Cinnamaldehyde Inhibits Visceral Fat Accumulation and the levels of Glucose, Insulin, Leptin in Serum of rats fed with High Fat Diet (HFD)

 

Haripriya Doraiswamy1, Vijayalakshmi Kirshnamurthy2*

1Research Scholar, Department of Biochemistry, Bharathi Women’s (Autonomous) College, Chennai: 600 108, India.

2Associate Professor, Department of Biochemistry, Bharathi Women’s College (Autonomous), Chennai – 600 108, India.

*Corresponding Author E-mail: bioharipriya@gmail.com

 

ABSTRACT:

The current study was undertaken to evaluate the efficacy of Cinnamaldehyde (CA) supplemented diet in management of obesity in HFD fed rats. 30 adult male rats were assigned to five group of 6 rats each; the standard diet group I (N ); the HFD group II; HFD supplemented with Orlistat (OR) III; group IV and V animals received CA at a dose level of 40, 80 mg/Kg body weight (CA-I, CA-II) along with HFD for 8 weeks. Weights of the animals were monitored every week and the serum parameters like glucose, insulin, leptin levels were analyzed. Insulin resistance were estimated by using Homeostasis model assessment (HOMA). Thoracic circumference (TC), Abdominal circumference (AC), BMI and weight of Internal organs and fat pad was carried out after 8 weeks. The results revealed that there was a significant increase in body weight, TC (p< 0.05), AC (p< 0.05), and BMI (p< 0.001) in HFD fed rats. Hyperinsulinemia, hyperglycemia and hyperleptinemia has been observed in HFD fed rats. Treatment with CA, reduced the body weight (p< 0.001), anthropometrical parameters (p< 0.05), serum glucose (p< 0.001), insulin (p< 0.001), leptin (p< 0.001) levels and weight of internal organs, visceral fat pad (p<0.05) were decreased, when compared with HFD induced rats. The results demonstrate clearly that repeated oral administration of CA treatment prevented the rats from becoming obese and the bio chemical, physical parameters were maintained to near normal levels. All the results were compared with Orlistat, a standard anti-obesity drug. Hence, Cinnamaldehyde may be taken up for further studies leading to a novel therapeutic drug for obesity.

 

KEYWORDS: Cinnamaldehyde, Visceral fat pad, Leptin, Insulin resistance, Obesity, High fat diet.

 

 


INTRODUCTION:

Obesity is a chronic metabolic disease caused by an imbalance between energy intake and energy expenditure [1]. The normal amount of body fat is between (25 and 31%) in women and (18 and 24%) in man and those who have more than the given limit can be called as obese. Generally, body lipid is necessary for storing energy, heat insulation and shock absorption. The fundamental cause of obesity is an energy imbalance between calorie intake and calories expended.

 

 

The regulation of energy balance requires a mechanism for sensing the level of energy stores in body lipids and relaying the information to controlling sites in the hypothalamus. Integration of information in the hypothalamus and determination of energy balance through control of food intake and energy expenditure helps to maintain normal weight [2]. The incidence of obesity and associated diseases is increasing at alarming rates almost over the entire world. Nearly 1 billion adult humans worldwide are overweight and at least 300 million are obese [3].

 

High fat diet is certainly of importance to obesity incidence and to its negative consequences such as Type II diabetes [4], dyslipidemia[5], cardiovascular diseases[6], aging[7] and cancer[8]. Adipose tissue has been considered as a highly specialised, endocrine and paracrine organ, producing an array of mediators called adipokines. One of the most important adipokines is leptin which significantly correlates with the amount of fat pad in humans and animals [9]. Normally, leptin functions to reduce food intake and maintain energy homeostasis but in obesity, the development of a state of leptin resistance results in a dysfunctional energetic state[10].

 

Leptin, a 144 amino acid, multifunctional protein that is considered the prototype adipokine [11], is predominantly involved in the regulation of appetite and body weight gain [12]. In addition, it affects insulin resistance, energy expenditure, immunity, coagulation as well as cardiovascular and endocrine functions [13]. Its levels correlated with body fat mass and are suppressed by food deprivation [14]. Although leptin deficiency is associated with morbid obesity [15], the vast majority of obese individuals demonstrate normal or increased serum levels accompanied by attenuated responsiveness to the adipokine, a condition known as leptin resistance [16].

 

Leptin has been suggested as a static index of the amount of Triglyceride stored in adipose tissue [17]. Leptin concentration has been reported to be positively correlated with circulating insulin levels. Insulin resistance associates with elevated leptin levels, independent of body fat content [18]. Increased abdominal adipose tissue mass has been of particular interest in elucidating the mechanisms of insulin resistance. Visceral fat pad has been implicated because it has a circulation draining into the portal vein and hence the liver compared with subcutaneous, visceral adipocytes have higher secretion rate of some adipokines and metabolites linked to insulin resistance including free fatty acids. In addition, visceral fat pad cells are resistant to insulin mediated suppression of lipolysis, leading to increased FFA delivery to the liver [19]. Increased release of FFA and or adipokines from the visceral fat depot may disrupt insulin action, most likely at the liver, a primary site of insulin resistance in diet induced obesity [20].

 

Many rodent studies suggest a linkage between visceral fat pad and insulin resistance and have focused on the removal of specific intra abdominal fat depots: epididymal and per renal fat [21]. Recent studies have found that natural bioactive compounds, like epigallo cathechin 3- gallate (EGCG), Quercetin, resveratrol and cur cumin can be used to treat obesity in an obese mouse model [22]. Despite the urgent need for safe and efficient therapeutics and the potential size of the market for anti obesity drugs, the current status for the development of such drugs is still unsatisfactory. So there is a need for the development of drugs for the treatment of obesity and alternative systems of medicine provide leads for the same. Cinnamaldehyde is the organic compound that gives cinnamon its flavour and odour. This pale yellow, viscous liquid occurs naturally in the bark of cinnamon trees and other species of the genus Cinnamomum. The essential oil of cinnamon bark is about 90% Cinnamaldehyde [23]. The important uses of cinnamaldehyde are fungicide, mild astringent, antimicrobial, anti-inflammatory and anti septic [24]. The observed effects of Cinnamaldehyde could be attributed to their property such as, antioxidant [25] and hypolipidemic [26].

 

Considerable advances have been made in diet, exercise and behaviour approaches for the obesity treatment and new drugs with even better profile of pharmacological activity continues to be introduced on a regular basis. In view of above facts, we examined the effect of cinnamaldehyde compared with a standard anti-obesity drug, Orlistat on the blood glucose, serum leptin, insulin, fat tissue weight and circumferences in high fat diet induced rats.

 

Methods:

Animal model:

An animal model that mimics the human counterpart is essential for preclinical evaluation of new treatment modalities for obesity. Wistar albino male rats weighing about 120-150g were used for the experiment. Animal were kept in animal house at an ambient temperature of 25ºC and 45-55% relative humidity with 12 hours each of dark/light (day and night) cycles. Animals were fed pellet diet and water ad – libitum. CPCSEA guidelines for laboratory animal facility (IJP 2003; 35: 257- 274) were followed. Experimental animals were handled according to the University and Institutional Legislation, regulation by the committee for the purpose of control and supervision of Experiments on Animals (CPCSEA), Ministry of Social Justice, and Empowerment, Government of India (IAEC No. SU/BRULAC/ RD/006/2013).

 

Experimental design:

All the rats were divided randomly into following 5 groups of 6 animals each: Group I (N):  rats were fed with normal or standard diet for 8 weeks. Group II (HFD): (Obesity induced rats) - rats were fed with high fat diet (HFD- Research diet (D 12492), USA) for 8 weeks. Group III (OR): (HFD + Orlistat) - rats with HFD and Orlistat (50mg/kg body weight) simultaneously for 8 weeks orally. Group IV (CA-I): (HFD + CA) - rats were fed with Cinnamaldehyde (40mg/Kg body weight) and HFD simultaneously for 8 weeks orally. Group V (CA-II): (HFD + CA) - rats were fed with Cinnamaldehyde (80mg/Kg body weight) and HFD simultaneously for 8 weeks orally. The Normal diet and HFD control rat were treated with vehicle (Corn Oil) only.

 

Estimation of body, organ and fat pad weight:

The body weights of different groups of rats were weighed for a period of eight weeks. After sacrifice, different organs (Liver, Kidney, brain, spleen, pancreas and heart) and fat pads perirenal, mesenteric, gonadal, subcutaneous fat pads were removed and weighed. 

 

Anthropometrical determinations:

The abdominal circumference (AC), thoracic circumference (TC) and body mass index were determined in all the rats at the end of the experimental period (8 weeks). The measurements were made in anaesthetized rats [5].

 

Biochemical determination:

Blood was collected from the retro-orbital plexus of overnight fasted rats using heparinised capillary tube after 8 weeks and serum was separated by centrifugation at 3000rpm for 15 mins. Serum glucose was measured. Insulin and leptin levels were assayed by ELISA technique using Life Technologies kit. HOMA- IR (homeostasis model assessment values for insulin resistance was calculated [27].

 

Statistical analysis:

The data were expressed as mean ± SD. All statistical analysis was performed using SPSS 20.0 statistical software (IBM, USA). Significant differences among the treatment groups were analyzed by variance (One way ANOVA) followed by least significant difference (LSD) test. Results were considered to be statistically significant at P values < 0.05. Graphs for this study were plotted using graph pad prism version 6.02.

 

Results:

Effect on body weight:

HFD fed rats showed significant increase in body weight during eight weeks as compared to normal control group as shown in Fig 1. Administration of CA and Orlistat elicited a significant reduction in body weight during eight weeks as compared to their respective HFD fed group (p< 0.001- Fig 1). The standard drug Orlistat produced a reduction in body weight when compared to HFD induced rats (p< 0.001). Decrease in the body weight was dose dependent with CA. Besides, there was a highly efficient decrease in body weight in CA treated rats at a dose of (80mg/ Kg body weight), when compared to other groups.

 

N: normal diet, HFD: high fat diet, OR: high fat diet+50mg/kg body weight of orlistat, CA-I: 40mg/kg body weight of Cinnamaldehde+high fat diet, CA-II: 80mg/kg body weight of Cinnamaldehyde+high fat diet. Values are expressed as mean ± SD (n=6). Significant at P values < 0.001*. a- Value compared with N, b- Value compared with HFD.

 

Effect on anthropometrical analysis:

Table 1 illustrates that there was significant increase in TC (p< 0.001) and AC (p< 0.001) of HFD fed rats when compared with normal group of rats. However, there was significant decrease in TC and AC of HFD treated with either CA (40, 80mg/Kg body weight) when compared to (p< 0.001) HFD fed rats. However, OR treated group showed significant decrease in AC and TC (p< 0.001) when compared with HFD induced rats. BMI of HFD induced rats showed significant increase (p< 0.001) when compared with that of normal group. However, a significant decrease (p< 0.001) in BMI was recorded in both CA and OR treated rats when compared with HFD induced group.


 

Figure 1: effect of cinnamaldehyde on body weight of rats fed with high fat diet for 8 weeks.

Table 1: Effect of Ca and or on anthropometric parameters of experimental animals

Groups

Abdominal Circumference (cm)

Thoracic Circumference (cm)

BMI (g cm-2)

Group  I (N)

8.4±0.65

11.12±0.65

0.46±0.002

Group II (HFD)

12.36±0.62 a*

15.58±1.28 a*

0.68±0.005 a*

Group III (OR)

9.3±0.56 a@b*

13.6±0.61 a*b*

0.50±0.004 a*b*

Group IV (CA-I)

9.5±0.63 a#b*

14.36±0.54 a*b@

0.51±0.003 a*b*

Group V (CA-II)

9.15±0.62 a@b*

12.4±0.76 a@b*

0.49±0.003 a*b*

Values are expressed as mean ± SD (n=6). Significant at P values < 0.05@, 0.01#, 0.001* and NS- non significant. a- Value compared with N, b- Value compared with HFD.

 

Table 2: effect of ca and or on weight of internal organs (g) of experimental animals

Treatment

Group I (N)

Group II (HFD)

Group III (OR)

Group IV  (CA-I)

Group V  (CA-II)

Brain (g)

1.18±0.09

1.55±0.06 a*

1.35±0.13 a#b*

1.46±0.07 a*b-ns

1.30±0.01 a@b*

Kidney (g)

1.12±0.07

1.81±0.11 a*

1.17±0.07 a-nsb*

1.32±0.09 a*b#

1.08±0.09 a-nsb*

Liver (g)

6.43±0.23

8.97±0.17 a*

5.28±0.28 a*b*

5.90±0.24 a*b*

5.08±0.22 a*b*

Pancreas(g)

0.33±0.01

1.53±0.07 a*

0.54±0.01 a*b*

0.60±0.01 a*b*

0.44±0.03 a*b*

Spleen (g)

0.23±0.07

0.45±0.06 a*

0.30±0.02 a-nsb*

0.37±0.09 a*b@

0.25±0.02 a-nsb*

Heart (g)

0.48±0.11

0.97±0.14 a*

0.45±0.05 a-nsb*

0.56±0.08 a-nsb@

0.33±0.04 a#b*

Values are expressed as mean ± SD (n=6). Significant at P values < 0.05@, 0.01#, 0.001* and NS- non significant. a- Value compared with N, b- Value compared with HFD.

 

Table 3: effect of ca and or on visceral fat pad (g) of experimental animals

Groups

Peri renal Fat Pad

Mesenteric Fat Pad

Epididymal Fat Pad

Group I (N)

1.15±0.08

0.31±0.08

0.88±0.06

Group II (HFD)

2.48±0.15 a*

2.92±0.05 a*

2.35±0.16 a*

Group III (OR)

1.31±0.12 a@b*

1.44±0.04 a*b*

1.73±0.12 a*b*

Group IV (CA-I)

1.53±0.12 a*b*

1.92±0.05 a*b*

1.92±0.06 a*b*

Group V (CA-II)

1.20±0.09 a-nsb*

1.04±0.05 a*b*

1.2±0.07 a*b*

Values are expressed as mean ± SD (n=6). Significant at P values < 0.05@, 0.01#, 0.001* and NS- non significant. a- Value compared with N, b- Value compared with HFD.

 

Table 4: effect of ca and or on biochemical parameters of experimental animals

Groups

Glucose (mg/dl)

Insulin (µU/ml)

Leptin (ng/ml)

Group I (N)

98.31±0.66

30.43±0.51

8.2±0.60

Group II (HFD)

160.3±0.68 a*

110.33±0.57 a*

25.28±0.56 a*

Group III (OR)

115.28±0.67 a*b*

56.41±0.54 a*b*

11.68±0.64 a*b*

Group IV (CA-I)

133.36±0.53 a*b*

80.35±0.50 a*b*

13.3±0.68 a*b*

Group V (CA-II)

104.21±0.67 a*b*

42.41±0.56 a*b*

10.4±0.55 a*b*

Values are expressed as mean ± SD (n=6). Significant at P values < 0.05@, 0.01#, 0.001* and NS- non significant. a- Value compared with N, b- Value compared with HFD.

 


 

Effect on weight of internal organ and visceral fat pad:

After 8 weeks of HFD administration, organ weight and fat pad weights increased significantly as compared with the normal group (p< 0.001) of rats. Feeding the rats with HFD increased the weight of the internal organs significantly (p< 0.001) as shown in Table 2.  Liver showed the maximum increase in weight when compared to other organs like pancreas, kidney, heart, spleen and brain. The CA and OR more significantly (p< 0.001) prevented the increase in weight of the internal organs. The weight of the visceral fat pads was significantly increased in HFD induced group of rats, as shown in Table 3. But in weight of visceral fat pad remained normal in CA and OR treated groups. CA at a dose of 80mg/Kg body weight was highly significant (p< 0.001) or effective to reduce the visceral fat mass (Table 3) in the rats.

 

Effect of biochemical parameters:

Table 4 demonstrate the various biochemical parameters like, levels of fasting glucose, insulin and leptin. Serum fasting glucose level showed significant increase in HFD fed rats (p< 0.001) as compared with that of normal group of animals. In contrast, administration of CA and OR (p< 0.001) significantly decrease and the serum fasting glucose levels. Serum insulin and insulin resistance level showed significant increase (p< 0.001) in HFD fed group of rats compared with the normal rats. Significant decrease (p< 0.001) in serum insulin and insulin resistance was recorded in both rats treated with CA and Orlistat, a standard anti-obesity drug. The serum leptin level showed significant increase in obese rats (p< 0.001), as compared with normal control rats. However, serum leptin level showed significant decrease in HFD treated with CA (p< 0.001) or with OR (p< 0.001), when compared with that of HFD fed rats.

 

Discussion:

Obesity is a chronic condition that is increasing rapidly throughout the world [28]. Obesity is a medical condition in which excess body fat mass has been accumulated mainly due to sedentary life styles, lack of exercise and intake of energy rich high fat diet. The global prevalence of obesity is increasing rapidly among adults as well as among children and is associated with serious mortalities

 

including a high incidence of type 2 diabetes, hyperlipidemia, hypercholesterolemia, fatty liver, cardiovascular diseases, osteoarthritis as well as an increased risk of many forms of cancer [29]. The currently available treatment methods are not potent enough to control obesity permanently besides they produce side effects. Hence, there is a great demand for safer and long term effective drugs to treat this global epidemic problem. Medicinal herbs are indispensable as traditional medicines and there is a big renaissance of the herbal medicines globally as these drugs are effective and safe without any side effects [30].  In the present study, anti-obese activity of CA was studied using dietary animal models of obesity that bear close resemblance to human obesity. The results of our study showed that rats fed with a variety of highly palatable, energy rich, high fat diet elicited significant increase in body weight, serum levels of glucose, insulin, leptin along with correspondent increase in liver, heart, kidney, pancreas, spleen and perirenal, mesenteric, gonadal and subcutaneous fat pad weights. Fat pad is a fatty tissue occurring in and around bony joints. It acts as a cushion helping to protect the joints from mechanical damage. On consuming high fat diet, the extra fat accumulates around the mesenteric, subcutaneous, perirenal and gonadal fat pads, which are easily prone for the accumulation of fat, and the weight increases [31].

 

All the results are compared with Orlistat; a standard anti-obesity drug. Treatment with CA and Orlistat has resulted in reduction in body weight in HFD fed rats. Administration of CA and Orlistat showed significant decrease in weight of different internal organs and fat depots in HFD fed rats, suggesting that CA reduces hyperplasia of adipose tissue.  The present data revealed that both TC and AC were significantly increased in HFD fed rats. In addition, BMI showed significant increase in obese rats when compared with control rats. These results indicate that there was fat accumulation in the thoracic and abdominal regions due to intake of high fat diet [5]. The increased body weight is due to excessive energy intake which was deposited as that in the adipose tissue. There was a positive correlation between daily lipid intake and BMI as well as fat deposition [32] demonstrating that BMI is a simple reliable estimate of body fat and obesity in rats [5].

 

The present data showed that HFD induced rats recorded significant elevation in serum glucose level [33]. The ability of CA and Orlistat to reduce serum glucose levels in rats could be attributed to the effect of this compound in lowering fat accumulation and hence improving the glycemic status of obese rats via reducing the gluconeogenesis process and elevating the efficacy of insulin on glucose disposal. Our results revealed that there was significant increase in serum insulin levels in HFD induced rats compared with that in normal animals. This could be explained as obesity is associated with low grade chronic systemic inflammation which potentially leads to insulin resistance [34]. Treatment of HFD with CA significantly decreased serum insulin levels compared with obese rats.

 

Adipose tissue acts as a endocrine functions, secreting leptin to play a regulatory role in the development of insulin resistance; other adipocyte secreted adipokines such as adiponectin, Visfatin, resistin, etc [35]. Circulating leptin is generally known to be correlated with body lipid stores; the concentration of this protein is markedly influenced by body energy balance. The relationship between leptin and insulin has been investigated in both humans and animals because of the possible role of leptin in the link between obesity and pancreatic beta- cell hyper secretion [36]. There was a positive correlation between leptin and body mass index in both obese, lean humans and rodents [9]. Serum leptin level showed significant increase in HFD induced rats as compared with normal control rats. Leptin is a cytokine like polypeptide produced by the adipocytes and it is overproduced during obesity [37].

 

This study shows that, CA can reduce cardiovascular complications by altering the levels of insulin and insulin resistance [38]. Our study has confirmed increased insulin resistance in rats fed with high fat diet. The results of animal studies indicate that Cinnamaldehyde supplementation may be a novel therapy for obesity and metabolic syndrome, acting via decreased blood glucose, insulin, leptin and insulin resistance levels. In conclusion, the effect of Cinnamaldehyde administration was accompanied by improvement in body weight, anthropomentrical determinations, hyperinsulinemia and hyperleptinemia in high fat diet induced obesity in rats.  Cinnamaldehyde also decreases the weight of internal organ and visceral fat pad mass and enhances insulin resistance. Cinnamaldehyde can act as an anti-obesity agent and can be taken up for further studies on human subjects.

 

ACKNOWLEDGEMENTS:

No conflict of interest

 

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Received on 24.11.2015             Modified on 05.12.2015

Accepted on 11.12.2015           © RJPT All right reserved

Research J. Pharm. and Tech. 8(12): Dec., 2015; Page 1701-1706

DOI: 10.5958/0974-360X.2015.00306.6