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Allium victorialis Leaf Extract Prevents High Fat Diet Induced Obesity in Mice
Sae-Kwang Ku, In-Kwon Chung, Woo-Hyun Cheon and Joo-Wan Kim*1
College of Oriental Medicine, Daegu Haany University, 290 Yugok-dong, Gyeongsan-si, Gyeongsangbuk-do 712-715, Korea
*Glucan Corp., Research Institute, Marine Biotechnology center 221, Busan 617-736, Korea (Accepted: June 13, 2011)
Abstract : The antiobese effects of Allium victorialis (AV) leaf methanol extract were evaluated in a high fat diet (HFD) supplied mice. The changes on the body weight, food consumption, leptin and adiponectin levels as well as the periovarian fat weights and histopathology of adipocytes were examined. The effects were compared with those of a group given 250 mg/kg of metformin. After 91 days of a continuous HFD supply, the mice were significantly showed obesity. However, the obesity induced by the HFD was inhibited by the AV extract treatment at the three different doses (62.5, 125 and 250 mg/kg) respectively. The results suggest that the AV methanol extract is beneficial for improving the diet-induced obesity in humans.
Key words : Allium victorialis, obesity, high fat diet, mouse, extracts.
Introduction
Recently, there has been a worldwide increase in the inci- dence of obesity associated with metabolic syndrome known as type 2 diabetes, the development of which appears to be the result of high-caloric diet intake and physical inactivity (9).
The predicted estimates suggest that the population with this syndrome may double to more than 300 million by the year 2025 (29). Considerable effort has been made to delineate the relationship between increased adiposity and insulin resis- tance. In this regard, some molecules known as adipokines (16), including leptin (5,26) and adiponectin (15,27), which are secreted by adipocytes, can modulate the sensitivity of insulin, the action of which activates multiple signaling events after phosphorylation of the insulin receptor and several other molecules in type 2 diabetes (21,20).
Obesity in mice can be developed by feeding them a high fat diet (HFD), and the obese mice show the characteristics of hyperglycemia, insulin resistance, hepatic steatosis, mild dia- betic nephropathy and hypolipemia (24,25,28). Many oral anti-diabetic medicines are currently used or have been devel- oped for its treatment, including the thiazolidinediones and metformin, which improve insulin resistance. Metformin in- hibits hepatic glucose production by reducing the rate of glu- coneogenesis (22), and effectively inhibits high-fat induced obesity in mice (18). In the present study, metformin was used as a reference drug.
The pharmacological agents currently available for meta-
bolic syndrome have a number of limitations, such as adverse effects and high rates of secondary failure (8). Therefore, patients with metabolic syndrome and healthcare profession- als are increasingly considering complementary and alterna- tive approaches, including the use of medicinal herbs. Allium victorialis var. platyphyllum (Liliaceae; AV) is an edible wild herb that has been used to treat heart failure and gastritis. Until now, AV extracts have been reported to have a range of phar- macological activities; anti-arteriosclerosis activity (10), anti- cancer activity (12),antioxidant activity (23), anti-diabetic activity on streptozotocin-induced type I diabetic rats (1), and nephroprotective and hepatoprotective effects on HFD supplied mice (11). However, there are no reports of the effects of AV extract on obesity. Therefore, this study evaluated the anti- obese effects of an AV methanol extract in mice supplied with a HFD to test the hypothesis that an AV extract can improve diet-induced obesity in humans.
Materials and Methods
Experimental animals
Female ICR mice (6-wk old upon receipt, SLC, Japan) were used in this study after allowing 7 days acclimatization.
The animals were allocated four per polycarbonate cage in a temperature (20-25oC) and humidity (40-45%) controlled room. The mice were placed in a 12hr : 12hr light : dark cycle with a normal rodent pellet diet and water supplied ad libitum during acclimatization. Forty eight mice (8 per group) were selected for the experiments based on their body weight at 7 days after initiating the HFD supply to selected adapted mice.
This study was carried out with prior approval of the Animal
1Corresponding author.
E-mail: warii@paran.com
Ethical Committee, The University of Daegu Haany University.
Experimental design
The experimental groups were divided into a normal pellet diet (Superfeed Co., Korea) supplied an intact control diet, HFD (Diet Research, USA; Table 1) supplied control, 250 mg/
kg of metformin-administered group, and 62.5, 125 and 250 mg/
kg AV extract groups. Forty mice were supplied with a HFD.
The remaining eight rats were used as the intact control. The dosing of the test articles was initiated from 7 days after HFD supply, and each sample was administered orally once a day over a 12 weeks period.
Preparation of AV extract
The AV was purchased from Cho-Heung Pharmaceutical Ind. Co. (Korea) after confirming its morphology under a microscope. The methanol AV extracts (yield 11.00%) were prepared from AV by routine methods using a rotary vacuum evaporator (Lab. Camp, Korea) and a programmable freeze dryer (Ilshin Lab., Korea). The dark black mucous AV extracts were stored in a desiccator to protect them from light and moisture. The AV extract was dissolved in injectable distilled water and administered by an oral gavage at a dose of 5 ml/kg.
Body weight
The changes in body weight were calculated 6 days after ini- tiating the HFD, at initial administration day, and then weekly until the end of the experiment using an automatic electronic
balance (Precisa Instrument, Switzland). At the initiation of administration and at the end of the experimental period, all experimental animals were fasted overnight (water was pro- vided; about 12hr) to decrease the effects of feeding. In addi- tion, the body weight gains after 84 days of AV extract administration were also calculated.
Food consumption
One hundred fifty gram of diets per individual cages were supplied, and reminder amounts of supplied diets were mea- sured at 24hrs after using an automatic electronic balance (Pre- cisa Instrument, Switzland). These are regarded as individual mean daily food consumption of mice (g/day/mice). These measurements were conducted once a week for 84 days of administration periods.
Changes in the fat weight
The weights of the periovarian fat pads at sacrifice were mea- sured in grams and are regarded as the absolute weight. In addi- tion, the percentage fat weight of the total body weight at sacrifice was calculated as the relative fat weights to reduce the error from the individual body weight differences using the fol- lowing formula:
Relative weights (%) = (Absolute periovarian fat pads/Body weight at sacrifice)× 100
Measurement of serum leptin and adiponectin levels The serum leptin levels were detected using a commercially available radioimmunoassay kit procedure (Linco Research, USA), and the serum adiponectin levels were detected using a commercially available ELISA kit (Otsuka Pharm., Japan) as previous reported (19).
Histology and histomorphometry
After measuring the fat weights, the left periovarian fat pads and dorsal abdominal fat pads attached to the muscularis quadratus lumborum were sampled. The sampled tissues were fixed in 10% neutral buffered formalin. After paraffin embed- ding, 3-4µm serial sections were prepared. The representative sections were stained with hematoxylin and eosin for an opti- cal microscopy examination. In addition, the mean diameter (in µm) of the periovarian and dorsal abdominal white adipo- cytes were calculated in a restricted field of view on a com- puter monitor using an automated image analyzer (DMI, Korea). At least 10 white adipocytes per fat pad were consid- ered along with the thickness (mm/mouse) of the dorsal abdominal fat pads. The histopathologist was blinded to the group distribution when performing the analysis.
Statistical analysis
The results are expressed as the mean ± standard deviation.
Statistical analyses were carried out using SPSS for Windows (Release 14.0K, SPSS Inc., USA). Multiple comparison tests for different dose groups were conducted. The variance homo- Table 1. Formulas of normal and high fat diet used in this study
Normal pellet diets (g/kg diet)a
High fat diets (g/kg diet)b Ingredient
Casein 200 200
L-Cystein 3 3
Corn starch 150 72.8
Sucrose 500 172.8
Cellulose 50 50
Soybean Oil 50 25
Lard 0 177.5
Mineral mixture 35 10
Vitamin mixture 10 10
Choline bitartrate 2 2
Energy (kcal/g) 0.21 4.73
Protein (% kcal/kg) 13.3 20
Carbohydrate (% kcal/kg) 47.4 35
Fat (% kcal/kg) 8.0 45
Fiber (% kcal/kg) 8.0 8.0
anormal rodents pellet diet (Superfeed Co., Korea) were used as normal diets
b45%Kcal/Fat pellet diets (D12451; Diet research, USA)
geneity was examined using the Levene test. If the Levene test indicated no significant deviations from variance homogene- ity, the data was analyzed by one way ANOVA test followed by a least-significant differences multi-comparison test to determine the pairs of group comparisons that were signifi- cantly different. A non-parametric comparison test, Kruskal- Wallis H test was conducted in the case of significant devia- tion from variance homogeneity in the Levene test. When a significant difference was observed in the Kruskal-Wallis H test, a Mann-Whitney U test was carried out to determine the specific pairs of group comparisons that were significantly different. A p value < 0.05 was considered significant.
Results
Changes in the body weight
Only adapted mice showing regular increases in body weight compared to the intact control during the first week of the HFD were selected. Consequently, all HFD supplied mice showed significant (p < 0.01) increases in body weight com- pared to the intact mice from 1 week after the HFD supply.
The body weight gains during the 84 day experimental period was also significantly higher (p < 0.01) in the HFD control than that of the intact control. However, marked decreases in body weight gain were detected in the metformin and AV extract-administered 3 groups (Table 2).
Changes on the food consumption
Significant (p < 0.01) decreases of mean daily food con- sumptions were detected in all HFD supplied mice groups as compared with intact control. No meaningful changes on the mean daily food consumptions were detected in all adminis- tered groups tested as compared with HFD control except for metformin and AV extract 125 mg/kg administered groups, in
which significant (p < 0.01 or p < 0.05) increases of mean daily food consumptions were detected as compared with HFD control, respectively (Fig 1).
Changes in the periovarian fat weights
The periovarian fat pad weights in the HFD control showed significant (p < 0.01) increases compared to the intact control.
However, these increases in periovarian fat pad weight were decreased significantly (p < 0.01) by a treatment with met- formin or the AV extract (at all three doses) (Fig 2).
Changes in the serum leptin levels
The serum leptin levels were significantly higher in the HDF control than the intact control (p < 0.01). However, the serum leptin levels were significantly lower in the metformin group and AV extract-administered 3 groups than that of the HDF controls (p < 0.01) (Fig 3).
Changes in the serum adiponectin levels
The serum adiponectin levels were significantly lower in the HDF control than the intact control (p < 0.01). However, there were significant (p < 0.01) increases in the serum adi- ponectin levels in the metformin and AV extract-administered 3 groups (Fig 4).
Changes in the histology and histomorphometry The periovarian and abdominal adipocyte diameters were significantly higher in the HFD control than that of the intact control (p < 0.01). However, both adipocyte diameters were significantly (p < 0.01) lower in the metformin and AV extract-
Table 2. Effect of the AV extracts on the body weight gains in HFD supplied mice
Groups
Body weights (g)
Gains during 84 days (g) At start of
administration At a termination Controls
Intact 25.90 ± 0.85 30.44 ± 2.47 04.54 ± 1.95 HFD 29.30 ± 1.34* 46.04 ± 4.49* 16.74 ± 5.32*
References
Metformin 28.91 ± 0.88* 39.43 ± 3.09*,## 10.51 ± 3.55*,##
AV extracts
62.5 mg/kg 28.30 ± 0.63* 39.20 ± 4.89*,## 10.90 ± 4.54*
125 mg/kg 28.31 ± 0.94* 35.80 ± 6.42# 07.49 ± 6.08##
250 mg/kg 28.68 ± 1.01* 38.01 ± 3.68*,# 09.34 ± 3.46*,##
Values are expressed as Mean ± S.D. of eight mice
*p < 0.01 vs intact control; #p < 0.01 vs HFD control; ##p < 0.05 vs HFD control.
Fig 1. Effect of the food consumptions in HFD supplied mice.
No meaningful changes on the mean daily food consumptions were detected in all administered groups tested as compared with HFD control except for metformin and AV extracts 125 mg/kg administered groups, in which significant increases of mean daily food consumptions were detected as compared with HFD con- trol, respectively; The values are expressed as Mean ± S.D. of eight mice. *p < 0.01 vs intact control; **p < 0.05 vs intact con- trol; #p < 0.01 vs HFD control; ## p < 0.05 vs HFD control.
treated 3 groups than that of the HFD control, respectively. In addition, the deposited abdominal fat pad thicknesses were higher in the HFD control than that of the intact control (p < 0.01). However, abdominal fat pad thicknesses were reduced significantly (p < 0.01) by a treatment with metformin and the AV extract (at all three doses) (Table 3, Fig 5 and 6).
Discussion
Obesity in mice was developed by feeding them a HFD, and the obese mice had the characteristics of hyperglycemia, insulin resistance and hypolipemia (24,25,28). HFD-induced hyperglycemia in ICR mice can rely on the development of obesity that follows protracted access to a HFD. In the present study, HFD supplied mice showed marked obese states - increases in body weights and fat deposition, adipocyte hyper- trophy, elevation of serum leptin and decreases in serum adi- ponectin levels. This means that obesity were induced by 91 Fig 3. Effect of the AV extract on the serum leptin levels on the
HFD supplied mice. The serum leptin levels were significantly lower in the metformin group and AV extract-administered groups (at all three doses) than the HDF controls; The values are ex- pressed as the mean ± S.D. of eight mice. *p < 0.01 vs intact con- trol; #p < 0.01 vs HFD control.
Fig 4. Effect of the AV extracts on the serum adiponectin levels on the HFD supplied mice. Note that significant increases in the serum adiponectin levels were detected in the metformin and AV extract-administered groups; The values are expressed as the mean ± S.D. of eight mice. *p < 0.01 vs intact control; #p < 0.01 vs HFD control.
Table 3. Effect of the AV extracts on the fat histomorphometry in HFD supplied mice
Groups
Mean diameters (µm) Abdominal fat pad thicknesses
(mm) Periovarian
adipocytes
Abdominal adipocytes Controls
Intact 069.53 ± 9.16 051.53 ± 12.96 0.485 ± 0.27 HFD 216.80 ± 42.99* 189.50 ± 33.94* 3.233 ± 0.54*
References
Metformin 116.44 ± 16.36*,#102.09 ± 26.90*,#1.277 ± 0.22*,#
AV extracts
62.5 mg/kg 118.36 ± 37.89**,#108.58 ± 37.75*,#1.405 ± 0.55*,#
125 mg/kg 107.76 ± 38.56*,#098.60 ± 39.92*,#1.182 ± 0.41*,#
250 mg/kg 115.14 ± 17.70*,#103.78 ± 22.47*,#1.383 ± 0.29*,#
Values are expressed as Mean ± S.D. of eight mice; *p < 0.01 vs intact control; **p < 0.05 vs intact control; #p < 0.01 vs HFD control Fig 2. Effect of the AV extract on the absolute (A) and relative (B) periovarian fat weight on the HFD supplied mice. Periovarian fat pad weight was decreased significantly by a treatment with metformin or the AV extracts. The values are expressed as Mean ± S.D.
of eight mice. *p < 0.01 vs intact control; **p < 0.05 vs intact control; #p < 0.01 vs HFD control; ##p < 0.05 vs HFD control.
days of a continuous HFD. However, the obesity induced by the HFD supply were inhibited by an 84 day continuous treat- ment with the AV extract at three different doses. Moreover, 125 mg/kg of the AV extract showed similar effects to those of metformin 250 mg/kg.
Inhibition of the increases in body weight and gains is con- sidered evidence of the treatment of obesity. The accumula- tion or increases in fat deposition in the body is a major characteristic of obesity, and cellular hypertrophy appears to be the major mode of expansion of the intra-abdominal adi- pose tissue in rodents (4,17). In obesity, increases in the accu- mulation of adipose tissues are common features of obesity.
Adipose tissue works not only as an organ for energy storage, but also as an endocrine and secretory organ (6).Adipose tis- sues secret adipokines, and changes in the expression, secre- tion, and action of the adipokines in obesity are have been implicated in the development of a range of diseases including insulin resistance (6,16). In the present study, dramatic in- creases in the body and fat weights, and the deposition of abdominal adipose tissues were detected as a result of the HFD with severe adipocyte hypertrophy. Consequently, the diame- ters of the adipocytes were increased considerably. However, an 84 day continuous treatment with the AV extract effec- tively inhibited the histopathological changes in fat, as well as the increases in body and fat weight induced by the HFD. This provides direct evidence that the AV extract has anti-obesity activity, which might be similar to or better than that of met- formin 250 mg/kg.
The decreases of mean daily food consumption detected in
all HFD supplied mice as compared with normal diet sup- plied mice considered as not critical problems in this study because the energy of HFD (4.73 kcal/g) used in the present study were much higher (about 20 folds; see Table 2) than that of normal diet (0.21 kcal/g). In the present study, the body weights in all HFD supplied groups showed marked increases as compared with intact group. Because there no marked decreases of food consumption were detected in all three dif- ferent dosages of AV extract treated groups, the anti-obesity effects of AV extract, therefore, were not from the inhibition of food consumption. In the present study, increased or similar food consumptions were detected in all three different dosages of AV extract treated groups rather than decreases as com- pared with HFD control, respectively.
Fig 5. Effect of the AV extracts on the histological profiles of the periovarian fat pads in HFD supplied mice. (A): intact control, (B): HFD control, (C): metformin 250 mg/kg-dosing group; (D):
AV extracts 62.5 mg/kg-dosing group, (E): AV extracts 125 mg/
kg-dosing group, (F): AV extracts 250 mg/kg-dosing group. Note that severe hypertrophy (increases of mean diameters) of perio- varian adipose cells was detected when compared with the intact control. However, adipocyte diameters were significantly lower in the metformin and AV extract-treated groups than the HFD con- trol.; H&E stain, Scale bars = 80µm.
Fig 6. Effect of the AV extracts on the histological profiles of the abdominal fat pads in HFD supplied mice. (A), (B): intact con- trol, (C), (D): HFD control, (E), (F): metformin 250 mg/kg-dos- ing group; (G), (H): AV extracts 62.5 mg/kg-dosing group, (I), (J): AV extracts 125 mg/kg-dosing group, (K), (L): AV extracts 250 mg/kg-dosing group. Note the severe hypertrophy of abdom- inal adipose cells with increases in deposits (thickness of deposit fat pads) as compared to the intact control. However, these adi- pocyte hypertrophy and deposition of fats were markedly decreased by a treatment with metformin and the AV methanol extracts; H&E stain, Scale bars = 80µm.
Leptin, which is produced predominantly by adipose tissue, was first examined as a satiety signal regulating the food intake and energy expenditure and effectively reducing the appetite (3). Deficiencies in leptin signaling or functioning in the hypo- thalamus are believed to contribute to the development of obe- sity (7). Adiponectin (also known as Acrp30) is a novel adipokine that was identified recently (15). It is expressed exclusively in adipose tissue (14) and released abundantly into the circulating blood (2). More recently, it has been reported that obesity decreases the plasma adiponectin levels in humans and experimental animals (2,13). In addition, hypoadiponecti- emia is closely related to insulin resistance (16). In the present study, the hyperleptinemia and hypoadiponectiemia in the mice given the HFD were inhibited markedly by a treatment with the AV extract (at all three doses), to a level similar to that obtained with metformin.
In conclusion, a methanol extract of AV showed relatively good inhibitory effects on the HFD-induced obese. The results suggest that the administration of the AV extract can improve the diet-induced obesity in humans. The AV extract (125 mg/
kg) showed similar favorable effects to metformin 250 mg/kg.
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고지방식이로 유발된 비만마우스에서 산마늘 잎추출물의 항비만효과
구세광·정인권·전우현·김주완*1
대구한의대 한의학과, *주식회사 글루칸
요 약 : 본 실험은 고지방식이로 유발된 비만마우스에서 산마늘 잎 메탄올 추출물의 항비만 효과를 알아보고자 체중 변화, 사료섭취량변화, 렙틴과 아디포넥틴 수치변화, 난소주위 지방무게 변화 측정과 지방세포의 조직병리학적 검사를 실시하였으며, 메트포민을 체중당 250 mg 투여한 약물대조군과 비교평가 하였다. 비만유발을 위하여 고지방식이를 13 주간 공급하였으며, 고지방식이 공급 7일째에 증류수(비만대조군), 메트포민(약물대조군), 산마늘 잎 메탄올 추출물을 투여하였다. 비만대조군은 확연한 비만이 유발되었으며, 산마늘 잎 메탄올 추출물(62.5, 125, 250 mg/kg) 투여군에서는 이러한 비만이 유의적으로 감소하였다. 결론적으로 산마늘 잎 메탄올 추출물은 비만유발 마우스에서 비만개선작용을 나타내었으며, 나아가 인체에서도 유의한 비만개선작용을 할 것으로 생각된다.
주요어 : 산마늘, 비만, 고지방식이, 마우스, 추출물
