Antiobesity Activity of Liraglutide on High Fat Diet-Induced Obesity in Wistar Rats_Juniper Publishers
Authored by Vinay Kumar
Abstract
Liraglutide is a glucagon like peptide-1 (GLP-1)
analogue. GLP-1 is a potent inhibitor of motility and gastric emptying
and has also been shown to inhibit gastric acid secretion. The
inhibition of gastric emptying leads to decreased food intake and
reduced body weight. The aim of the present study was to investigate the
antiobesity effect of the Liraglutide on high fat diet (HFD) induced
obesity in Wistar rats. Obesity was induced by oral feeding of HFD for
six weeks. The antiobesity effect of Liraglutide (0.2mg/kg, i.p. for 14
days) in HFD fed rats was evaluated by the measurement of body mass
index (BMI), body weight gain, food intake, hemodynamic changes
(systolic, diastolic, mean blood pressure and heart rate), serum leptin,
lipid profiles (triglycerides, total cholesterol, LDL-cholesterol,
HDL-cholesterol), glucose. Organ (Liver) and visceral fat pad weights
were measured. Liraglutide significantly reduced BMI, body weight gain,
and mean blood pressure, serum leptin, lipids and glucose levels while
it significantly increased the serum HDL-cholesterol, as compared to the
HFD fed rats. The results of the present study suggest that a potential
role of Liraglutide as a clinical tool for obesity treatment.
Introduction
Obesity has increased at an alarming rate in recent years and is now a worldwide public health problem [1].
It is one of the most common nutritional disorders in humans. Obesity
can be defined as syndrome characterized by an increase in body fat
stores, mainly due to an imbalance between energy intake and energy
expenditure. Obesity results when energy intake exceeds energy
expenditure. The global epidemic of obesity is rapidly evolving as one
of the major global health issues as it is frequently associated with a
number of diseases with high mortality and morbidity such as diabetes,
cancer, arthritis, hypertension, stroke, and myocardial infarction [2].
It is generally accepted that the tremendous rise in the obesity
prevalence across the globe is driven primarily by a combination of
increased calorie intake and decreased physical activity, and strongly
influenced by our genetic background [3].
Obesity is associated with substantial increases in morbidity,
premature mortality, impaired quality of life and large healthcare costs
[4].
The major co-morbidities include type 2 diabetes, metabolic syndrome,
hypertension, dyslipidaemia, myocardial infarction, stroke, certain
cancers, sleep, apnoea and osteoarthritis [5].
Easy access to high-calorie packaged foods, sedentary lifestyles and a
predilection for gizmos have resulted in almost 70% Indians in
mega-cities such as Mumbai, Delhi, Bangalore or Chennai being overweight
or obese, says a new multi-city survey. Diet and physical activity
remain the cornerstones of therapy for obesity, although results have
been disappointing. Obese patients who are able to lose weight by eating
better and exercising generally regain the lost weight over time. The
difficulty in maintaining long-term weight loss through behaviour
modification has led to an increasing interest in other avenues of
treatment, particularly pharmacotherapy. To date, only two
medications-Sibutramine and Orlistat-have been approved for long-term
use in the treatment of obesity and additional effective pharmacological
treatments are needed [6].
Liraglutide is a glucagon-like peptide-1 receptor
analogue, which is obtained by derivatising glucagon-like peptide-1 with
a fatty acid. The liraglutide is well tolerated, sustains weight loss
over 2 years and improves cardiovascular risk factors [7]. Liraglutide suppress the food intake and body weight in rats [8].
Obesity management is a modern challenge because of the rapid evolution
of unfavorable lifestyles and unfortunately there are no safe and
effective treatments applicable to the large majority of
obese/overweight people [9].
Therefore, the present study was designed to investigate the
antiobesity effect of Liraglutide on high fat diet induced obesity in
Wistar rats.
Materials and Methods
Animals
The experimental study was carried out in male Wistar
rats weighing 150-200g body weight and the experimental protocol was
approved by Institutional Animal Ethics Committee (IAEC) of KIET School
of Pharmacy, Ghaziabad (UP) (Registration number: 1099/07/CPCSEA, dated
27.07, 2007) as per the Committee for the Purpose of Control and
Supervision of Experiments on Animals (CPCSEA) guidelines. The animals
were kept in polypropylene cages (6 in each cage) under standard
laboratory conditions (12 hrs. light and 12hrs. dark :: day : night
cycle) and had free access to commercial pellet diet (Pranav Agro
Industries, New Delhi) and water ad libitum. The animal house
temperature was maintained at 25±2 °C and relative humidity was also
maintained at 50±15%.
Induction of obesity by feeding high fat diet
Experimental obesity was induced by feeding of high
fat diet consisting of the following materials (corn starch, casein,
lard, cholesterol, sodium cholate, soybean oil, coconut oil, wheat bran,
mineral mix, vitamin mix were added to 1kg of rat chow diet) to rats
for period of six weeks.
Experimental design
30 male Wistar rats were included in the present
study. Animals were randomly allocated into five groups of six animals
each and treated as follows: Normal Control Group: Rats fed with normal
rat chow diet for 6 weeks; High Fat Diet Control Group: Rats fed with
high fat diet for 6 weeks; Liraglutide Treated Group: Rats fed with high
fat diet for 6 weeks+from 29th day Liraglutide (0.2mg/kg, i.p) for 2 weeks; Orlistat Treated Group: Rats fed with high fat diet for 6 weeks+from 29th day Orlistat (10mg/kg, i.p) for 2 weeks; Perse Group: Rats fed with normal chow diet for 6 weeks+from 29th day Liraglutide for 2 weeks.
Measurement of anthropometric parameters
Body mass index (BMI kg/m2), daily food intake (g/d) and daily water intake (ml/d) were measured.
Measurement of hemodynamic parameters
Hemodynamic parameters (systolic, diastolic and mean
arterial blood pressure) were measurement by non-invasive blood pressure
recorder using rat tail-cuff method (AD Instrument, Australia).
Biochemical estimations in serum
Blood was collected from the retro-orbital plexus of the both groups of overnight fasted rats using microcapillary tubes on 29th
day. Serum was separated by centrifugation (4000rpm, 10min) and
transferred to Eppendorf tubes. The concentrations high density
lipoprotein-cholesterol (Reckon Diagnostics Pvt. Ltd., Baroda, Gujarat,
India), glucose, total cholesterol (TC) and triglycerides (TGs) (all the
three from Span diagnostics Ltd., Surat, Gujarat, India), in serum were
measured with commercial kits. The concentration of leptin in the serum
was measured with rat leptin ELISA kit (BioVendor, Brno, Czech
Republic).
Determination of Liver Weight and Visceral Fat Pad Weights
On the final day of experiment the rats were fasted
overnight and sacrificed by cervical dislocation and then liver and
visceral fat pads (epididymal, perirenal and mesentric) were removed,
washed with normal saline and weighed [10].
Statistical analysis
All values were expressed as Mean IS Standard Error
of Mean (S.E.M). Statistical analysis was performed using InStat
3Software. Groups of data were compared with the analysis of variance
(ANOVA) followed by Dunnett's test. Values were considered statistically
significant when p<0.05.
Results
Effect of liraglutide on BMI, food intake and water intake
All values were expressed as Mean±SEM, (n=6); aP<0.01 as compared to the Normal Control Group; bP<0.05 as compared to the high fat diet Group; cP>0.05 as compared to Normal Control Group.
The mean BMI, food intake and water intake were
decreased the BMI, food intake and water intake as compared to
significantly (p<0.01) increased in high fat diet fed group as the
HFD treated group, while there was no significant changes compared to
the normal control group. Liraglutide (0.2mg/kg,(p>0.05) in the BMI
in perse group as compared to the normal i.p) and Orlistat (10mg/kg,
i.p) treatment significantly (p<0.05)control group (Table 1).
Effect of liraglutide on hemodynamic parameters
All values were expressed as Mean±SEM, (n=6); aP<0.01 as compared Group; cP>0.05 as compared to Normal Control Group.
All hemodynamic parameters (systolic, diastolic, mean
arterial BP and heart rate) were significantly increased (p<0.01) in
high fat diet treated group as compared to the normal control group.
All hemodynamic parameters were significantly decreased (p<0.01) in
Liraglutide and Orlistat treated groups as compared to HFD treated group
(Table 2).
Effect of liraglutide on serum leptin and glucose levels
All values were expressed as Mean±SEM, (n=6);
aP<0.01 as compared to the Normal Control Group; bP<0.05 as
compared to the high Fat Diet Group; cP>0.05 as compared to Normal
Control Group.
All values were expressed as Mean±SEM, (n=6);
aP<0.01 as compared to the Normal Control Group; bP<0.05 as
compared to the high Fat Diet Group; cP>0.05 as compared to Normal
Control Group.
Figure 1 & 2
shows that Liraglutide treatment serum leptin and glucose levels were
significantly (p<0.01) increased in HFD treated rats as compared to
the normal control rats. Serum leptin and glucose levels were
significantly decreased in Liraglutide and Orlistat treated groups as
compared to the HFD fed group.
Effect of liraglutide on serum lipid profile levels
HFD treated group showed significant (p<0.01)
increased levels TC, TGs, low density lipoprotein-cholesterol (LDL-C)
and very low density lipoprotein-cholesterol (VLDL-C) and while HDL-C
levels significantly (p<0.01) decreased as compared to the normal
control group. All these levels were significantly reversed in
Liraglutide and Orlistat treated groups as compared to the HFD fed group
(Table 3).
Effect of liraglutide on liver weight and visceral fat pad weights
Liver weight and visceral fat pad weights
(mesenteric, perirenal and epididymal) were significantly increased in
HFD fed group as compared to the normal control group. The visceral fat
pad weights of perirenal fat, mesenteric and epididymal fat in the HFD +
Liraglutide and HFD + orlistat groups were significantly (p<.001)
decreased as compared with those of the HFD group (Table 4).
Discussion
Obesity is a medical condition in which excess body
fat 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, osteroarthritis as well as an increased risk of
many forms of cancer [11].
The currently available treatment options 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. Hence, in the present work the
anti-obesity activity of Liraglutide on high fat diet induced obesity in
Wistar was investigated by analyzing the BMI, body weight, organ and
fat pad weight and blood biochemical profiles. Dietary fat is
calorically dense and extremely palatable. It is easily over consumed
because it can cause less satiety than carbohydrate and protein [12].
Therefore, a HFD can lead to hyperphagia, weight gain, and
increased adiposity. The feeding of HFD for 4 weeks produced a
significant increase in body weight, total fat pad weight, basal/
fasting plasma glucose, insulin, basal triglyceride (TG) and total
cholesterol (TC) levels in male rats [13].
In present study, there was significant increase in body mass index
(BMI) and body weight gain in rats fed with high fat diet as compared to
the normal control rats. BMI is a simple index of weight-for-height
that is commonly used to classify underweight, overweight and obesity in
adults [14]. This study corroborate with the findings of Altunkaynak [15]
who reported that BMI was significantly increased in rats with high fat
diet fed for 8 weeks as compared to the control group The increased
body weight found in HFD rats might be due to the consumption of a diet
rich in energy in the form of saturated fats (lard) and its deposition
in various body fat pads and decreased energy expenditure.
Liraglutide (0.2mg/kg, i.p) and Orlistat (10mg/kg,
i.p) treatment significantly (p<0.01) decreased the BMI and body
weight gain as compared to the HFD treated group. Further, our results
showed a significant (p<0.05) decrease in food intake and water
intake by administration of Liraglutide (0.2 mg/kg, i.p). After 6 weeks
feeding with HFD, hemodynamic parameters were significantly (p<0.01)
elevated in HFD fed rats as compared to normal healthy control rats.
Activation of the sympathetic nervous system contributes to blood
pressure (BP) elevation in high-fat diet-induced obesity [16].
When HFD fed rats were treated with Liraglutide (0.2mg/kg, i.p), there
were significant (p<0.01) decrease in hemodynamic changes.
In the present study, serum glucose and leptin levels
were increased in the HFD group as compared to the normal control
group, while glucose levels were significantly decreased by Orlistat and
Liraglutide treatment. Diet-induced obesity dysregulated glucose
homeostasis and causes hyperglycemia [17].
This is consistent with previous study that feeding of HFD for a period
of 4 weeks produced a significant increase in plasma glucose levels.
Fried et al. [18]
indicated that basal levels of leptin are known to be strongly
positively correlated with body fat on a HFD. A fat-enriched diet is
regarded as an important factor in the development of cardiac diseases
because it leads to the development of hyperlipidemia, atherosclerosis,
and abnormal lipid metabolism [19].
The data of present study clearly showed that feeding of the HFD
increased the concentrations of serum TC, LDL- C, VLDL-C, TGs in
experimental rats. Lavie & Milani [20]
indicated that obesity adversely affects plasma lipids, especially by
increasing TC, LDL- C, VLDL-C, TGs and decreasing the level of
HDL-cholesterol. The levels of TGs, TC, LDL- C, VLDL-C were
significantly (p<0.01) decreased by Liraglutide (0.2mg/kg, i.p) and
Orlistat treatment (10mg/kg, i.p) treatment groups. Organ's weight
(liver) and visceral fat pad weights (perirenal, mesentric fat and
epididymal fat) were significantly increased in rats fed with HFD. HFD
produces adiposity i.e. deposition of fat on the adipose tissues. Liver
weight and visceral fats were significantly decreased by Liraglutide.
Conclusion
The possible explanation for an anti-obesity effect
of Liraglutide via suppression of dyslipidaemia, leptin, insulin,
gastric emptying and reduction of appetite in obese rats fed with HFD.
The results of the present study provide initial evidence that
Liraglutide could be useful intervention for the treatment of obesity.
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