Open Access, Peer-reviewed
pISSN 2765-4362
eISSN 2765-4699
    Food Suppl Biomater Health. 2021 Mar;1(1):e8. English.
    Published online Mar 24, 2021.
    https://doi.org/10.52361/fsbh.2021.1.e8
    © 2021 Health Supplements Future Forum
    Original Article

    Anti-Obesity Effect of Licorice Acetone Extract in a Mouse Model of Obesity Induced by a High-Fat Diet

    Mun-Hoe Lee,1 Jae-Min Hwang,2 Eun-Ju Kang,1 Hyeong-Min Kim,1 Sung-Woo Yoon,1 Hee-Chul Chung,1 and Jin-Hee Lee1
      • 1Health Food Research and Development, NEWTREE Co., Ltd., Seoul, Korea.
      • 2Food Biotechnology Department, Gachon University, Seongnam, Korea.
    • Correspondence: Jin-Hee Lee, PhD. Health Food Research and Development, NEWTREE Co., Ltd., 6-14 Baekjegobun-ro 27-gil, Songpa-gu, Seoul 05604, Korea. Email: jhlee@inewtree.com
    Received December 03, 2020; Revised March 15, 2021; Accepted March 21, 2021.

    This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

    Abstract

    In this study, the anti-obesity effect of licorice (root of Glycyrrhiza glabra) acetone extract (LE) standardized by glabridin content was examined by oral administration of 50 or 100 mg/kg per day of LE for 12 weeks to C57BL/6N mice with high-fat-diet-induced obesity. The following results were obtained. In mice treated with LE, body weight and epididymal fat mass, which were increased by the induction of obesity, were decreased significantly. Serum levels of total cholesterol, aspartate aminotransferase, alanine aminotransferase, and hepatic steatosis were ameliorated. Furthermore, LE suppressed the expression of acetyl-CoA carboxylase and peroxisome proliferator-activated receptor gamma in the liver. LE also increased serum level of adiponectin significantly, which inhibits lipid anabolism and promotes lipid catabolism. These findings suggest that licorice extracted with acetone has the potential as an anti-obesity agent.

    Keywords
    Licorice Acetone Extract; Glabridin; Anti-Obesity; High-Fat Diet; Health Supplement

    INTRODUCTION

    According to the World Health Organization,1 the obese population has nearly tripled worldwide since 1975, and as of 2016, 1.9 billion adults are overweight, of which 650 million are obese. Excluding genetic factors, obesity is caused mainly by an imbalance between food intake and energy consumption. It is a serious disorder because it is accompanied by various chronic diseases.2, 3 Therefore, several types of substances to prevent or ameliorate obesity are being investigated, and their mechanisms are diverse and include the acceleration of lipid catabolism, inhibition of lipid anabolism, suppression of intestinal lipid absorption, and inhibition of adipocyte differentiation.4, 5, 6, 7

    The high-fat diet (HFD)-induced obesity mouse model is a representative model to screen anti-obesity substances.8, 9 Obesity induced by HFD changes phenotypes, such as body-weight gain in mice, and affects gene expression related to lipid metabolism. The activation level of adenosine monophosphate-activated protein kinase (AMPK) in mice with HFD-induced obesity is lower than that in normal mice.10 The activation of AMPK is a key factor in suppressing obesity because it inhibits lipid anabolism and the differentiation of adipocytes and promotes lipid catabolism. Additionally, peroxisome proliferator-activated receptor gamma (PPARγ) is a master regulator of adipocyte differentiation; it has been reported that PPARγ is also highly expressed in HFD mice.11, 12

    Licorice, the root of Glycyrrhiza glabra, has been used for many years as an herbal medicine because of its various health benefits, including anti-inflammation and protection from Helicobacter pylori colonization in the gastric mucosa.13, 14 The anti-obesity effect of licorice has also been reported in vitro, in vivo, and at the clinical level from extracts obtained through alcohol or supercritical extraction.15, 16, 17 However, the anti-obesity effect of licorice acetone extract (LE) has not been studied in vivo or at the clinical level. Depending on the extraction solvent, the components extracted and their health benefits can vary greatly.18, 19 For this reason, to increase the practical and clinical applications related to the anti-obesity effect of licorice in the food industry, it is necessary to confirm whether licorice extract obtained through various extraction methods, including acetone, has an anti-obesity effect in vivo and at the clinical level. Thus, we studied the anti-obesity effect of LE and its mechanism using the HFD-induced obesity model.

    METHODS

    LE

    LE was prepared by the same method as in our previous study.20 Briefly, dried licorice (G. glabra) was extracted under reflux for 8 hours at 60°C using acetone as an extraction solvent and then filtered through a fine cloth. The extract was dried in a vacuum concentrator at 55°C for 6 hours until a thick paste was obtained and then completely dried in a 70°C vacuum tray dryer. The dried product was ground and passed through a sieve to prepare the final form of the extract. LE was standardized based on its content of glabridin (≥ 2.90% w/w).

    High-performance liquid chromatography (HPLC)

    The amount of glabridin in LE was quantified via the HPLC-ultraviolet (UV) technique using the Shiseido Nanospace SI-2 series HPLC system (Shiseido, Tokyo, Japan). A Capcell Pak C18 column (250 × 4.6 mm; i.d., 5 mm; Shiseido) was used for the HPLC analysis. The eluent was composed of mobile phase A (10 mM KH2PO4 [0.5 mL H3PO4 in 1 L water]) and mobile phase B (acetonitrile). The gradient of mobile phase B was 0 minutes, 25%; 10 minutes, 55%; 30 minutes, 75%; 35 minutes, 100%; 40 minutes, 100%; 45 minutes, 25%; and 50 minutes, 25%. Other parameters included a column temperature of 35°C, an injection volume of 10 μL, a flow rate of 0.4 mL/min, and a detection wavelength of 280 nm UV.

    Animal study

    Twenty-four 5-week-old male C57BL/6N mice were purchased from Orient Bio Co. (Gapyeong, Korea) and maintained in the animal facility at CHA University, Seongnam, Korea (Institutional Animal Care and Use Committee [IACUC] Approval Number 190199). Three mice per cage were housed under a controlled environment (12-hour light/dark cycle, 20°C–24°C, 44.5%–51.8% humidity). All mice were fed a normal diet (ND) (D10012G; Research Diets, New Brunswick, NJ, USA) for 1 week for acclimation and then divided randomly into 4 groups (n = 6 per group) as follows.

    • ND group: mice fed a ND with 200 μL of vehicle for 12 weeks.

    • HFD group: mice fed a HFD (60% kcal% fat, D12492; Research Diets) with 200 μL of vehicle for 12 weeks.

    • LE 50 group: mice fed a HFD with LE 50 mg/kg body weight/200 μL per day for 12 weeks.

    • LE 100 group: mice fed a HFD with LE 100 mg/kg body weight/200 μL per day for 12 weeks.

    All test compounds were administered by oral sonde each day, and medium-chain triglyceride oil was used as the vehicle. The food was refreshed twice per week, and the amount of feed intake was measured. Mice were allowed free access to diet and water, and their body weight was measured once per week.21

    At the end of the experiment, mice were fasted for about 12 hours before blood collection and euthanasia. Adipose tissue (epididymal fat, subcutaneous fat, mesenteric fat, perirenal fat, and inguinal fat) and livers of the mice were removed, weighed, and snap-frozen in liquid nitrogen. Frozen tissue was stored at −80°C until analysis.

    Biochemical and histological analyses

    Blood was collected from the retro-orbital venous plexus of all the mice. The serum was separated using a serum separator tube (BD, 365967; Becton, Dickinson and Company, Franklin Lakes, NJ, USA), by centrifugation at 3,000 rpm for 15 minutes, and stored at −80°C until analysis. Total cholesterol, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) levels in the serum were measured using an auto-analyzer TOSHIBA ACCUTE (Tba-40fr; TOSHIBA, Tokyo, Japan) with specific kits, according to the manufacturer's instructions. Serum adiponectin levels were measured using an ELISA kit (MRP300; R&D Systems, Minneapolis, MN, USA), according to the manufacturer's instructions.

    White adipose tissue and livers obtained from the mice were fixed in 4% paraformaldehyde and embedded in paraffin. Paraffin-embedded tissues were cut into 4-μm sections, and hematoxylin and eosin (H&E) staining was performed to analyze hepatic lipid accumulation and adipocyte size under a bright-field microscope (CX41; Olympus, Tokyo, Japan) at 200× magnification. Hepatic steatosis was scored according to the percentage of fat deposits in the total liver tissue with the following grading criteria: 0.5, < 5%; 1, 5%–10%; 2, 10%–30%; 3, 30%–50%; and 4, > 50%. The adipocyte size was measured using an image analyzer (iSolution Lite; IMT iSolution, Burnaby, Canada).

    Western blotting

    Tissues were homogenized and lysed with Pro-Prep (17081; Intron, Seongnam, Korea) supplemented with phosphatase inhibitor cocktail 2 and 3 (Sigma, St. Louis, MO, USA). Proteins were quantified by the BCA assay, and 30 μg of each sample was separated on an acrylamide gel and then transferred onto a polyvinylidene fluoride membrane. Membranes were blocked with 5% skim milk for 2 hours and then incubated with specific primary antibodies overnight. After 2 hours of incubation with secondary antibodies, proteins were reacted with EZ-Western Lumi Femto (DG-WF100; DoGenBio, Seoul, Korea) and visualized using chemiluminescence (Invitrogen, iBright FL100). Specific proteins were standardized against glyceraldehyde 3-phosphate dehydrogenase.20

    Statistical analyses

    All statistical analyses were performed using SPSS v26.0 software from SPSS, Inc. (Chicago, IL, USA), and the results were expressed as means ± standard deviations. Differences were analyzed using one-way analysis of variance, followed by the Duncan's test.

    RESULTS

    Standardization of licorice extract

    We standardized the extraction process of licorice by analyzing glabridin using HPLC (Fig. 1). Glabridin is a major bioactive compound of licorice, with various health benefits, such as antioxidant activity and estrogen-like properties.22, 23 The glabridin content of LE used in these experiments was 38.14 mg/g.

    Fig. 1
    High-performance liquid chromatogram of glabridin in licorice extracted by acetone. (A) Standard compound of glabridin and (B) glabridin in licorice acetone extract.

    Anti-obesity effect of LE on body weight in mice with HFD-induced obesity

    To determine the anti-obesity effect of LE, C57BL/6N mice with HFD-induced obesity were orally given 50 or 100 mg/kg per day of LE for 12 weeks (Fig. 2A). LE treatment suppressed the HFD-induced increase in body size and fat accumulation, as observed through a macroscopic view (Fig. 2B). Moreover, without changing the HFD feed intake, LE reduced the weight gain and epididymal fat mass of the HFD group significantly (Fig. 2C-F). The adipose tissue (subcutaneous, mesenteric, perirenal, and inguinal fat) was also weighed, but no significant difference between the HFD and LE groups was observed (data not shown). The liver weights of the LE groups were the same as those of the ND group, indicative that LE does not cause serious side effects on the liver. These results suggest that LE has an anti-obesity effect by regulating the body weight and the accumulation of visceral fat.

    Fig. 2
    Anti-obesity effect of LE in a mouse model of obesity. C57BL/6N mice were fed a ND or a HFD and treated with vehicle or 50 or 100 groups by oral gavage once per day for 12 weeks. (A) Schematic of experimental schedules. (B) Photographs are the gross appearance and the abdominal cavities of representative mice from each group. (C) Body-weight changes in mice during the experiment and (E) body-weight gain for 12 weeks. (D) Food intake of mice during the experiment. (F) Weights of epididymal fat and livers. Data are represented as means ± standard deviations (n = 6).
    LE = licorice acetone extract, ns = no significant difference, ND = normal diet, HFD = high-fat diet, 50 = licorice acetone extract at 50 mg/kg, 100 = licorice acetone extract at 100 mg/kg.

    Different letters indicate significant differences calculated using one-way analysis of variance (P < 0.05), followed by the Duncan's test.

    LE ameliorates serum parameters in HFD-induced obese mice

    As HFD-induced obesity alters serum parameters in mice, we evaluated whether LE could ameliorate these (Fig. 3). Total cholesterol was decreased significantly in the LE groups compared with the HFD group. Furthermore, LE reduced serum levels of AST and ALT significantly, which are indicators related to hepatic steatosis. By contrast, LE increased serum adiponectin significantly, which was reduced by the HFD, to the level of the ND group. These data indicated that LE ameliorated the serum parameters exacerbated by obesity.

    Fig. 3
    Effect of LE on serum parameters in a mouse model of obesity. C57BL/6N mice were fed a ND or a HFD and treated with vehicle or 50 or 100 groups by oral gavage once per day for 12 weeks. (A) Serum levels of total cholesterol, (B) AST, ALT, and (C) adiponectin are shown. Data represent means ± standard deviations (n = 6).
    LE = licorice acetone extract, ND = normal diet, HFD = high-fat diet, 50 = licorice acetone extract at 50 mg/kg, 100 = licorice acetone extract at 100 mg/kg, AST = aspartate aminotransferase, ALT = alanine aminotransferase.

    Different letters indicate significant differences calculated using one-way analysis of variance (P < 0.05), followed by the Duncan's test.

    LE reduces steatosis in the liver and adipocyte size in white adipose tissue

    We investigated the anti-obesity effect of LE on the tissue by examining H&E-stained liver and epididymal fat sections. HFD induced severe hepatic steatosis, which was reduced by the administration of LE, thereby reducing fat deposition (Fig. 4). To quantify this, hepatic steatosis was scored by evaluation criteria, and a significant decrease in the hepatic steatosis scores of the LE-treated groups was found compared with the HFD group. Additionally, the adipocyte size of epididymal fat was decreased significantly in the LE 100 group compared with the HFD group.

    Fig. 4
    LE reduces hepatic steatosis and adipocyte size of epididymal fat in a mouse model of obesity. C57BL/6N mice were fed a ND or a HFD and treated with vehicle or 50 or 100 groups by oral gavage once daily for 12 weeks. (A) Representative H&E images of the liver and epididymal fat (magnification, 200×). (B) Grading scores of hepatic steatosis and diameters of adipocytes.
    LE = licorice acetone extract, ND = normal diet, HFD = high-fat diet, 50 = licorice acetone extract at 50 mg/kg, 100 = licorice acetone extract at 100 mg/kg, H&E = hematoxylin and eosin.

    Different letters indicate significant differences calculated using one-way analysis of variance (P < 0.05), followed by the Duncan's test.

    Effect of LE on protein expression levels of ACC and PPARγ

    Our data showed the anti-obesity effect of LE at the phenotypic level during HFD-induced obesity. Therefore, to elucidate the molecular biological mechanism of LE, specific protein expression levels in the liver and epididymal fat of mice were measured using western blotting (Fig. 5). In the liver, the expression levels of PPARγ, which were increased by the HFD, were decreased significantly in the LE 100 group. By contrast, the expression level of acetyl-CoA carboxylase (ACC), which was reduced by the HFD, was increased significantly in the LE groups. Although LE regulated the expression levels of PPARγ and ACC in the liver, it did not cause significant differences in the expression levels of PPARγ and ACC in epididymal fat. These results suggested that LE exhibits anti-obesity effects by regulating the expression of proteins at the molecular level in the liver.

    Fig. 5
    Effect of LE on protein expression levels of ACC and PPARγ in the liver and epididymal fat. C57BL/6N mice were fed a ND or a HFD and treated with vehicle or 50 or 100 groups by oral gavage once daily for 12 weeks. Data are represented as means ± standard deviations (n = 6).
    LE = licorice acetone extract, ND = normal diet, HFD = high-fat diet, 50 = licorice acetone extract at 50 mg/kg, 100 = licorice acetone extract at 100 mg/kg, ACC = acetyl-CoA carboxylase, PPARγ = peroxisome proliferator-activated receptor gamma, GAPDH= glyceraldehyde 3-phosphate dehydrogenase.

    Different letters indicate significant differences calculated using one-way analysis of variance (P < 0.05), followed by the Duncan's test.

    DISCUSSION

    In this study, we demonstrated that LE has anti-obesity effects in a mouse model of HFD-induced obesity. LE ameliorated body-weight gain and visceral (epididymal) fat effectively, the most prominent biomarkers of an anti-obesity effect. This anti-obesity effect may result from glabridin, one of the main bioactive compounds of licorice. Licorice flavonoid oil (LFO), a complex of licorice ethanol extract and medium-chain triglyceride oil containing about 1% glabridin, ameliorated HFD-induced obesity in rats.24, 25 Additionally, the anti-obesity effect of LFO was confirmed in clinical trials.17 The daily oral administration of LFO to overweight subjects for 8 weeks decreased their body weights and body mass index compared with the placebo group. Recently, Ahn et al.16 reported that the supercritical carbon dioxide extract of licorice containing 4.5% glabridin suppressed the obesity of HFD mice.

    The amelioration of obesity by LE also changed blood biomarkers. Total cholesterol levels decreased after LE treatment, which was increased by obesity. Interestingly, LE dramatically increased the concentration of serum adiponectin, which is involved in lipid catabolism, promotes β-oxidation of fatty acids in muscle, and inhibits lipid anabolism in adipose tissue.26 A negative correlation between obesity and serum adiponectin has been reported in clinical research.27, 28 In our experiment, LE normalized serum adiponectin, which decreased as obesity was induced by the HFD. These data indicate that LE inhibits obesity by strongly regulating the expression of the adiponectin hormone.

    LE also affected serum concentrations of AST and ALT, known as hepatic steatosis indicators.29 Obesity has been reported to increase serum AST and ALT levels by increasing lipid accumulation in the liver. As observed in our histopathological results, LE inhibited hepatic steatosis effectively. Therefore, the decreased levels of serum AST and ALT in our study may have been due to LE suppressing hepatic steatosis. Collectively, LE-related changes in blood parameters support the anti-obesity effects of LE directly and indirectly.

    To confirm the anti-obesity molecular biological mechanism of LE, we observed the AMPK pathway in the liver and epididymal fat. In our previous study, LE activated the AMPK pathway by promoting the phosphorylation of AMPK in 3T3-L1 cells, resulting in the suppression of cellular lipid accumulation.20 Furthermore, glabridin contained in LE was reported to ameliorate HFD-induced obesity in mice by activating the AMPK pathway.30 However, contrary to this theory, in the current study, there was no significant difference in the AMPK pathway activity between HFD-fed obese mice and normal mice, and activation of the AMPK pathway by LE was also not observed (data not shown). In general, many anti-obesity substances demonstrate their effects by inhibiting lipid synthesis through the phosphorylation of AMPK or ACC.31, 32 However, LE increased the expression level of ACC without promoting phosphorylation in the liver. Although ACC is a lipid synthesis-related enzyme, the trend of changes in ACC expression by LE was the same as that observed in normal mice. This trend indirectly supports the anti-obesity effect of LE.

    The difference in ACC expression levels between normal mice and those with HFD-induced obesity was also remarkable. In previous anti-obesity research, no attention was paid to the difference in ACC expression between mice with HFD-induced obesity and normal mice.33, 34 Additionally, no difference in expression levels was observed previously between these groups. However, in our study, ACC expression in normal mice was consistently high in the liver and epididymal fat compared with that in HFD mice, and we predict that these results were due to homeostasis. These results, which differ from those known previously, suggest the necessity of re-examining the role of the AMPK pathway in models of HFD-induced obesity.

    Here, the epididymal fat tissue weight was reduced, and hypertrophy and hyperplasia of epididymal fat were suppressed histopathologically by LE. However, the expression levels of proteins related to the differentiation of adipocytes, such as PPARγ and CCAAT/enhancer-binding protein α, also known as the master regulator of adipogenesis, were not changed (data not shown).35 In the liver, the expression of PPARγ was downregulated by LE, partially suggesting a mechanism of the inhibition of lipid accumulation in the liver. However, it cannot explain the full extent of this inhibition because the expression level of PPARγ decreased only at 100 mg/kg LE, whereas the suppression of hepatic steatosis was observed at both 50 and 100 mg/kg LE. Therefore, in addition to PPARγ, other factors related to lipid metabolism must be involved in suppressing hepatic steatosis. In this study, the anti-obesity effect of LE was confirmed, but its underlying mechanism was not clearly revealed. In particular, the mechanism resulting in the improvement of adipose tissue by LE was not clearly revealed. Since this study confirmed that LE strongly regulates adiponectin in the serum of obesity-induced mice, further in vitro and in vivo studies focusing on the adiponectin are necessary to elucidate the mechanism in detail.

    In conclusion, licorice extracted using acetone has anti-obesity effects in a mouse model of HFD-induced obesity. LE standardized by glabridin content effectively suppressed body-weight gain, epididymal fat mass, and hepatic steatosis, which are increased by HFD. LE showed anti-obesity effects by strongly regulating serum adiponectin. The amelioration of blood indices and changes in the expression levels of ACC and PPARγ in the liver caused by LE supported the inhibitory effect of LE on obesity. These results increase the possibility that the anti-obesity effect of LE can be applied to the food industry, although additional experiments at the clinical level are required.

    Notes

    Funding:This research was supported by NEWTREE Co., Ltd.

    Disclosure:The authors have no potential conflicts of interest to disclose.

    Author Contributions:

    • Conceptualization: Lee MH.

    • Data curation: Lee MH, Hwang JM.

    • Formal analysis: Lee MH, Hwang JM.

    • Funding acquisition: Kim HM, Yoon SW, Chung HC, Lee JH.

    • Investigation: Lee MH, Hwang JM.

    • Methodology: Lee MH, Hwang JM.

    • Project administration: Kim HM, Yoon SW, Chung HC, Lee JH.

    • Resources: Lee MH.

    • Software: Lee MH.

    • Supervision: Kim HM, Yoon SW, Chung HC, Lee JH.

    • Validation: Lee MH.

    • Visualization: Lee MH.

    • Writing - original draft: Lee MH.

    • Writing - review & editing: Lee MH, Kang EJ, Kim HM, Yoon SW, Chung HC, Lee JH.

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    MeSH Terms
    Acetone*
    Acetyl-CoA Carboxylase
    Adipocytes
    Adiponectin
    Administration, Oral
    Alanine Transaminase
    Animals
    Aspartate Aminotransferases
    Cholesterol
    Diet, High-Fat*
    Exhibition
    Glycyrrhiza*
    Lipids
    Liver
    Metabolism
    Mice*
    Obesity*
    PPAR gamma
    Metrics
    Share
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