Journal of Ethnopharmacology 178 (2016) 229–237

Contents lists available at ScienceDirect

Journal of Ethnopharmacology
journal homepage: www.elsevier.com/locate/jep

Effects of Korean red ginseng (Panax ginseng) on obesity and adipose

inflammation in ovariectomized mice
Hyunghee Lee a, Jeonghyun Choi a, Soon Shik Shin b,n, Michung Yoon a,n
a
Department of Biomedical Engineering, Mokwon University, Daejeon 35349, Republic of Korea
b
Department of Formula Sciences, College of Korean Medicine, Dongeui University, Busan 47227, Republic of Korea

art ic l e i nf o a b s t r a c t

Article history: Ethnopharmacological relevance: Korean red ginseng (ginseng, Panax ginseng C.A. Meyer) is a famous
Received 17 August 2015 traditional drug used in Korea for the treatment and prevention of obesity, type 2 diabetes, cancer, and
Received in revised form liver and cardiovascular diseases. Menopause is strongly associated with many of the aforementioned
11 December 2015
metabolic diseases and increased visceral obesity. The aims of this study were to investigate whether
Accepted 15 December 2015
ginseng inhibits obesity and related disorders in ovariectomized (OVX) C57BL/6J mice, which is a mouse
Available online 17 December 2015
model of postmenopausal women, and to determine the mechanism of action involved in this process.
Keywords: Materials and methods: After OVX mice were treated with 5% (w/w) ginseng for 15 weeks, we de-
Panax ginseng termined the effects of ginseng on obesity and adipose inflammation, angiogenesis, metalloproteinase
Obesity
(MMP) activity and metabolic parameters.
Angiogenesis
Results: OVX mice had higher body weight, adipose tissue mass and adipocyte size when fed a high fat
MMP
Ovariectomized diet (HFD) compared with HFD-fed sham-operated mice. All of these parameters were significantly re-
Inflammation duced in OVX mice fed a HFD supplemented with ginseng. Ginseng treatment also decreased blood
Adipocyte hypertrophy vessel density, MMP activity, and mRNA levels of angiogenic factors (e.g., VEGF-A and FGF-2) and MMPs
(e.g., MMP-2 and MMP-9) in adipose tissues of OVX mice. Infiltrating inflammatory cells and expression
of inflammatory cytokines (e.g., CD68, TNFα and MCP-1) in adipose tissue were reduced by ginseng.
Ginseng not only reduced the circulating levels of free fatty acids and triglycerides, but also normalized
hyperinsulinemia and hyperglycemia in OVX mice. Hepatic lipid droplets were almost completely
abolished by ginseng.
Conclusions: These results suggest that ginseng inhibited ovariectomy-induced obesity, adiposity, and
adipocyte hypertrophy by modulating angiogenesis and MMP activity. Ginseng also suppressed adipose
inflammation, insulin resistance, and hepatic steatosis in OVX mice. Thus, it is likely that ginseng may be
a promising drug for the prevention and treatment of obesity and related disorders in obese post-
menopausal women.
& 2015 Elsevier Ireland Ltd. All rights reserved.

1. Introduction blood vessel formation (angiogenesis) (Crandall et al., 1997; Rup-

Obesity is characterized by increased adipose tissue mass that
results from increases in fat cell number (hyperplasia) and size
(hypertrophy). Development of obesity is associated with ex-
tensive modifications in adipose tissue involving adipogenesis,
angiogenesis, and extracellular matrix (ECM) remodeling (Crandall
et al., 1997).
The extensive capillary network in highly vascularized adipose
tissue nourishes each adipocyte (Cao, 2007; Bouloumié et al.,
2002). Consequently, adipose tissue growth in adults requires new
n
Corresponding authors.
E-mail addresses: ssshin@deu.ac.kr (S. Shik Shin),
yoon60@mokwon.ac.kr (M. Yoon).
nick et al., 2002). Given the dependency of adipose tissue growth
on angiogenesis, it has been suggested that growth can be regu-
lated by modifications of adipose tissue vasculature (Rupnick et al.,
2002; Bråkenhielm et al., 2004; Kim et al., 2010). Extensive ECM
remodeling changes have also been shown to occur during adipose
tissue growth. Matrix metalloproteinases (MMPs) have been im-
plicated in tissue remodeling via either degradation of the ECM
and basement membrane components or activation of adipocyte
growth factors (Lijnen et al., 2002; Visse and Nagase, 2003). Sev-
eral MMPs, including MMP-2 and MMP-9, play important roles in
the development of adipose tissue and microvessel maturation by
modulating the ECM (Lijnen et al., 2002; Bouloumié et al., 2001).
Thus, modifying or blocking angiogenesis and MMPs may help
manage or eliminate obesity and related disorders.
Ginseng, the root of Panax ginseng C.A. Mayer (Araliaceae), has

http://dx.doi.org/10.1016/j.jep.2015.12.017
0378-8741/& 2015 Elsevier Ireland Ltd. All rights reserved.
230 H. Lee et al. / Journal of Ethnopharmacology 178 (2016) 229–237
historically been one of the most popular herbal medicines used to
treat various diseases in Korea, China, and Japan for thousands of
years. Ginseng has been traditionally used in the treatment of
most aging-related diseases, such as diabetes, obesity, and dysli-
pidemia (Yin et al., 2008). Ginseng has also been reported to
prevent tumor growth by inhibiting angiogenesis (Sato et al.,
1994). Ginsenosides, the major active components of ginseng,
exhibit potential as potent cancer chemopreventive agents be-
cause of their anti-angiogenic activity (Yue et al., 2006; Jeong et al.,
2010). Based on the suggestion that ginseng modulates angio-
genesis (Sato et al., 1994; Liu et al., 2009) and the well-docu-
mented regulation of adipose tissue growth by angiogenesis (Cao,
2010), it is likely that the anti-angiogenic properties of ginseng
may reduce adipose tissue mass and prevent obesity.
Men and women differ in the regulation of body weight and fat
mass. Moreover, postmenopausal women accumulate greater
amounts of visceral fat than premenopausal women and men of
like age, resulting in a greater risk of metabolic disorders asso-
ciated with obesity for postmenopausal women (Shi and Clegg,
2009; Tan et al., 2010). Evidence from both humans and laboratory
animals suggests that estrogen plays an important role in body
weight and visceral adipose tissue regulation. Removal of ovarian
steroids, particularly estrogen, by ovariectomy in mice mimics
women in menopause. Ovariectomized (OVX) mice have an in-
creased susceptibility to obesity and its complications including
adipose inflammation, insulin resistance, and hepatic steatosis
(You et al., 2004; Kaaja, 2008; Hong et al., 2009; Ludgero-Correia
et al., 2012). Conversely, estrogen replacement decreases body
weight and blood pressure and protects against fatty liver and
insulin resistance (Zhu et al., 2013; Wang et al., 2015). Our pre-
vious study demonstrated that ginseng prevented obesity through
angiogenesis inhibition (Lee et al., 2013, 2014); however, these
results were obtained using male mice and db/db mice. We hy-
pothesized that ginseng may inhibit obesity by regulating angio-
genesis in high fat diet (HFD)-fed female OVX C57BL/6J mice. In
addition, we examined whether ginseng also inhibits obesity-as-
sociated adipose inflammation by down-regulating angiogenesis.
2. Materials and methods
2.1. Ginseng preparation
Korean red ginseng extract powder (Korean Red Ginseng Ex-
tract Powder TeaⓇ) was manufactured by Korea Ginseng Cor-
poration (Seoul, Korea) from the root of 6-year-old Panax ginseng
harvested in Korea. Korean ginseng was cultivated with special
care and managed by Good Agricultural Practices established by
the Rural Development Administration. The manufacture of gin-
seng was admitted and regulated by Korean Food and Drug Ad-
ministration. A voucher specimen was deposited at the laboratory
of Korea Ginseng Corporation and the batch number of ginseng
used in our study is 6510100112048. Briefly, red ginseng was
boiled in distilled water for 24 h at 95 °C. The aqueous extracts
were then filtered and freeze-dried under vacuum for the pro-
duction of ginseng extract powder. For analysis of the quality of
ginseng, ginseng extract powder (100 g) was placed into a 1-L flask
with a refluxing condenser and extracted twice with 500 mL of
water-saturated 1-butanol for 1 h at 80 °C. The extracted solution
was passed through Whatman filter paper (No. 41) after cooling.
The process was repeated twice. The residue and filter paper were
washed with 100 mL of water-saturated 1-butanol, and then the
filtrate was washed twice with 100 mL of water in a 2-L separating
funnel. The butanol layer was then evaporated to dryness. The
concentrate was extracted to remove any traces of fat with 100 mL
of diethyl ether for 30 min at 36 °C in a flask with a refluxing
Table 1
Contents of ginsenosides in ginseng extract.
Ginsenosides (%)
Rb1 Rb2 Rc Rd Re Rf Rg1 Rg2 Rg3 Rh1 Rh2
0.29 0.11 0.08 0.04 0.08 0.04 0.21 0.02 0.02 0.01 0
condenser, after which the ether solution was decanted. The re-
sidue was dried at 50 °C and weighed. The quality control of gin-
seng was analyzed by the HPLC/ELSD system and the HPLC profile
of ginseng extract was described previously (Lee et al., 2014). The
contents of ginsenosides in ginseng extract are shown in Table 1.
Ginseng extract contained major active compounds Rb1 and Rg1
(4 mg/g).
2.2. Animal treatments
For all experiments, 8-week-old female mice (C57BL/6J) were
housed and bred at Mokwon University under pathogen-free
conditions with a standard 12-h light/dark cycle. Before the ad-
ministration of special diets, mice were fed standard rodent chow
and given water ad libitum. Mice were sham-operated (Sham) or
OVX and then divided into three groups (n ¼8/group): a Sham
group given a HFD (24% fat w/w, Research Diets, New Brunswick,
NJ, USA) (Sham), an OVX group given a HFD (OVX) or an OVX
group given a HFD supplemented with Korean red ginseng extract
(5% w/w; Korea Ginseng Corp., Daejeon, Korea) (OVX plus ginseng)
for 15 weeks. For ginseng-supplemented HFD, 50 g of ginseng
extract powder was mixed with 1 kg of HFD (Lee et al., 2013). A
person blinded to each treatment group measured body weights
daily. Fat pads were removed, weighed, snap-frozen in liquid ni-
trogen, and stored at  80 °C until use. Portions of the fat pads and
liver were prepared for histology. Levels of serum triglycerides and
free fatty acids were measured using an automatic blood chemical
analyzer (CIBA Corning, Oberlin, OH, USA) and SICDIA NEFAZYME
(Shinyang Chemical, Seoul, Korea), respectively. Levels of serum
glucose and insulin were measured using an Accu-Chek Performa
System (Roche, Germany) and an insulin radioimmunoassay kit
(Linco, St. Charles, MO, USA), respectively. All animal experiments
were approved by the Institutional Animal Care and Use Com-
mittee of Mokwon University and were conducted according to
National Research Council Guidelines.
2.3. Histological analysis
Tissue specimens were fixed in 10% phosphate-buffered for-
malin for 1 day and embedded in paraffin. Tissue sections (5 μm)
were cut and stained with hematoxylin-eosin (HE) and toluidine
blue for microscopic examination. To quantify adipocyte size, the
HE stained sections of visceral adipose tissue were analyzed using
the Image-Pro Plus analysis system (Media Cybernetics, Bethesda,
MD, USA).
2.4. Immunohistochemistry
Blood vessel staining was performed using a blood vessel
staining kit (Chemicon, Billerica, MA, USA). Visceral adipose tissues
were fixed in 10% phosphate-buffered formalin for 1 day and
processed for paraffin sectioning. Sections of 3 μm thickness were
cut and irradiated in a microwave oven for epitope retrieval, and
then were sequentially incubated with rabbit anti-von Willebrand
factor (VWF) antibody as a primary antibody, goat anti-rabbit
antibody as a secondary antibody, and streptavidin-alkaline
phosphatase solution for visualization. A freshly prepared
 H. Lee et al. / Journal of Ethnopharmacology 178 (2016) 229–237 231

chromogen reagent was added to the sections for the visualization
of blood vessels. Blood vessel density was analyzed using the
Image area analyzer program and then normalized with the
number of adipocytes.
Infiltrated macrophages were detected using a monoclonal
mouse anti-CD68 antibody (ab955, Abcam, Cambridge, UK). Irra-
diated adipose tissue sections were incubated with a CD68 pri-
mary antibody (1:200 dilution), an anti-mouse IgG biotinylated
secondary antibody (Vector Laboratories, Burlingame, CA, USA),
and diaminobenzidine (Vector Laboratories) as a color substrate.
2.5. Zymography
MMP activity in the visceral adipose tissues was determined by
gelatin zymography. Adipose tissues were extracted with 10 mM
sodium phosphate buffer (pH 7.2) containing 150 mM NaCl, 1%
Triton X-100, 0.1% sodium dodecyl sulfate (SDS), 0.5% sodium
deoxycholate, and 0.2% NaN3 (250 mg wet weight tissue per 1 ml
buffer) at 4 °C. Adipose tissue extracts were mixed with zymo-
graphy sample buffer (63 mM Tris–HCl, pH 6.8, 10% glycerol, 2%
SDS, and 0.0025% bromophenol blue) without heat denaturation.
Electrophoresis was performed at 125 V in 10% SDS-poly-
acrylamide gels containing 0.1% gelatin. After electrophoresis, the
gels were incubated in renaturing buffer containing 0.25% Triton
X-100 for 30 min at room temperature and equilibrated in devel-
oping buffer (50 mM Tris-base, 40 mM HCl, 200 mM NaCl, 5 mM
CaCl2, and 0.2% Brij-35) for 30 min at room temperature. The gels
were then incubated in developing buffer overnight at 37 °C,
stained with 0.1% Coomassie Brilliant Blue R-250, and destained
with 10% acetic acid in 40% methanol. MMP activities were
quantified from gels using GeneGenius (Syngene, Cambridge, UK).
analyses are listed in Table 2. The conditions of PCR were a de-
naturing step at 95 °C for 5 min, followed by 50 cycles at 95 °C for
10 s, 60 °C for 40 s, and 72 °C for 10 s. The concentrations were
calculated as number of copies per one microliter using the stan-
dard curve and the relative expression levels were presented as
ratios of the target gene cDNA vs. β-actin cDNA.
2.7. Statistics
All values are expressed as mean 7standard deviation (SD).
Statistical analysis was performed by Tukey's Multiple Comparison
Test of One-Way ANOVA using SigmaPlotⓇ13 (SPSS Inc, Chicago,
IL, USA). Statistical significance was defined as a value of p o0.05.
3. Results
3.1. Effects of ginseng on body weight, adipose tissue mass, and
adipocyte size in OVX mice
OVX mice had higher body weight (Fig. 1A) and adipose tissue
mass (Fig. 1B) than Sham mice. However, ginseng-treated OVX
mice had 19% lower body weight and 31% lower total adipose
tissue weight compared with untreated OVX mice. Analysis of HE-
stained visceral adipose tissue sections revealed that the size of
adipocytes was lower in the ginseng-treated than untreated OVX
mice (Fig. 1C). The average size of adipocytes in OVX mice was
10,095 71318 μm2 whereas adipocyte size was 4764
OVX7467 μm2 in ginseng-treated OVX mice (Fig. 1D).
3.2. Effects of ginseng on angiogenesis in adipose tissue of OVX mice

2.6. Real-time PCR To determine whether the ginseng-mediated changes in adi-

Total cellular RNA from visceral adipose tissues was prepared
using the Trizol reagent (Gibco-BRL, Grand Island, NY, USA). An-
tisense primer cDNA was generated by reverse transcription of
2 μg of total cellular RNA using Moloney murine leukemia virus
reverse transcriptase. Synthesized cDNA fragments were amplified
using AccuPowers GreenStarTM qPCR PreMix (Bioneer, Deajeon,
Korea) on an ExcyclerTM 96 Real Time Quantitative Thermal Block
machine (Bioneer). The PCR primers used for gene expression
pose tissue mass resulted from angiogenesis inhibition, we studied
the effects of ginseng on blood vessel density in adipose tissue.
Staining of adipose tissue sections with an antibody against the
endothelial cell marker vWF showed that blood vessel density was
106% higher in OVX mice than in Sham mice (Fig. 2A and B).
However, ginseng treatment decreased the ovariectomy-induced
increases in blood vessel density by 54%.
The mRNA levels of angiogenic factors were downregulated in
ginseng-treated OVX mice compared with untreated OVX mice.

Table 2
Sequences of primers used for the real-time PCR assays.

Genes GeneBank Primer sequences Size (bp)

VEGF-A NM_001287056.1 Forward: 5′-gcagcttgagttaaacgaacg-3′ 94

Reverse: 5′-ggttcccgaaaccctgag-3′
FGF-2 NM_008006.2 Forward: 5′-ccaaccggtaccttgctatga-3′ 153
Reverse: 5′-ttcgtttcagtgccacatacca-3′
TSP-1 BC050971.1 Forward: 5′-tgttcaagaggaccgggct-3′ 75
Reverse: 5′-tggatgggtacatccagctcc-3′
MMP-2 M84324 Forward: 5′-agatcttcttcttcaaggaccggtt-3′ 225
Reverse: 5′-ggctggtcagtggcttggggta-3′
MMP-9 AY902320.1 Forward: 5′-gagctgtgcgtcttccccttc-3′ 204
Reverse: 5′-ggaatgatctaagcccagtgc-3′
TIMP-1 NM_001044384 Forward: 5′-ggcatcctcttgttgctatcactg-3′ 170
Reverse: 5′-gtcatcttgatctcataacgctgg-3′
TIMP-2 NM_021989 Forward: 5′-gagatcaagcagataaagatg-3′ 321
Reverse: 5′-gacccagtccatccagaggc-3′
CD68 NM_009853 Forward: 5′-aacaggacctacatcagagc-3′ 218
Reverse: 5′-ctgtagccttagagagagca-3′
TNF-α NM_013693 Forward: 5′-ggcaggtctactttggagtcattgc-3′ 300
Reverse: 5′-acattcgaggctccagtgaattcgg-3′
MCP-1 NM_011333 Forward: 5′-tgatcccaatgagtaggctggag-3′ 132
Reverse: 5′-atgtctggacccattccttcttg-3′
β-actin NM_007393.3 Forward: 5′-taccacaggcattgtgatgg-3′ 199
Reverse: 5′-tttgatgtcacgcacgattt-3′
232 H. Lee et al. / Journal of Ethnopharmacology 178 (2016) 229–237

Fig. 1. Effects of ginseng on body weight, adipose tissue mass and adipocyte size in ovariectomized C57BL/6J mice. Mice were sham-operated (Sham) or ovariectomized
(OVX) and then divided into three groups (n¼ 8/group): a Sham group given a high fat diet (Sham), an OVX group given a high fat diet (OVX), or an OVX group given a high
fat diet supplemented with ginseng extract (5% w/w) (OVX plus ginseng) for 15 weeks. (A) Body weight. (B) Total adipose tissue mass. (C) Histology of visceral adipocytes.
Representative HE-stained sections of visceral adipose tissues are shown (original magnification  100). (D) Size of visceral adipocytes. All values are expressed as mean 7SD.
#
p o 0.05 versus Sham group. *p o0.05 versus OVX group.

After ginseng administration, mRNA levels of vascular endothelial
growth factor A (VEGF-A) and fibroblast growth factor 2 (FGF-2)
were reduced by 32% and 24%, respectively, in visceral adipose
tissue of OVX mice (Fig. 2C).
3.3. Effects of ginseng on MMP activity in adipose tissue of OVX mice
Adipose tissue MMP activities were examined using zymo-
graphy on gelatin-containing gels. Gelatin zymography revealed
that the activities of proMMP-2 (68 kDa) and proMMP-9 (92 kDa)
were reduced by 60% and 91%, respectively, in the visceral adipose
tissue of ginseng-treated OVX mice compared with untreated OVX
mice (Fig. 3A and B).
MMP mRNA expression was also inhibited by ginseng treat-
ment in OVX mice. MMP-2 and MMP-9 mRNA levels were de-
creased by 21% and 56%, respectively, in the visceral adipose tissue
of ginseng-treated OVX mice (Fig. 3C). The mRNA levels of the
MMP inhibitor, tissue inhibitor of metalloproteinase-1 (TIMP-1)
and TIMP-2 were increased in ginseng-treated OVX mice com-
pared with untreated OVX mice.
3.4. Effects of ginseng on inflammation in adipose tissue of OVX mice
Adipose tissue inflammation was investigated using toluidine
 H. Lee et al. / Journal of Ethnopharmacology 178 (2016) 229–237 233

Fig. 2. Effects of ginseng on angiogenesis in adipose tissue. Mice were sham-operated (Sham) or ovariectomized (OVX) and then divided into three groups: a Sham group
given a high fat diet (Sham), an OVX group given a high fat diet (OVX), or an OVX group given a high fat diet supplemented with ginseng extract (5% w/w) (OVX plus ginseng)
for 15 weeks. (A) Representative sections stained with an antibody against von Willebrand factor (original magnification  100). The blood vessels in visceral adipose tissue
are shown. (B) Quantitative analysis of vessel densities. (C) The mRNA expression of genes involved in angiogenesis in visceral adipose tissue. All values are expressed as
mean 7 SD. *p o 0.05 versus OVX group.

blue and an anti-CD68 antibody. Compared with Sham mice, OVX
mice had higher levels of toluidine blue-detected mast cells
(Fig. 4A) and CD68-positive macrophages (Fig. 4B) in adipose tis-
sue. However, ginseng treatment decreased the levels of infiltrat-
ing mast cells and macrophages in the adipose tissue of OVX mice.
Gene expression analysis of the inflammatory genes showed that
ginseng-treated OVX mice had lower mRNA levels of CD68, tumor
necrosis factor α (TNFα), and monocyte chemoattractant protein 1
(MCP-1) in the adipose tissue of OVX mice (Fig. 4C).
3.5. Effects of ginseng on circulating levels of lipids, glucose, and
insulin in OVX mice
Serum free fatty acid and triglyceride levels were higher by 6%
and 27%, respectively, in OVX mice compared with Sham mice
(Table 3). However, serum free fatty acid levels decreased by 20%
and serum triglycerides levels decreased by 39% in ginseng-treated
OVX mice compared with those in untreated OVX mice. Ginseng
also reduced both serum insulin and glucose levels by 41% and
38%, respectively.
3.6. Effects of ginseng on hepatic lipid accumulation in OVX mice
Hepatic accumulation of lipids was evident in OVX mice
(Fig. 5). However, ginseng-treated OVX mice showed considerably
lower hepatic lipid accumulation than untreated OVX mice. The
triglyceride droplets in OVX mice almost completely disappeared
after ginseng treatment.
4. Discussion
Postmenopausal women accumulate more fat in their intra-
abdominal depot than do premenopausal women and therefore
have a greater risk of developing metabolic disorders associated
with obesity. For example, the prevalence of diabetes, dyslipide-
mia, hypertension, and coronary heart disease increases more ra-
pidly in aging women than in premenopausal women. OVX mice
mimic women in menopause and estrogen deficiency in mice
causes obesity and its associated complications including adipose
inflammation, hyperglycemia, and hepatic steatosis. Based on the
documented roles of ginseng on obesity and angiogenesis, we in-
vestigated whether ginseng regulates obesity and adipose in-
flammation in OVX mice and examined the mechanism of the
actions involved in this process. The present study demonstrates
that ginseng inhibited obesity, adipocyte hypertrophy and adipose
inflammation in HFD-fed OVX mice and that this process may be
mediated in part through the anti-angiogenic actions of ginseng.
A 15-week administration of HFD to OVX mice increased body
weight by 28% and adipose tissue mass by 90% compared with
HFD-fed Sham mice. These effects were prevented by ginseng.
234 H. Lee et al. / Journal of Ethnopharmacology 178 (2016) 229–237
Fig. 3. Effects of ginseng on MMP-2 and MMP-9 activity in adipose tissue. Mice
were sham-operated (Sham) or ovariectomized (OVX) and then divided into three
groups: a Sham group given a high fat diet (Sham), an OVX group given a high fat
diet (OVX), or an OVX group given a high fat diet supplemented with ginseng ex-
tract (5% w/w) (OVX plus ginseng) for 15 weeks. (A) Zymographic analysis of
visceral adipose tissue. Protein extracts from visceral adipose tissue were applied to
a gelatin-containing gel. Gelatinolytic activity was measured by zymography.
(B) Quantitative analysis of MMP-2 and MMP-9 activity. (C) The mRNA expression
of MMPs and their inhibitors in visceral adipose tissue. All values are expressed as
mean 7SD. #p o0.05 versus Sham group. *p o 0.05 versus OVX group.
Ginseng-treated OVX mice had a final body weight and adipose
tissue mass that were similar to Sham mice. The reduction in body
weight correlated with a decrease in adipose tissue mass. This
result is supported by reports that ginseng can modulate body
weight and adipose tissue mass in several animal models (in-
cluding ob/ob mice, HFD-fed Sprague Dawley rats, Balb/c mice, and
C57BL/6J mice) and can effectively regulate energy metabolism in
male animals (Attele et al., 2002; Kim et al., 2005; Karu et al.,
2007; Mollah et al., 2009; Lee et al., 2013). Taken together, our
results and reports in the literature indicate that ginseng acts as a
weight-stabilizer in both male and OVX mice. Ginseng also sig-
nificantly inhibited adipocyte hypertrophy in OVX mice. Consistent
with body weight and adipose tissue mass changes, the size of
visceral adipocytes was significantly decreased by ginseng in OVX
mice, eventually resulting in decreased adipose tissue mass and
the loss of body weight. Visceral obesity due to adipocyte hyper-
trophy is known to be closely associated with various metabolic
syndromes, including insulin resistance, with large adipocytes
being associated with insulin resistance and smaller adipocytes
associated with insulin sensitivity (Okuno et al., 1998; Jeong and
Yoon, 2009). Ginseng appears to alleviate insulin resistance due to
its ability to inhibit adipocyte hypertrophy in obese OVX mice.
Inhibition of angiogenesis and MMPs in growing adipose tissue
leads to the loss of adipose tissue mass and reduced body weight
in obese mice. Treatment with angiogenesis inhibitors has been
shown to result in weight reduction and adipose tissue loss, de-
monstrating that adipose tissue mass is sensitive to angiogenesis
inhibitors and can be regulated by the adipose tissue vasculature
(Rupnick et al., 2002; Bråkenhielm et al., 2004; Kim et al., 2010).
Similarly, treatment of obese mice with galardin, a synthetic MMP
inhibitor, leads to significant reductions in fat mass (Lijnen et al.,
2002). Moreover, both synthetic and endogenous MMP inhibitors
inhibit angiogenic responses (Stetler-Stevenson, 1999; Van Hul and
Lijnen, 2011). MMPs are essential regulators of various phases of
the angiogenic process, indicating the synergistic actions of an-
giogenesis and MMPs on the regulation of adipose tissue growth.
MMPs have been shown to influence endothelial cell survival and
proliferation by modifying the balance between angiogenic and
anti-angiogenic molecules (Gabison et al., 2003). Furthermore, it
has been reported that MMP-2 and MMP-9 indirectly stimulate
angiogenesis (Bergers et al., 2000; Park et al., 2001), suggesting
that obesity may be regulated by the synergistic actions of an-
giogenesis and MMPs.
Evidence also suggests that ginseng exerts anti-angiogenic ac-
tivities and as such, is a potential cancer chemopreventive agent
(Sato et al., 1994). For example, the active ginsenosides Rb1 and
Rb3 inhibit the early step in angiogenesis and chemoinvasion of
endothelial cells and suppress tumor metastasis, in part due to the
inhibition of angiogenesis (Sengupta et al., 2004; Yue et al., 2006).
The ginsenoside metabolite compound K exerts anti-angiogenic
activity by inhibiting the migration and tube formation of en-
dothelial cells (Jeong et al., 2010). Ginseng has also been reported
to decrease MMP activities; Rg3 inhibits MMP-2 and MMP-9
protein expression, and compound K suppresses MMP-9 protein
expression in endothelial cells and human astroglioma cells (Jung
et al., 2006; Yue et al., 2006; Xu et al., 2008; Jeong et al., 2010).
Recently, it was reported that ginseng, ginsenosides, and com-
pound K inhibit adipogenesis by decreasing angiogenesis and
MMP activity in 3T3-L1 cells (Oh et al., 2012; Park and Yoon, 2012),
suggesting that ginseng may reduce adipose tissue mass and body
weight gain in obese animals. Supporting this hypothesis, our
previous study demonstrated that ginseng regulated adiposity and
obesity in diet-induced obese male mice, in part by reducing an-
giogenesis and MMP activity in adipose tissue (Lee et al., 2013). In
our study, ovariectomy induced many more blood vessels and
higher MMP activity; however, ginseng significantly decreased
blood vessel density and MMP-2 and MMP-9 activities in OVX
mice. Blood vessel density in ginseng-treated OVX mice was
comparable to that in Sham mice. Moreover, MMP-2 and MMP-9
activities were lower in ginseng-treated OVX mice than in Sham
mice. These results suggest that ginseng regulates ovariectomy-
induced obesity and adiposity through its effects on adipose an-
giogenesis and MMP activity.
Adipose angiogenesis and MMP activities are regulated by a
number of angiogenic factors and inhibitors produced by adipose
tissues. Angiogenic factors, such as VEGF-A and FGF-2, promote
the proliferation and differentiation of endothelial cells within fat
tissue (Carmeliet et al., 1996; Kawaguchi et al., 1998), whereas TSP-
1 inhibits angiogenesis in vivo and impairs the migration and
proliferation of cultured microvascular endothelial cells (Arm-
strong and Bornstein, 2003). Adipocytes also produce MMPs and
MMP inhibitors that are differentially expressed in adipose tissue
during obesity (Bouloumié et al., 2001; Chavey et al., 2003). A
balance between MMPs and their inhibitors is presumed to control
 H. Lee et al. / Journal of Ethnopharmacology 178 (2016) 229–237 235

Fig. 4. Effects of ginseng on inflammation in adipose tissue. Mice were sham-operated (Sham) or ovariectomized (OVX) and then divided into three groups: a Sham group
given a high fat diet (Sham), an OVX group given a high fat diet (OVX), or an OVX group given a high fat diet supplemented with ginseng extract (5% w/w) (OVX plus ginseng)
for 15 weeks. (A) Representative toluidine blue-stained sections of visceral adipose tissue are shown (original magnification  400). (B) Representative sections stained with
an antibody against CD68 (original magnification  200). (C) The mRNA expression of inflammatory factors in visceral adipose tissue. All values are expressed as mean 7 SD. #
p o 0.05 versus Sham group. *p o 0.05 versus OVX group. (For interpretation of the references to color in this figure legend, the reader is referred to the web version of this
article.)

Table 3 the adipose inflammation. Hypertrophied adipocytes have been

Circulating levels of insulin, glucose, free fatty acids and triglycerides after ginseng found to secrete large amounts of inflammatory cytokines such as
treatment.
MCP-1, which stimulates macrophage infiltration in the adipose
Groups Insulin (ng/ml) Glucose Free fatty acids Triglycerides tissue of obese mice and humans (Xu et al., 2003; Curat et al.,
(mg/dl) (μRq/L) (mg/dl) 2004). Adipose tissue of lean individuals usually consists of ap-
proximately 5–10% macrophages, whereas macrophage content in
Sham 0.38 7 0.09 110 715 1752 7 158 987 9
adipose tissue can increase up to 50% of the total number of cells
OVX 0.617 0.14# 161 728# 1856 7 70 1357 12#
OVX þginseng 0.36 7 0.08* 100 724* 1493 7 112#,* 837 8*
in obese patients (Weisberg et al., 2003). OVX mice have larger
adipocytes relative to Sham mice. In agreement with these results,
Female mice were sham-operated (Sham) or ovariectomized (OVX) and then di- we observed that adipose inflammatory cells, including toluidine
vided into three groups (n¼ 8/group): a Sham group given a high fat diet (Sham), an blue-stained mast cells and CD68-positive macrophages, were
OVX group given a high fat diet (OVX) or an OVX group given a high fat diet
higher in OVX mice compared with Sham mice. However, ginseng
supplemented with ginseng extract (5% w/w) (OVX plus ginseng) for 8 weeks. All
values are expressed as the mean 7 SD. inhibited the infiltration of mast cells and macrophages into adi-
#
p o 0.05 versus Sham group. pose tissues. This result may be due to the ability of ginseng to
*
p o 0.05 versus OVX group. convert large adipocytes to smaller adipocytes by inhibiting an-
giogenesis. The inflammatory markers are directly related to in-
adipose tissue development and maintenance. OVX mice had flammation in obesity (Guilherme et al., 2008; Tilg and Moschen,
higher mRNA levels of VEGF-A compared with Sham mice. In re- 2008). Obese OVX mice exhibited increased expression of in-
sponse to ginseng treatment, OVX mice had less VEGF-A mRNA flammatory genes, such as CD68 and MCP-1, whereas the ex-
expression in adipose tissues. Similarly, ginseng decreased MMP-2 pression of these genes was decreased in the adipose tissues of
and MMP-9 mRNA levels. Our data indicate that ginseng exerts a ginseng-treated OVX mice. These results suggest that ginseng
specific regulatory effect on the genes involved in both angio- regulates obesity-associated adipose inflammation in OVX mice.
genesis and ECM remodeling in adipose tissues of OVX mice. It has been suggested that adipocyte dysfunctions that are due
The obese state is characterized by adipocyte hypertrophy and to adipocyte hypertrophy and inflammation cause obesity and
236 H. Lee et al. / Journal of Ethnopharmacology 178 (2016) 229–237

Fig. 5. Inhibition of hepatic lipid accumulation by ginseng. Mice were sham-operated (Sham) or ovariectomized (OVX) and then divided into three groups (n¼ 8/group): a
Sham group given a high fat diet (Sham), an OVX group given a high fat diet (OVX), or an OVX group given a high fat diet supplemented with ginseng extract (5% w/w) (OVX
plus ginseng) for 15 weeks. (A) Representative HE-stained sections of liver are shown (original magnification  100). (B) Histological analyses of hepatic lipid accumulation.
Pathological scores of hepatic lipid accumulation are as follows: 0, no lesion; 1, mild; 2, moderate; 3, severe; 4, very severe. All values are expressed as mean 7SD. *p o 0.05
versus OVX group.

related disorders such as insulin resistance, type 2 diabetes and
hepatic steatosis (Guilherme et al., 2008; Ludgero-Correia et al.,
2012). Large adipocytes and infiltrating macrophages secrete in-
flammatory adipokines, which lead to chronic inflammation with
impaired triglyceride deposition and increased lipolysis. The in-
creases in circulating triglycerides and free fatty acids cause the
accumulation of activated lipids in skeletal muscle, liver and
pancreatic β-cells, thus resulting in the development of insulin
resistance. Ovariectomy increased circulating triglycerides, and
induced lipid accumulation, whereas ginseng improved dyslipi-
demia and hepatic triglyceride accumulation in obese OVX mice.
These results suggest that ginseng is an effective drug for the
prevention and treatment of hypertriglyceridemia and hepatic
steatosis in obese postmenopausal women. Importantly, the de-
velopment of the inflammatory state in adipose tissue is asso-
ciated with insulin resistance. Moreover, molecules produced hy-
pertrophic adipocytes in obesity cause insulin resistance (Okuno
et al., 1998; Jeong and Yoon, 2009). Insulin resistance refers to the
impairment in the actions of insulin in insulin-target tissues, such
as skeletal muscle, liver, and adipocytes, which results in the hy-
perglycemia. In insulin-resistant states, pancreatic islet β cells
usually respond by increasing insulin secretion to maintain normal
blood glucose levels (Prentki and Nolan, 2006). Expansion of β cell
mass has been observed in obese and rodents compared with lean
nondiabetic subjects (Butler et al., 2003), consequently leading to
high levels of both circulating insulin and glucose. Obese OVX mice
exhibited hyperinsulinemia and hyperglycemia. Along with the
decreased expression of inflammatory markers in adipose tissue,
ginseng significantly decreased both blood glucose and insulin
levels in OVX mice.
5. Conclusion
Ginseng significantly reduced ovariectomy-induced increases
in body weight, adipose tissue mass, and adipocyte size by in-
hibiting angiogenesis and MMP activity. Hepatic steatosis and
hypertriglyceridemia were improved as consequences of ginseng-
induced weight reduction in obese OVX mice. Ginseng also sup-
pressed adipose inflammation, resulting in amelioration of hy-
perinsulinemia and hyperglycemia. Thus, it is likely that the anti-
angiogenic properties of ginseng may be used to effectively reg-
ulate obesity and metabolic disorders in estrogen-deficient states
such as menopause.
Conflict of interest
None declared.
Acknowledgments
This work was supported by the National Research Foundation
of Korea (NRF) Grants funded by the Korea Government
(MEST) (2012R1A1A3002100, 2012R1A2A2A01004508, and
2015R1A1A3A04001016), Korea.
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