3):e0195411.
Hua H, Yang J, Lin H, Xi Y, Dai M, Xu G, et al. PPARalpha-independent action against metabolic syndrome development by fibrates is mediated by inhibition of STAT3 signalling. J Pharm Pharmacol. 2018;70(12):1630-42.
Luo Y, Yang J, Kang J, Chen K, Jin X, Gonzalez FJ, et al. PPARalpha mediates night neon light-induced weight gain: role of lipid homeostasis. Theranostics. 2020;10(25):11497-506.
Ding J, Li M, Wan X, Jin X, Chen S, Yu C, et al. Effect of miR-34a in regulating steatosis by targeting PPARalpha expression in nonalcoholic fatty liver disease. Sci Rep. 2015;5:13729.
Zhai X, Chen X, Lu J, Zhang Y, Sun X, Huang Q, et al. Hydrogen-rich saline improves non‑alcoholic fatty liver disease by alleviating oxidative stress and activating hepatic PPARalpha and PPARgamma. Mol Med Rep. 2017;15(3):1305-12.
Hinds TD, Jr., Burns KA, Hosick PA, McBeth L, Nestor-Kalinoski A, Drummond HA, et al. Biliverdin Reductase A Attenuates Hepatic Steatosis by Inhibition of Glycogen Synthase Kinase (GSK) 3beta Phosphorylation of Serine 73 of Peroxisome Proliferator-activated Receptor (PPAR) alpha. J Biol Chem. 2016;291(48):25179-91.
Barbiero JK, Santiago RM, Persike DS, da Silva Fernandes MJ, Tonin FS, da Cunha C, et al. Neuroprotective effects of peroxisome proliferator-activated receptor alpha and gamma agonists in model of parkinsonism induced by intranigral 1-methyl-4-phenyl-1,2,3,6-tetrahyropyridine. Behav Brain Res. 2014;274:390-9.
Cheng YH, Lai SW, Chen PY, Chang JH, Chang NW. PPARalpha activation attenuates amyloid-beta-dependent neurodegeneration by modulating Endo G and AIF translocation. Neurotox Res. 2015;27(1):55-68.
Hua H, Dai M, Luo Y, Lin H, Xu G, Hu X, et al. Basal PPARalpha inhibits bile acid metabolism adaptation in chronic cholestatic model induced by alpha-naphthylisothiocyanate. Toxicol Lett. 2019;300:31-9.
Saha L, Bhandari S, Bhatia A, Banerjee D, Chakrabarti A. Anti-kindling Effect of Bezafibrate, a Peroxisome Proliferator-activated Receptors Alpha Agonist, in Pentylenetetrazole Induced Kindling Seizure Model. J Epilepsy Res. 2014;4(2):45-54.
Harris RB. Chronic and acute effects of stress on energy balance: are there appropriate animal models? Am J Physiol Regul Integr Comp Physiol. 2015;308(4):R250-65.
Alario P, Gamallo A, Beato MJ, Trancho G. Body weight gain, food intake and adrenal development in chronic noise stressed rats. Physiol Behav. 1987;40(1):29-32.
Kight CR, Swaddle JP. How and why environmental noise impacts animals: an integrative, mechanistic review. Ecol Lett. 2011;14(10):1052-61.
Atherton HJ, Gulston MK, Bailey NJ, Cheng KK, Zhang W, Clarke K, et al. Metabolomics of the interaction between PPAR-alpha and age in the PPAR-alpha-null mouse. Mol Syst Biol. 2009;5:259.
Pawlak M, Lefebvre P, Staels B. Molecular mechanism of PPARalpha action and its impact on lipid metabolism, inflammation and fibrosis in non-alcoholic fatty liver disease. J Hepatol. 2015;62(3):720-33.
Bougarne N, Weyers B, Desmet SJ, Deckers J, Ray DW, Staels B, et al. Molecular Actions of PPARalpha in Lipid Metabolism and Inflammation. Endocr Rev. 2018;39(5):760-802.
Gao Q, Jia Y, Yang G, Zhang X, Boddu PC, Petersen B, et al. PPARalpha-Deficient ob/ob Obese Mice Become More Obese and Manifest Severe Hepatic Steatosis Due to Decreased Fatty Acid Oxidation. Am J Pathol. 2015;185(5):1396-408.
Heneka MT, Landreth GE. PPARs in the brain. Biochim Biophys Acta. 2007;1771(8):1031-45.
Mandrekar-Colucci S, Sauerbeck A, Popovich PG, McTigue DM. PPAR agonists as therapeutics for CNS trauma and neurological diseases. ASN Neuro. 2013;5(5):e00129.
Fain JN, Cheema P, Tichansky DS, Madan AK. Stimulation of human omental adipose tissue lipolysis by growth hormone plus dexamethasone. Mol Cell Endocrinol. 2008;295(1-2):101-5.
Harris C, Roohk DJ, Fitch M, Boudignon BM, Halloran BP, Hellerstein MK. Large increases in adipose triacylglycerol flux in Cushingoid CRH-Tg mice are explained by futile cycling. Am J Physiol Endocrinol Metab. 2013;304(3):E282-93.
Karatsoreos IN, Bhagat SM, Bowles NP, Weil ZM, Pfaff DW, McEwen BS. Endocrine and physiological changes in response to chronic corticosterone: a potential model of the metabolic syndrome in mouse. Endocrinology. 2010;151(5):2117-27.
Fransson L, Franzen S, Rosengren V, Wolbert P, Sjoholm A, Ortsater H. beta-Cell adaptation in a mouse model of glucocorticoid-induced metabolic syndrome. J Endocrinol. 2013;219(3):231-41.
Rafacho A, Abrantes JL, Ribeiro DL, Paula FM, Pinto ME, Boschero AC, et al. Morphofunctional alterations in endocrine pancreas of short- and long-term dexamethasone-treated rats. Horm Metab Res. 2011;43(4):275-81.
Rafacho A, Marroqui L, Taboga SR, Abrantes JL, Silveira LR, Boschero AC, et al. Glucocorticoids in vivo induce both insulin hypersecretion and enhanced glucose sensitivity of stimulus-secretion coupling in isolated rat islets. Endocrinology. 2010;151(1):85-95.
Shpilberg Y, Beaudry JL, D'Souza A, Campbell JE, Peckett A, Riddell MC. A rodent model of rapid-onset diabetes induced by glucocorticoids and high-fat feeding. Dis Model Mech. 2012;5(5):671-80.

Graphical Abstract is not available with this version.

Graphical Abstract Summary of PPARα suppresses noise-induced body weight gain in mice on high-fat-diet. Chronic exposure to low-intensity noise exposure inhibited BWG by PPARα-dependent activation of the HPA axis.

Supplementary Table is not available with this version.

There is NO conflict of interest to disclose

Download PDF

Journal Publication

published 20 Jun, 2024

Read the published version in International Journal of Obesity →

Editorial decision: revise
24 Aug, 2023
Review #2 received at journal
17 Aug, 2023
Review #1 received at journal
03 Aug, 2023
Reviewer #2 agreed at journal
02 Aug, 2023
Reviewer #1 agreed at journal
02 Aug, 2023
Reviewers invited by journal
28 Jul, 2023
Submission checks completed at journal
18 Jul, 2023
First submitted to journal
17 Jul, 2023
Unknown event
17 Jul, 2023
Editor assigned by journal
16 Jul, 2023

You are reading this latest preprint version

PPARα suppresses low-intensity-noise-induced body weight gain in mice: the aggravation of fatty liver is covered up

Status:

Journal Publication

Version 1

Abstract

Figures

Introduction

Methods

Materials and reagents

Animals and treatments

Noise exposure

Cell culture of 3T3-L1

Measurement of TC and TG

Assay of APOB, ACTH, INS and GH

Histopathological analysis

Oil red O staining

Q-PCR analysis

Statistical Analysis

Results

Chronic noise exposure inhibited BWG and the adipocyte enlargement

Fatty liver was aggravated by the noise challenge in two mouse lines

Lipid transport and ACTH activation laid basis for BWG

Lipid metabolism modification in WT mice supported the BWG inhibition

Discussion

Declarations

References

Graphical Abstract

Supplementary Table

Additional Declarations

Status:

Journal Publication

Version 1