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 Table of Contents  
ORIGINAL ARTICLE
Year : 2019  |  Volume : 17  |  Issue : 3  |  Page : 233-241

Correlation between serum and liver levels of some adipokines and oxidative parameters in obese adult male rats with and without antioxidant


Al-Azhar Faculty of Medicine for Girls Physiology Department, Nasr City in Front of El-Massa Hotel, Cairo, Egypt

Date of Submission20-Feb-2019
Date of Decision18-Mar-2019
Date of Acceptance07-Apr-2019
Date of Web Publication26-Nov-2019

Correspondence Address:
Mohammad M El-Shawwa
Al-Azhar Faculty of Medicine for Girls Physiology Department, Nasr City in Front of El-Massa Hotel, Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/AZMJ.AZMJ_32_19

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  Abstract 


Background Obesity is associated with insulin resistance (IR), type 2 diabetes, dyslipidemia, and cardiovascular diseases. Apelin and chemerin were identified as adipose tissue markers. Several adipokines are known to influence food intake, including apelin, whose expression is regulated by insulin and chemerin. Because oxidative stress (OS) is involved in the complications associated with obesity, the antioxidant activity of Lepidium sativum may be of benefit, as L. sativum showed maximum antioxidant activity by inhibiting hazardous effects of many oxidants.
Objective To clarify the pathophysiology of obesity by studying the nature of correlation between serum and liver levels of apelin and chemerin and oxidative parameters in obese rats with and without antioxidant.
Materials and methods A total of 30 adult male albino rats were divided into three equal groups: group I was control, group II received high-fat diet (HFD), and group III received HFD as well as L. sativum. At the end of the experiment, blood samples were collected for estimation of the serum levels of chemerin, apelin, fasting glucose, insulin, IR, lipid profile, glutathione (GSH) and malondialdehyde (MDA). Levels of MDA, catalse (CAT), chemerin and apelin were estimated in liver homogenate.
Results After 8 weeks, HFD group showed a significant increase in serum levels of apelin, chemerin, fasting glucose, insulin, IR, total cholesterol, very low-density lipoprotein, triglycerides, low-density lipoprotein cholesterol, and MDA and a significant decrease in high-density lipoprotein cholesterol and GSH. HFD also caused a significant increase in the tissue levels of MDA, CAT, and chemerin with a significant decrease in apelin, compared with control group. However, addition of L. sativum to HFD caused a significant decrease in serum levels of apelin, chemerin, fasting glucose, insulin, IR, total cholesterol, very low-density lipoprotein, triglycerides, low-density lipoprotein cholesterol, and MDA and a significant increase in high-density lipoprotein cholesterol and GSH. L. sativum also caused a significant decrease in tissue levels of MDA, chemerin, and CAT and a significant increase in apelin, compared with HFD group.
Conclusion This study showed a significant positive correlation between liver and serum chemerin and between liver and serum MDA. On the contrary, it showed a significant negative correlation between liver and serum apelin as well as between liver CAT and serum GSH.

Keywords: apelin, CAT, chemerin, glutathione, high-fat diet, Lepidium sativum, malondialdehyde, obesity


How to cite this article:
El-Shawwa MM. Correlation between serum and liver levels of some adipokines and oxidative parameters in obese adult male rats with and without antioxidant. Al-Azhar Assiut Med J 2019;17:233-41

How to cite this URL:
El-Shawwa MM. Correlation between serum and liver levels of some adipokines and oxidative parameters in obese adult male rats with and without antioxidant. Al-Azhar Assiut Med J [serial online] 2019 [cited 2020 Jul 10];17:233-41. Available from: http://www.azmj.eg.net/text.asp?2019/17/3/233/271676




  Introduction Top


Global increasing prevalence of obesity is a pressing health concern. Worldwide obesity has nearly tripled since 1975. In 2016, more than 650 million were obese [1]. Obesity is associated with insulin resistance (IR), type 2 diabetes, dyslipidemia, cardiovascular diseases, and increase incidence of cancer [2].

White adipose tissue is recognized as a dynamic endocrine organ able to release numerous bioactive polypeptides known as adipokines, which play an important role in the development of diseases related to obesity [3]. Adipokines were related to liver pathology and morbid obesity [4]. One such adipokine is apelin, a biologically active peptide, identified in 1998 [5]. Apelin mRNA is highly expressed in various tissues, including adipose tissue [6]. Insulin is considered one of the main regulators of apelin production, as it increases the expression and secretion of apelin by adipocytes [7]. Apelin and its receptor have an abundant distribution in central nervous system, peripheral tissues, and liver [8].

Chemerin is a novel adipokine highly expressed and secreted in liver and abdominal white adipose tissue [9]. It regulates adipogenesis and adipocyte metabolism [10]. Elevated levels of chemerin have been found in patients with obesity, inflammation, diabetes, and fatty liver disease [11],[12]. Moreover, chemerin might be considered as a genetic determinant of disproportionate regional body fat distribution [13]. The strong relation of chemerin to central obesity and waist circumference has been reported in several studies [14].

Oxidative stress (OS) reflects an imbalance between antioxidant capacity and toxic oxidant products, which causes tissue damage. OS is thought to be involved in the development of complications associated with obesity [15]. Chemically, OS is associated with increased levels of OS parameters such as malondialdehyde (MDA) and a significant decrease in the effectiveness of antioxidants, such as glutathione (GSH) [16].

Lepidium sativum or garden cress is a fast-growing annual herb that is native to Egypt and west Asia, although it is currently cultivated worldwide [17]. Extracts of Lepidium sativum seeds showed maximum antioxidant activity by inhibiting diphenylpicrylhydrazyl, O−2, HO, NO, and H2O2 scavenging activities [18].

The aim of the work is to clarify the pathophysiology of obesity by studying the nature of correlation between serum and liver levels of apelin, chemerin, and oxidative parameters in obese rats with and without antioxidant.


  Materials and methods Top


Animals and experimental design

This study was performed on 30 adult male albino rats, obtained from Helwan farm, Cairo, Egypt. Their body weight ranged from 140 to 170 g at the time they were purchased. The experimental procedures were done at the animal house of the faculty of medicine for girls, Al-Azhar University. Rats were housed as three rats in a cage, measuring 80×40×30 cm, at room temperature on a normal 12/12 light/dark cycle. Before the start of the experiment, rats were left for 10 days for adaptation and had free access to food and water [19]. The biochemical analysis was performed in Biochemistry Department, Faculty of Medicine, Cairo University. The Animal Care First Committee of Al-Azhar University 2018 approved all procedures. The ‘principles of laboratory animal care’ were followed, as well as specific national laws, where applicable.

Rats were divided into three equal groups, with 10 rats each. All rats were exposed to experimental interventions for eight weeks.
  • Group I (control): rats were kept on a balanced diet of ordinary rat chow.
  • Group II (HFD): rats were kept on HFD to induce obesity [20].
  • Group III (HFD and L. sativum): rats were kept on HFD mixed with L. sativum powdered seeds (6 g/kg) for 8 weeks [21].


Diets and plant material

Commercial rat chow diet (balanced diet) was used. The composition of the commercial rat chow diet was 5.4% fat; 53.8% carbohydrate; 21.9% protein; 2.9% fiber; 15.8% minerals; vitamins A, D, and E; and 0.2% cholesterol (a total of 350 kcal/100 g) [22]. Commercial HFD consisted of 80% balanced diet and 20% beef tallow [19],[20].

Plant material

The L. sativum seeds used in this study were purchased from local market in Cairo. The seeds were freshly ground into fine powder, then weighed and added to the diet [21].

Measurement of the body weight

The weight of each rat was measured and recorded weekly. At the end of the 8-week experimental period, weight gain was calculated relative to the initial body weight by using the following equation: body weight gain (g)=final body weight (g)−initial body weight (g) [23].

Blood sampling

At the end of the 8-week experimental period, blood samples were collected from the retro-orbital sinus with heparinized capillary tubes under light ether anesthesia, and then centrifuged at 3000 rpm for 15 min. Serum was separated from each sample and stored frozen at −80°C until the time of analysis [24].

Liver extract

Homogenous extraction of liver tissue was done by removal of excess blood, and the liver tissue was weighed before homogenization. Then, it was centrifuged at 500–800 rpm. The supernatants were collected, assayed immediately, or stored samples at −4°C [25].

Biochemical analysis

Biochemical analysis was done as follows

  1. Liver extract and serum apelin level measurement was done using kits [26].
  2. Liver extract and serum chemerin level measurement was done by kits [27].
  3. Fasting serum glucose was measured chemically [28].
  4. Fasting serum insulin level was measured by kits [29].
  5. IR index was calculated by homeostasis model assessment for IR formula [30]: homeostasis model assessment IR=fasting insulin (µIU/l)×fasting glucose (mmol/l) divided by 22.5.
  6. Lipid profile, including serum total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), very low-density lipoprotein (VLDL), and low-density lipoprotein cholesterol (LDL-C), was assessed chemically [31],[32],[33],[34].
  7. Serum GSH level was measured chemically [35].
  8. Liver extract and serum MDA level was measured chemically [36].
  9. Liver extract catalse (CAT) level was measured chemically [37].


Statistical analysis was carried out using statistical package for the social sciences, version 18 (SPSS Inc., Chicago, Illinois, USA) for Windows [38]. The contrast parameter values (mean±SD) among the three groups were carried out using analysis of variance test followed by Tukey’s multiple comparison test. Level of significance was defined as P value less than 0.05.


  Results Top


The results of this study showed that administration of HFD to rats for 8 weeks caused a significant increase in serum levels of chemerin, apelin, fasting glucose, insulin, and IR, when compared with control rats. HFD also caused a significant increase in serum levels of MDA, TC, VLDL, TG, and LDL-C and a significant decrease in the serum levels of GSH and HDL-C, compared with control rats.

The addition of L. sativum to the HFD significantly decreased serum levels of apelin, chemerin, fasting glucose, insulin, IR, TC, TG, VLDL, LDL-C, and MDA, compared with HFD group. Additionally, L. sativum significantly increased serum levels of HDL-C and GSH, compared with HFD group. Moreover, apelin, chemerin, insulin, TG, and VLDL-C could reach the normal levels, as there was nonsignificant difference between their levels in HFD+L. sativum rats and normal rats ([Table 1]).
Table 1 Effect of Lepidium sativum administration on serum levels of the measured parameters in high-fat diet-fed rats

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Concerning liver tissue homogenous extract, the administration of HFD caused significant increase in chemerin, MDA, and CAT and significant decrease in apelin, compared with control rats.

The addition of L. sativum to the HFD significantly decreased chemerin, MDA, and CAT and significantly increased apelin, compared with the HFD-fed rats. However, chemerin, CAT and MDA were still higher and apelin was still lower than the control group ([Table 2]).
Table 2 Effect of Lepidium sativum administration on tissue levels of the measured parameters in high-fat diet-fed rats

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[Table 3] shows a significant negative correlation between tissue and serum apelin, and also between tissue CAT and serum GSH. On the contrary, it showed significant positive correlation between tissue and serum chemerin and between tissue and serum MDA.
Table 3 Correlation between tissue and serum parameters

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  Discussion Top


Adipose tissue is considered one of the largest endocrine organs in the body owing to its ability to synthesize and release a large number of hormones, cytokines, extracellular matrix proteins, and growth and vasoactive factors, collectively termed adipokines, which influence a variety of physiological and pathophysiological processes [39]. In obesity, excessive fat accumulation causes adipose tissue dysfunction and imbalances in adipokine secretion, which strongly contribute to the onset of obesity‐related comorbidities such as IR [15]. IR through inhibition of lipid oxidation and increased fatty acid and triglycerides synthesis is believed to be a key factor in the development of fatty liver [40]. Studies have speculated that activated hepatic stellate cells represent a potential source for apelin in the liver and that apelin could be a good predictor for metabolic syndrome and fatty liver [41]. In addition, hepatocytes express chemerin; thus, a contribution of liver to chemerin concentrations might be considered [42].

The results of the present study showed a significant increase in chemerin levels in both serum and liver tissue of rats after intake of HFD for 8 weeks, compared with control rats. Sell et al. [43] reported that chemerin concentrations are elevated in morbidly obese patients and correlated with IR and markers of liver pathology. Zhao et al. [44] reported that administration of high-fat diet (HFD) to mice induced a significant increase in plasma and white adipose tissue chemerin levels. The mechanism by which increased adipose tissue mass and the concomitant increase of adipokines might be involved in hepatosteatosis includes the infiltration of macrophages in adipose tissue [45]. Thus, it might be speculated that chemerin could be a link between adipose tissue inflammation and liver pathology in obesity [43]. Bozaoglu et al. [46] also reported that gene expression of chemerin and its receptor, chemokine-like receptor 1, was significantly higher in adipose tissue of obese and type 2 diabetic animal models of obesity. These findings are also consistent with several studies that found significant increase of serum chemerin levels in obese adults and children, such as Hron et al. [47] and Niklowitz et al. [48]. Higher chemerin levels were related to hypertriglyceridemia, low HDL-C, and increased IR [30]. This increase in serum chemerin levels was owing to excessive adiposity as evidenced by decreased chemerin with weight loss owing to reduced amount of adipose tissue [49]. These latter effects may have been related to insulin stimulation of prochemerin secretion by adipocytes [5]. This study revealed significant increase in chemerin, apelin levels, and the calculated IR in HFD groups. This is consistent with the study of Shan et al. [24] who reported that the levels of chemerin and apelin in obese diabetic patients were closely related to IR. The increased levels may be a result of compensatory response to IR and may be the causative factor of IR.

Ercin et al. [50] showed that serum apelin correlated with hepatic fat content and hepatic IR. Studies also showed that apelin expression was higher in animal models of obesity-associated with hyperinsulinemia, adipogenesis, and steatosis [12],[51]. The study of Hashim et al. [41] showed that the apelin is involved in metabolic abnormalities that lead to steatosis in patients with nonalcoholic fatty liver disease. Abd-Elbaky and Abo-ElMatty [52] also found higher significant values of apelin in obese diabetic subjects compared with healthy ones. In addition, it was reported that the increase of some parameters involved in IR development, such as fat mass, glucose, insulin, lipid plasma levels, and TNF-α, may positively influence apelin circulating levels by upregulating its expression [53]. Circulating apelin increases in obesity as a compensatory mechanism to improve insulin sensitivity [54]. Apelin effects on insulin sensitivity may be direct via improved glucose uptake and intracellular insulin signaling [55] or indirect through improvements of energy metabolism including increased mitochondrial biogenesis and fatty acid oxidation [56]. It may be postulated that the apelin levels are directly proportional to the degree of IR.

This study also revealed a significant decrease in apelin levels in liver tissue of HFD group, compared with control one. Qasim et al. [16] also found significant reduction of serum apelin concentration of obese diabetic patients as compared with control subjects. The same findings were obtained by Erdem et al. [57] who reported that apelin level was lower in obese type 2 diabetic subjects than in healthy control subjects and explained this by the negative correlation of apelin tissue level and body fat. In addition, it might be due to increase in liver gene expression of apelin, which is responsible for regulation of cell proliferation, apoptosis, proinflammatory activity, and revascularization, as was reported by Li et al. [8]. In this study, there was a significant increase in serum glucose, insulin levels, and IR in rats after intake of HFD for 8 weeks, when compared with their corresponding control rats. These results are in agreement with Winzell and Ahrén [22] who reported the presence of hyperglycemia and hyperinsulinemia in HFD-fed mice. This was attributed to IR that occurred by HFD and decreased uptake of glucose by tissues, which results in hyperglycemia [58]. Hussien et al. [2] reported that fasting blood glucose, insulin, and IR were higher in obese patients. The same findings were observed by Assaad et al. [59] who confirmed the association between hyperinsulinemia and obesity.

This study showed that administration of HFD to rats caused significant increase in serum lipid profile in the form of TC, VLDL, triglycerides, and LDL-C and significant decrease in serum level of HDL-C, compared with control rats. Cavaliere et al. [60] showed significant increase in the serum concentrations of TG and TC after administration of HFD in male Wistar rats. Shirasuma et al. [61] also showed a significant increase in the serum concentrations of TG, TC and LDL-C after administration of HFD in male Wistar rats.

Regarding serum level of HDL, the results of this study were in agreement with Lavie and Milani [62] who reported that the reduction in HDL cholesterol level in animals fed HFD may be due to the decrease in lecithin-cholesterol acyltransferase activity, the key enzyme for extracellular cholesterol metabolism. This enzyme facilitates uptake of cholesterol from peripheral tissues to HDL particles by maintaining a concentration gradient for the efflux of free cholesterol; moreover, it is important in the maturation of HDL particles. Therefore, decreased lecithin-cholesterol acyltransferase leads to decrease in mature HDL generation with augmentation of atherosclerosis [63].

The results of this study revealed that administration of HFD caused significant increase in serum and tissue MDA and significant decrease in serum GSH levels in obese rats, compared with control rats. Lorizola et al. [64] reported that the induction of obesity by the HFD was able to induce OS in mice, as demonstrated by high MDA levels and glutath reductase and low GSH in the liver of HFD mice, compared with the control group. Yu et al. [65] also reported that HFD induces significant increase in MDA and significant decrease in antioxidant enzymes (CAT and superoxide dismutase) in the liver of HFD mice, compared with the control group. Patel et al. [66] reported that a diet high in fat and carbohydrates induces significant increase in OS parameters and inflammation in blood of obese persons. Obesity also increases the mechanical load and myocardial metabolism. Therefore, oxygen consumption is increased. One negative consequence of increased oxygen consumption is the production of reactive oxygen species (ROS) such as superoxide, hydroxyl radical, and hydrogen peroxide derived from the increase in mitochondrial respiration and from the loss of electrons produced in the electron transport chain, resulting in the formation of superoxide radical [67].

The present study showed that administration of HFD to rats caused a significant increase in serum and tissue CAT, compared with control rats. Dhuley [68] reported the elevation of CAT, superoxide dismutase, and glutath peroxidase in the livers and hearts of rats receiving HFD for 90 days. The excess of lipid can contribute to increase free radical production, in turn activating and increasing the expression of these antioxidant enzymes [69]. However, the activity of these enzymes was not enough to prevent the damage from reactive species, as demonstrated by the increase in MDA levels in the HF group [64]. In the study by Denisenko et al. [70], there was a significant increase in glutath levels in the blood and liver of rats receiving HFD for 90 days. This increase in antioxidants may occur as a compensatory mechanism and reveals an antioxidant protection to arrest the development of the OS and to minimize the accumulation of the highly toxic lipoperoxides in the blood and liver [70]. Obesity induced by HFD is known to enhance OS in white adipose tissue (WAT), in the plasma, and in the liver, which probably contributes to hepatic steatosis and other disorders [10]. The administration of antioxidants may be useful in the prevention and treatment of these diseases [6]. L. sativum has been widely used to treat a number of diseases in conventional medicine. It exhibited significant cytoprotective effects against oxidation by modulating ROS generation and lipid peroxidation [71]. The addition of L. sativum to HFD of rats for 8 weeks, significantly decreased serum glucose, insulin, and IR in rats when compared with their corresponding HFD-fed rats. El-Dakak et al. [72] reported significant reduction in the blood glucose level after the administration of aqueous extract of L. sativum to diabetic rats. Platel and Srinivasan [73] attributed the hypoglycemic effect of L. sativum owing to the inhibition of intestinal glucose absorption. L. sativum also possesses insulin mimetic properties because its biologically active substances such as alkaloids enhance glucose uptake by activating insulin receptor kinase activity and autophosphorylation of the insulin receptor.

In the same group, there was a significantly decrease in serum apelin and chemerin and tissue chemerin levels, but tissue apelin was significantly increased, compared with HFD group. El-Zawahry et al. [74] showed significant decrease in serum apelin level in rats that received L. sativum with HFD. In the present study, the significant decrease in serum chemerin and apelin levels observed in L. sativum groups can be explained by the reported parallel relation of chemerin and apelin with IR [24]. So the reduction in serum chemerin and apelin by L. sativum may be attributed to the decrease in serum insulin levels. Previous studies have reported that other antioxidants such as lipoic acid increased apelin secretion in adipocytes [32]. Another study found that dietary supplementation of HFD with vitamin C counteracts the upregulation of apelin mRNA expression in WAT induced by HFD, probably because of the reduction observed on the size of this fat depot. These also may be attributed to the link between the WAT apelin gene expression and IR that were found, suggesting a high interplay between insulin signaling and apelin gene expression [10]. Furthermore, these data showed that this effect of the HFD supplemented with antioxidant on apelin gene expression could be an indirect result of adiposity protection promoted by the antioxidant rather than a possible direct effect of this antioxidant on the peptide expression [10].

Regarding the chemerin level, the results of this study were in agreement with Ma et al. [75] who reported that the administration of Co Q 10 which is known as an antioxidant led to significant decrease in serum chemerin level in these patients. They attributed this effect to the decrease in glucose level and IR. The study of Prieto-Hontoria et al. [76] also reported the ability of α-lipoic acid to inhibit chemerin production, suggesting that the reduction of chemerin could contribute to the antiobesity/antidiabetic properties described for this antioxidant. This antioxidant also reduced basal chemerin secretion in both subcutaneous and omental adipocytes in overweight/obese subjects. Moreover, α-lipoic acid was able to abolish the stimulatory effects of the proinflammatory cytokine TNF-α on chemerin secretion [76].

The addition of L. sativum powder to HFD diet also caused significant decrease in serum TC, VLDL, triglycerides, and LDL-C and significant increase in serum level of HDL-C in these rats, compared with HFD-fed rats. These results are in agreement with Mishra et al. [13], who reported the hypolipidemic and hypoglycemic effects of methanol extract of L. sativum in alloxan-induced diabetic male rats. In addition, Amawi and Aljamal [77] studied the effect of L. sativum seed aqueous extract on lipid profiles and blood glucose levels of hypercholesterolemic and alloxan-induced diabetic albino rats. They reported better lipid profile and reduction in blood glucose level in both cases. The hypolipidemic effect of L. sativum might be attributed to inhibition of absorption and enhanced excretion of lipids [21]. L. sativum might lead to inhibition of cholesterol biosynthesis. This is through the inhibition of hydroxymethylglutaryl co-enzyme A reductase, the rate-limiting enzyme that mediates the first step in cholesterol biosynthesis [78]. Moreover, antioxidant profile showed significant increase in serum GSH and significant decrease in serum and tissue MDA, when compared with their corresponding HFD-fed rats. Al-Sheddi et al. [71] reported the antioxidant nature of L. sativum, as it inhibited the production of ROS generation and lipid peroxidation and increased GSH levels in human liver. These results are in agreement with the study of Qusti et al. [79] who reported a significant increase in the levels of GSH and a significant decrease in the levels of MDA in serum and kidney tissue homogenate in rats that received methanolic L. sativum extract for 4 weeks. In addition, these results are in correlation with the study of Mohamed and Safwat [9], who reported a diet supplemented with L. sativum seed powder restored the levels of myocardial MDA and GSH. They attributed this effect to its high content in antioxidants (vitamin C and E, carotenoids, polyphenols, and flavonoids). Addition of L. sativum also showed significant increase in tissue CAT, compared with control rats and significant decrease compared with the HFD-fed rats. Al-Sheddi et al. [71] reported that administration of L. sativum to alloxan-induced diabetic rats, induced significant increase in antioxidants in blood. All these results regarding OS indicate that L. sativum is a potent antioxidant.

The negative correlation between serum levels of leptin and adiponectin with obesity is well documented to the degree that it is used as promising index to estimate adipose tissue dysfunction in relation with obesity-associated cardiometabolic risk [80]. However, in this study, a negative correlation occurs between liver and serum apelin as well as between tissue CAT and serum GSH, that is, on both oxidative and adipokines levels. This could add more diversity and complexity to the pathophysiology of obesity which might possibly be clarified by future studies.


  Conclusion Top


This study showed significant positive correlation between tissue and serum chemerin and between tissue and serum MDA. On the contrary, it showed significant negative correlation between tissue and serum apelin, and also between tissue CAT and serum GSH. Apelin and chemerin serum concentrations are significantly elevated in obesity and were correlated to increased adiposity and IR. This study also revealed that L. sativum has a potent hypoglycemic, hypolipidemic, and antioxidant effects.

Study limitations

The following are the study limitations:
  1. As apelin and chemerin are adipokines, so it might be more beneficial to measure their levels by gene expression rather than homogenous extract.
  2. Longer duration of the experiment than 8 weeks might give more elucidative results.
  3. The dose of L. sativum (6 g/kg) was low, and its addition to diet as a powder wasted some of its effects. Therefore, it might be better to give L. sativum extract than its addition to diet as powder.


Acknowledgements

The authors thank Assistant Professor Dr Fathy A. for revising the text and statistics, and Dr Hikal S. for revising the References

Conflicts of interest

There are no conflicts of interest.



 
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