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 Table of Contents  
ORIGINAL ARTICLE
Year : 2017  |  Volume : 15  |  Issue : 2  |  Page : 78-84

Value of oxytocin in modifying metabolic changes and atherosclerosis in rat model of diet-induced obesity


Physiology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt

Date of Submission21-Jun-2017
Date of Acceptance17-Jul-2017
Date of Web Publication21-Nov-2017

Correspondence Address:
Randa S Gomaa
Faculty of Medicine, Zagazig University, 44519
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AZMJ.AZMJ_33_17

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  Abstract 

Background Oxytocin (OT) has effects on uterine contraction and milk ejection, but growing evidence suggests that OT plays an important role in the regulation of energy homeostasis and development of obesity.
Objective The aim of this study was to investigate the effect of OT in modifying metabolic changes and atherosclerosis in diet-induced obesity rat model and its possible mechanisms.
Materials and methods A total of 30 male rats and 60 female adult albino rats were divided into three main groups: male, female, and the ovariectomized group. Each group was subdivided into three equal groups: control, high-fat diet (HFD) fed, and HFD-OT-treated groups. Body mass index, body weight gain and mean arterial blood pressure were measured. Serum cholesterol, triglycerides, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, nitric oxide, reduced glutathione, malondialdehyde, C-reactive protein, insulin, and glucose were estimated, and atherogenic index was calculated. Aortic artery histopathology was studied.
Results In all groups, OT treatment to HFD-fed rats decreased body mass index and weight gain and improved hyperlipidemia, high glucose, low insulin levels, and elevated mean arterial blood pressure caused by HFD. It showed antioxidative stress activity as indicated by decreased C-reactive protein and malondialdehyde (MDA) and elevated nitric oxide and glutathione levels. OT treatment reveled anti-inflammatory action as indicated by aortic histopathology.
Conclusion OT administration to HFD-fed rats reduced body mass index and weight gain and improved metabolic changes associated with lipid profile, glucose tolerance, and blood pressure. In addition, it dramatically ameliorated the aortic atherosclerotic changes. This effect is due to its antioxidative stress activity and anti-inflammatory action, and this effect was more prominent in female and ovariectomized female rats. Further studies are recommended for more evaluation of other mechanisms that explain the metabolic action of OT and to clarify the difference in its action on sex and other species of experimental animals.

Keywords: atherosclerosis, hyperlipidemia, inflammation, oxytocin


How to cite this article:
Ibrahim MN, Alghannam MA, Gomaa RS, Elsayed NA. Value of oxytocin in modifying metabolic changes and atherosclerosis in rat model of diet-induced obesity. Al-Azhar Assiut Med J 2017;15:78-84

How to cite this URL:
Ibrahim MN, Alghannam MA, Gomaa RS, Elsayed NA. Value of oxytocin in modifying metabolic changes and atherosclerosis in rat model of diet-induced obesity. Al-Azhar Assiut Med J [serial online] 2017 [cited 2018 Oct 19];15:78-84. Available from: http://www.azmj.eg.net/text.asp?2017/15/2/78/218854




  Introduction Top


Although the nonapeptide oxytocin (OT) is well known for its peripheral effects on uterine contraction during parturition and milk ejection during lactation [1], growing evidence suggests that OT plays an important role in the regulation of energy homeostasis [2] plus other paraventricular nucleus functions such as regulation of food intake, responses to stress, modulation of metabolic rate, thermoregulation, and modulation of sympathetic nerve activity and cardiovascular (CV) function [3],[4].

Obesity has been thought to be growing problem in the world even in young ages. Although the most severe complications of obesity do not manifest until later in life, CV health consequences may already be evident at a young age [5]. Obesity is associated with increased rates of hypertension, hyperlipidemia, type 2 diabetes mellitus, and early development of atherosclerotic lesions. The effects of obesity and overweight affect the CV system in the form of arrhythmias, peripheral vascular disease, stroke, sudden death, coronary heart disease, hypertension, congestive heart failure, and most predominantly atherosclerosis [6].

Menopause, characterized by a reduction in the circulating levels of the ovarian hormones progesterone and estrogen, is an important risk factor for CV diseases. More specifically, ovarian hormone deprivation has been shown to lead to hypertension, abnormal plasma lipids, endothelial dysfunction, elevated oxidative stress, autonomic imbalance, and baroreflex impairment, which collectively result in high morbidity and mortality [7].

Numerous subsequent studies supported that adipose tissue is producing a variety of proinflammatory mediators such as tumor necrosis factor-α (TNF-α), interleukins (IL)-1, IL-6, and monocyte chemotactic protein 1 factors traditionally associated with inflammatory cells [8]. Similar to TNF-α the production of these ‘adipokines’ is a function of the health of the tissue and under conditions of nutrient excess, obesity, and progressive insulin resistance, there is substantial proinflammatory adipokine production [9].

On the basis of these observations, the aim of the current study was to investigate the effect of OT in modifying changes associated with lipid profile, glucose tolerance, and blood pressure and the susceptibility to develop atherosclerosis in diet-induced obesity (DIO) rat model and to study the possible mechanisms of this effect.


  Materials and methods Top


A total of 30 male rats and 60 female adult albino rats of 12–15 weeks old weighing 180–220 g were provided from The Animal House Faculty of Veterinary Medicine, Zagazig University. They were maintained for a week for acclimatization under conditions of controlled temperature (24–26°C), humidity (50–60%), and 12 h light–dark cycle. They were fed a standard diet with free access to water [10]. All experimental procedures were carried out in accordance with research protocols established by the Institutional Review Board (IRB) Committee, Faculty of Medicine, Zagazig University, Egypt.

The animals were divided into three main groups of 30 rats each:
  1. Group I: the male group.
  2. Group II: the female group.
  3. Group III: the ovariectomized female group.


All groups were subdivided into three equal subgroups (each contained 10 rats):
  1. Groups Ia, IIa, and IIIa (the control groups) were fed normal diet.
  2. Groups Ib, IIb, and IIIb) [the high-fat diet (HFD)-fed groups] were fed HFD comprising 16.45% protein, 25.6% carbohydrate, and 58.0% fat in the form of cotton seed oil added to the laboratory chow diet for 12 weeks [11].
  3. Groups Ic, IIc, and IIIc) (the OT-treated groups) were fed HFD as HFD groups and on the 10th week of the experiment they were treated with OT at a dose of 0.01 ml/100 g/day for 14 days [12]. While the control and HFD-fed groups were injected with i.m saline at a dose 0.01 ml/100 gm/day on the 10th week of the experiment for 14 days.


Experimental protocol

Ovariectomy technique was performed after acclimatization according to Veronique et al. [13]. Body weight gain was measure using a sensitive digital scale by calculating the difference between body weights at the start and at the end of the experiment. Weight gain was calculated as percentage change in the initial body weight. Body mass index (BMI) was calculated for each animal at the end of the experiment by the equation: BMI (gm/cm2) = body weight/length2 (nose to anus length) this index can be used as an indicator of obesity where the cutoff value of obesity BMI is more than 0.68 gm/cm2 [12].

Mean arterial blood pressure (MABP) was measured at the end of the experiment using tail-cuff device (Narco Biosystem Inc., Huston, Texas, USA) after the animals had been warmed for 30 min in a metabolic chamber maintained at 300 by 30°C. All measurements were made at the same time of the day. The mean values of MABP obtained from three consecutive measurements were recorded as the pressure values for each rat.

After that, the rats were killed after 12 h of fasting under anesthesia (chloral hydrate inhalation). Blood samples were obtained by means of exsanguination at the time of scarification, collected, and allowed to clot for 2 h at room temperature before centrifugation. The sera were stored at −20°C until analysis. Repeated freezing and thawing was avoided. Thereafter, the thoracic aorta was rapidly removed and fixed in 10% neutral-buffered formalin. Sections of 5 μm were stained with hematoxylin and eosin and then were examined with light microscopy for histopathology.

The sera were examined for the following: levels of insulin using enzyme-linked immunosorbent assay (ELISA) kits (Bio Basic INC, USA) according to the method of Temple et al. [14]; levels of glucose using ELISA kits according to the method of Tietz [15]; levels of total cholesterol (TC) using colorimetric method according to the method of Allain et al. [16]; and triglyceride (TG) levels using enzymatic assay according to the method of Wahlefeld [17]. Determination of high-density lipoprotein-cholesterol (HDL-C) was carried out using enzymatic assay according to the method of Finely [18]. Low-density lipoprotein-cholesterol (LDL-C) was calculated using Friedewald’s formula [19]: LDL-C=[TC − (HDL-cholesterol − TG)/5]. The atherogenic index (AI) was calculated from the following formula [20]:



Estimation of serum C-reactive protein (CRP) level was carried out using immune enzymatic assay technique described by Ridker et al. [21]. Nitric oxide (NO) was determined using Rat ELISA kits for evaluation of its oxidant products, nitrates and nitrites, using Griess reaction [22]. Plasma levels of malondialdehyde (MDA) were determined using Rat ELISA kits as described by Ohkawa [23]. Reduced glutathione (GSH) levels were determined using spectrophotometry according to the method of Jayatilleke and Shaw [24].

Statistical analysis

The results were presented as mean±SD. Statistical analysis was performed using the statistical package for the social sciences, version 19.0 (SPSS Inc., Chicago, Illinois, USA). Repeated measures of analysis of variance was applied followed by least significance differences for multiple comparisons. Levels of significance (P) were considered to be statistically significant when P value less than 0.05 [25].


  Results Top


Effect of high-fat diet and treatment with oxytocin on BMI, weight gain and lipid profile

There was an increase in BMI and weight gain with increase in serum levels of TC, TG, LDL-C, and AI with decrease in HDL-C serum level in all HFD-fed groups (groups Ib, IIb, and IIIb) in comparison with their controls (groups Ia, IIa, and IIIa). OT-treated groups (groups Ic, IIc, and IIIc) showed a decrease in weight gain with significantly decreased serum levels of TC, TG, LDL-C, and AI with increase in HDL-C serum level in comparison with HFD-fed groups ([Table 1],[Table 2],[Table 3]).
Table 1 Comparison of all studied parameters in male groups

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Table 2 Comparison of all studied parameters in female groups

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Table 3 Comparison of all studied parameters in ovariectomized female groups

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Effect of high-fat diet and treatment with oxytocin on glucose metabolism

There was an increase in serum glucose with decrease in serum insulin levels in all HFD-fed groups (groups Ib, IIb, and IIIb) in comparison with their controls (groups Ia, IIa, and IIIa). OT-treated groups (groups Ic, IIc, and IIIc) showed a decrease in serum glucose with increase in serum insulin levels in comparison with HFD-fed groups ([Table 1],[Table 2],[Table 3]).

Effect of high-fat diet and treatment with oxytocin on mean arterial blood pressure

MABP results revealed a significant increase in it in all HFD groups (groups Ib, IIb, and IIIb) in comparison with their controls (groups Ia, IIa, and IIIa). OT-treated groups (groups Ic, IIc, and IIIc) showed a significant decrease in MABP in comparison with HFD-fed groups ([Table 1],[Table 2],[Table 3]).

Effect of high-fat diet and treatment with oxytocin on oxidative stress markers

There was a significant increase in CRP and MAD serum levels with a significant decrease in NO and GSH serum levels in all HFD-fed groups (groups Ib, IIb, and IIIb) in comparison with their controls (groups Ia, IIa, and IIIa). OT-treated groups (groups Ic, IIc, and IIIc) showed a significant decrease in CRP and MDA serum levels, whereas a significant increase in NO and GSH serum levels in comparison with HFD-fed groups ([Table 1],[Table 2],[Table 3]).

Histopathological results

Groups Ia, IIa, and IIIa

The wall of the aorta in the rats showed normal architecture with normal three layers: the tunica intima with characteristic endothelial layer and delicate subendothelial connective tissue; the tunica media, which is formed of several layers of smooth muscle fibers intermingled with a large amount of elastic fibers; and the tunica adventia, which is formed of loose connective tissues rich in elastic fibers ([Figure 1]-I).
Figure 1 Photograph of transverse sections of the aorta. (Slide 1-I): Transverse section of the aorta of control groups (Groups Ia, IIa & IIIa) showing normal histological structures of intima, media and adventitia. (Slide 1-Ib): Transverse section of the aorta of group Ib shows focal areas of intimal thickening (A) with atheromatous cap formation and intimal protrusion into lumen (B). (Slide1- IIb): Transverse section of the aorta of group IIb shows focal areas of intimal thickening (A) and atheromatous cap formation with intimal protrusion into lumen (B) with focal ulceration of intimal lining (C) with focal atrophy of media (D). (Slide1- IIIb): Transverse section of the aorta of group IIIb shows focal areas of intimal thickening with sub-intimal proliferation and migration of smooth muscle cells associated with extra cellular matrix deposition (A) and intimal protrusion into lumen (B) with focal ulceration; by higher power (slide 1-IIIbH): there is intimal proliferation and subintimal migration of smooth muscle cells, macrophages and mononuclear cells infiltration, formation of foam cells with extracellular needle-like crystal of fat. (Slides1- Ic, IIc & IIIc): Transverse section of the aorta of Groups Ic, IIc & IIIc show The thickness of the walls of the aortas and histological structure of these groups similar to those of the control groups except presence of intimal protrusion into lumen (B) in all treated groups and remnants of intimal damage in the form of residual ulceration (C) in group IIIC (slid1- IIIC).

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Groups Ib, IIb, and IIIb

The wall of the aorta showed atherogenic changes in the form of focal areas of intimal thickening with atheromatous cap formation and intimal protrusion into lumen in group Ib ([Figure 1]-Ib). In group IIb, in addition to these changes there was focal ulceration of intimal lining and focal atrophy of media ([Figure 1]-IIb). In group IIIb, in addition to the changes that appeared group IIb, except for focal atrophy of the media, there was subintimal proliferation and migration of smooth muscle cells associated with macrophages and mononuclear cells infiltration, formation of foam cells, and extracellular needle-like crystal of fat ([Figure 1]-IIIb).

Groups Ic, IIc, and IIIc

The thickness of the wall of the aorta and histological structure of these groups were similar to those of the control groups except for the presence of except presence of intimal protrusion into lumen (B) in all treated groups and remnants of intimal damage in the form of residual ulceration (C) in group IIIC (slid IIIC) ([Figure 1]-Ic, [Figure 1]IIc and [Figure 1]IIIc).


  Discussion Top


The results of the current study revealed that OT treatment to HFD-fed rats decreased BMI and weight gain and improved hyperlipidemia, high serum glucose level, low serum insulin level, and the elevated MABP caused by HFD in male, female, and ovariectomized female white albino rats.

These results are in accordance with Deblon et al. [12] who reported that chronic subcutaneous infusion of OT to DIO rats, OT reduces body weight at doses that not reducing food intake. They also reported that chronic central OT infusion dose-dependently restricted weight gain and increased adipose tissue lipolysis in rats with HFD-induced obesity and decreased plasma TG level. These changes were accompanied by increases in the epididymal adipose tissue expression of enzymes involved in lipolysis and fatty acid β-oxidation, indicating that OT negatively modulates adipogenesis. They found that chronic central and peripheral OT administration improved glucose tolerance and significantly reduced insulin secretion during the glucose tolerance test and indicated increased insulin sensitivity, which is unrelated to the decrease in food intake.

In addition, Zhang et al. [26] reported that, in mice with HFD-induced obesity, acute treatment with OT reversed insulin resistance and glucose intolerance before reduction of obesity, thus dissecting the OT’s glucoregulatory pathways from its long-term effect on body weight.

In another research, Blevins et al. [27] found that in male DIO rhesus monkeys maintained on chow and a daily 15% fructose-sweetened beverage, chronic administration of OT for 4 weeks reduced BW and food intake, increased energy expenditure with elevations of free fatty acids and glycerol and reductions in TG suggesting increased lipolysis, and decreases the plasma glucose level, whereas increases insulin plasma level, especially with the higher dose of OT.

In addition, Lawson et al. [28] reported that there was a trend toward reduction in TG level and reduced average insulin levels, but there was no effect on glucose levels following a single dose of intranasal OT in fasting healthy men; this indicated that OT may improve insulin sensitivity independently of its effects on weight. However, Ott et al. [29] showed that intranasal OT reduced postprandial glucose but not insulin levels in healthy men.

In contrast, Ahmed and Elosaily [30] found that male albino rats that received OT treatment for 10 weeks showed a nonsignificant change in the plasma levels of TC and TGs LDL-C and HDL-C but decreased mean systolic blood pressure values nearly similar to those of the control group.

In addition, Altirriba et al. [31] found that in mice model of obesity, hyperinsulinemia, and diabetes treated for 2 weeks with different doses of OT, surprisingly, treatment of mice model was accompanied by worsened glucose tolerance likely due to increased corticosterone levels and stimulation of hepatic gluconeogenesis. These effects were independent of food intake, but the treatment increased basal insulinemia in that model.

Adding to Szeto et al. [32], who reported that chronic OT treatment in an animal model, the Watanabe heritable hyperlipidemic rabbit did not differentially affect serum cholesterol, TGs, and free fatty acids but decreased serum level of glucose and increased serum level of insulin and showed no differences in blood pressure or heart rate compared with their controls.

The present results revealed that OT treatment to HFD-fed rats showed antioxidative stress activity that developed by HFD in male, female, and ovariectomized female rats as indicated by decreased levels of CRP and MAD and elevated levels of NO and GSH. At the same time, OT treatment reveled anti-inflammatory action, which was more prominent in female and ovariectomized female rats as indicated by aortic histopathological examination.

These findings are in agreement with the research, which reported that OT administration led to an increase in the plasma levels of NO and GSH and decreased the plasma levels of MDA and CRP to normal and confirm these findings by aortic histopathology, mostly because OT administration prevented both lipid peroxidation and GSH depletion. Thus, it supports the maintenance of cellular integrity indicating that the protective effect of OT involves the maintenance of antioxidant capacity in protecting the tissues against oxidative stress [30].

Moreover, Oliveira-Pelegrin et al. [33] demonstrated that OT administration in male Wistar rats led to the release of NO and affected cytokine production by macrophages and abolished the sepsis-induced increase in TNF-α. It has also been reported that OT decreased IL-6 secretion from macrophages and endothelial cells in a dose-dependent manner, and attenuated superoxide production in aortic endothelial and smooth muscle cells, monocytes, and macrophages.In addition, Nation et al. [34] found that in-vivo chronic OT infusion in Apo E knockout mice, which is more liable to develop atherosclerosis, attenuated aortic atherosclerotic changes and plasma CRP and inhibited the secretion of the proinflammatory cytokine IL-6 in visceral adipose tissue.

Szeto et al. [32] reported in their study that chronic OT treatment slows the progression of atherosclerosis in the animal model described before. Reduced atherosclerosis was associated with decreased systemic inflammation, as reflected by circulating CRP, but without affecting other traditional risks factors for atherosclerosis or stress hormones supporting the argument that the OT-related attenuation of atherosclerosis may be through the suppression of local vascular and systemic inflammation.

In contrast, other researchers suggested that OT has stimulator effect on oxidative stress reaction as Schneid-Kofman [35], who demonstrated that, in pregnant women who received OT for augmentation of labor, there were lower GSH levels in comparison with women who did not receive OT, which indicated an oxidative stress reaction.

In addition, Iqbal et al. [36] reported that in 20 buffaloes, which were injected with OT before each milking (morning and evening) for milk let down and then they were assessed for oxidative stress biomarkers; they showed elevated total oxidant status, total homocysteine, and ceruloplasmin oxidase activity in lactating buffaloes injected with OT as compared with the control group. However, serum levels of total antioxidant capacity and paraoxonase-1 were significantly lower in the treated group.


  Conclusion Top


OT administration to HFD rats reduced BMI and weight gain and improved MABP and the metabolic changes associated with lipid profile, glucose tolerance, and blood pressure. In addition, it dramatically ameliorated the aortic atherosclerotic changes. This effect is due to its antioxidative stress activity and anti-inflammatory action, and this effect was more prominent in female and ovariectomized female rats. Further studies are recommended for more evaluation of other mechanisms that explain the metabolic action of OT and to clarify the difference in action of OT on sex and other species of experimental animals.

Acknowledgement

The histopathological assessment in the current study was done by Prof. Mohammad Ahmad Fouad Hussin Professor of Pathology, faculty of Medicine, Zagazig University.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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