Nutrition Research and Practice (Nutr Res Pract) 2011;5(3):198-204
Herbal extract THI improves metabolic abnormality in mice fed a high-fat diet
Sora Han1, Ki Sook Oh1, Yoosik Yoon2, Jeong Su Park1, Yun Sun Park1, Jeong Hye Han1, Ae Lee Jeong1,
Sunyi Lee1, Miyoung Park1, Yeon A Choi1, Jong Seok Lim1 and Young Yang1§
1Department of Biological Science, Sookmyung Women's University, Cheongpa-ro 47-gil 100, Yongsan-gu, Seoul 140-742, Korea
2Department of Microbiology, College of Medicine, Chung-Ang University, Seoul 156-756, Korea
Target herbal ingredient (THI) is an extract made from two herbs, Scutellariae Radix and Platycodi Radix. It has been developed as a treatment
for metabolic diseases such as hyperlipidemia, atherosclerosis, and hypertension. One component of these two herbs has been reported to have
anti-inflammatory, anti-hyperlipidemic, and anti-obesity activities. However, there have been no reports about the effects of the mixed extract of
these two herbs on metabolic diseases. In this study, we investigated the metabolic effects of THI using a diet-induced obesity (DIO) mouse model.
High-fat diet (HFD) mice were orally administered daily with 250 mg/kg of THI. After 10 weeks of treatment, the THI-administered HFD mice
showed reduction of body weights and epididymal white adipose tissue weights as well as improved glucose tolerance. In addition, the level of
total cholesterol in the serum was markedly reduced. To elucidate the molecular mechanism of the metabolic effects of THI in vitro, 3T3-L1 cells
were treated with THI, after which the mRNA levels of adipogenic transcription factors, including C/EBPα and PPARγ, were measured. The results
show that the expression of these two transcription factors was down regulated by THI in a dose-dependent manner. We also examined the combinatorial
effects of THI and swimming exercise on metabolic status. THI administration simultaneously accompanied by swimming exercise had a synergistic
effect on serum cholesterol levels. These findings suggest that THI could be developed as a supplement for improving metabolic status.
Key Words: Triglyceride, baicalin, glucose tolerance, exercise
Platycodi Radix has long been used as an expectorant in
traditional Oriental medicine. Recently, it was reported that
Platycodi Radix has anti-inflammatory, anti-allergy, anti-tumor,
apoptosis-inducing, and immune-stimulating activities [1-4]. Several
reports have also shown that platycodin saponins, a major
component of Platycodi Radix, have beneficial effects on the
treatment of metabolic disorders, including obesity and hyperli-
pidemia . Platycodi Radix has been found to reduce hepatic
and serum triglyceride levels in Sprague-Dawley rats fed a
high-fat diet (HFD)  as well as inhibit adipogenesis by modulating
kruppel-like factor 2 (KLF2) and peroxisome proliferator-activated
receptor γ (PPAR-gamma) .
Scutellariae Radix has also been widely used for the clinical
treatment of hyperlipidemia, atherosclerosis, and hypertension in
East Asian countries, including China, Korea, and Japan. The
active component of Scutellariae Radix is baicalin, which is well
known as an anti-inflammatory and antioxidant agent [8-10].
Baicalin inhibits adipogenesis through the downregulation of
pro-adipogenic genes, including PPARγ, C/EBPα, and KLF15,
as well as the upregulation of anti-adipogenic regulators,
including C/EBPγ and KLF2 . It was also reported that
baicalin exerts an anti-adipogenic effect through the maintenance
of β-catenin expression, which is reduced during normal
Although Platycodi Radix and Scutellariae Radix show
anti-adipogenic effects, studies have not been performed on the
combinatorial effects of Platycodi Radix and Scutellariae Radix
on metabolic disease. Thus, we examined the metabolic effects
of a mixture of Platycodi Radix and Scutellariae Radix using
a diet-induced obesity model.
Materials and Methods
Chemicals and reagents
Cell culture reagents were obtained from Life Technologies
(Grand Island, NY, USA). Anti-C/EBPα and anti-C/EBPβ antibodies
were purchased from Santa Cruz Biotechnology (Santa Cruz, CA,
USA). Anti-PPARγ antibody and secondary antibody were purchased
from Cell Signaling (Beverly, MA, USA). Other chemicals were
purchased from Sigma-Aldrich (St. Louis, MO, USA).
This work was supported by the Biogreen 21 project (20070301034031) of Rural Development Administration and Sookmyung Women’s University 2009.
§Corresponding Author: Young Yang, Tel. 82-2-710-9590, Fax. 82-2-2077-7322, firstname.lastname@example.org
Received: December 24, 2010, Revised: April 6, 2011, Accepted: April 8, 2011
ⓒ2011 The Korean Nutrition Society and the Korean Society of Community Nutrition
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/)
which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Sora Han et al.
Animals and experimental groups
All animals were obtained from the Korea Research Institute
of Bioscience and Biotechnology, Daejoen, Korea. Seven-week-
old C57BL/6 male mice were subdivided, acclimatized for 1
week, and divided randomly into five groups: (1) sedentary,
normal diet, and vehicle treatment (ND-Veh), (2) sedentary,
high-fat diet, and vehicle treatment (HFD-Veh), (3) sedentary,
high-fat diet, and THI treatment (HFD-THI), (4) exercise,
high-fat diet, and vehicle treatment (E/HFD-Veh), and (5)
exercise, high-fat diet, and THI treatment (E/HFD-THI). Bedding
was changed once a week, and the temperature and humidity
were controlled. Mice were housed under 12 hr light/12 hr dark
conditions. The plans and protocols for animal experiments were
approved by the Institutional Animal Care and Use Committee
of Sookmyung Women’s University, Seoul, Korea.
Preparation of herbal mixture
The roots of Platycodon grandiflorum and Scutellariae
baicalensis were obtained from Namil Farm & Ginseng Co.
(Geumsam, Korea); voucher specimens were preserved at
Chug-Ang University College of Medicine, Seoul, Korea (No.
2009.11-12). The two herbs were mixed in a 1:1 ratio and
extracted with 70% ethanol. The extract was concentrated by
evaporating solvent under low pressure conditions. The final
yield of extract compared with raw herbal material was 25%
Diet and THI treatment
Purina Diet (Koatech, Seoul, Korea) was provided to mice in
the normal diet group, whereas a pellet rodent diet with 60%
K cal fat (Central Lab. Animal Inc., Seoul, Korea) was provided
for 10 weeks to the HFD group. Each mouse was administered
25 mg of THI orally, as determined in previous studies. For the
vehicle treatment group, the same volume of distilled water was
administered orally every day for 10 weeks by the same method
used for THI treatment. Each group comprised six mice, and
all mice were allowed free access to the described diet and water
during experimental periods. Body weights and food intake were
measured weekly at regular times.
Tissue preparation and blood chemistry
Mice were dissected to collect tissues for analysis. Blood was
collected from the retro-orbital sinus by using sodium-heparinized
microhaematocrit capillary tubes (Marienfeld-superior, Lauda-
Königshofen, Germany) and then transferred to Eppendorf tubes
and incubated at room temperature. After 3 hr, all samples were
centrifuged at 13,500 rpm for 5 min, after which serum was taken
to measure triglyceride, glucose, and total cholesterol levels using
an automatic blood chemistry analyzer Dry-Chem 4000i (Fujifilm,
Saitama, Japan) at the Yonsei Laboratory Animal Research
For exercise experiments, exercise groups of HFD mice were
divided into two groups. One group was subjected to exercise
without administration of THI while the other group was
subjected to swimming exercise with oral administration of 25
mg of THI to each mouse. Mice underwent compulsory
swimming exercise at 9:00 am and 5:00 pm twice a day, 5 days
per week for 10 weeks. In the first week, mice swam voluntarily
for 40 min, and this time was increased gradually up to 60 min
for intensification of exercise. Mice swam at 31℃ in a
temperature-controlled water bath, and the water bath was
cleaned once a week.
Total RNA samples were prepared by homogenizing epididymal
tissues and liver tissues with 500 μL of RNA iso-plus (Takara,
Shiga, Japan). Prepared total RNAs were reverse-transcribed
using M-MuLV reverse transcriptase (Promega, Madison, WI,
USA) at 37℃ for 1 hr. PCR for amplification of mRNAs
encoding hormone-sensitive lipase (HSL), adipose triglyceride
lipase (ATGL), mitochondrial uncoupling protein 2 (UCP2), and
carnitine palmitoyltransferase 1a (CPT1a) was performed using
appropriate primer pairs: ATGL forward, 5’-CTCCGAGAGATG
TGCAAACA-3’, reverse, 5’-CAGTTCCACCTGCTCAGACA-3’;
HSL forward, 5’-CTTCCTGCAAGAGTATGTCACG-3’, reverse,
5’-TGGAGGTGAGATGGTGACTG-3; UCP2 forward, 5’-CTG
GCAGGTAGCACCACAGGTG-3’, reverse, 5’-GCATGGTAAG
GGCACAGTGAC-3’; CPT1a forward, 5’-GTCTGGAATCAAC
TCCTGGAAG-3’, reverse, 5’-CAGTGACGTTGGAAGCTGTA
G-3’. RT-PCR products were visualized by 1% agarose gel
electrophoresis, and the intensity of the bands was measured
using a DNR Bio-Imaging system (Kiryat Anavim, Jerusalem,
Oral glucose tolerance test (OGTT)
Mice were fasted for 14 hr before experiments, and D-glucose
(Duchefa Biochemie, Haarlem, Netherlands) was administered to
mice at a dose of 1 g per kg of body weight. Glucose level
of the blood taken from the tail vein was measured using
Accu-Chek (Roche Diagnostics, Basel, Switzerland) at 30 min
intervals for 120 min.
The 3T3-L1 cells were purchased from the American Type
Culture Collection (Manassas, VA, USA). Two days after reaching
confluence (day 0), 3T3-L1 cells were cultured in Dulbecco’s
THI improves metabolic abnormality
Fig. 1. THI administration reduces body weight in the diet-induced obesity (DIO)
model. (A) Body weight changes were measured once a week, and mice were
photographed after 10 weeks. HFD-Veh, high-fat diet with water administration;
ND-Veh, normal diet with water administration; HFD-THI, high-fat diet with THI
administration. *P < 0.05 and **P < 0.01 indicate statistical significance between the
HFD-Veh and HFD-THI groups. (B) Food intake per mouse per day was measured.
Data show average food intake over 10 weeks. All values are given as mean ±
SEM (n = 7) for all groups.
Modified Eagle’s Medium (DMEM) containing 1 μg/mL of
insulin, 0.25 μM dexamethasone, 0.5 mM 3-isobutyl-1-methyl-
xanthine, and 10% fetal bovine serum (differentiation induction
medium) for 2 days. Cells were then maintained in DMEM
containing 1 μg/mL of insulin and 10% fetal bovine serum
(differentiation maintenance medium). The differentiation
maintenance medium was changed every 2 days until the cells
were harvested on day 7. To test the effects of THI on
adipogenesis, various concentrations of THI were added to the
differentiation induction and maintenance media until cells were
harvested. Differentiated cells in each well of 6-well plates were
harvested in 500 μL of phosphate-buffered saline (PBS), frozen,
and then sonicated. The triglyceride contents of the cell lysates
were measured using a TG-S reaction kit (Asan Pharm., Seoul,
Korea). Lipid droplets in cells were stained with Oil Red O,
as previously described .
Protein extraction and Western blotting
Cultured and differentiated cells were harvested using a cell
scraper and lysed with ice-cold RIPA buffer containing 25 mM
Tris-HCl, pH 7.6, 150 mM NaCl, 1% Nonidet P-40, 1% sodium
deoxycholate, 0.1% SDS, and a protease inhibitor cocktail
(Sigma-Aldrich). The total cell lysates were centrifuged at 14,000
rpm for 20 min at 4℃ to remove insoluble materials. The protein
concentrations were determined using a BCA protein assay kit
(Pierce, Rockford, IL, USA). Fifty micrograms of protein extract
was resolved by 10% SDS-polyacrylamide gel electrophoresis
at 150 mA for 1 hr and then transferred to nitrocellulose
membranes. The membranes were next blocked for 2 hr at room
temperature with PBS containing 5% skim milk and 0.1% Tween
20, incubated with 1:1,000-dilutions of primary antibodies
overnight at 4℃, and then with horseradish peroxidase-conjugated
anti-rabbit secondary antibody for 1 hr at room temperature.
Peroxidase activity was visualized using an ECL kit (Pierce,
Rockford, IL, USA).
Statistical analysis was performed using SPSS statistical
software. When differences among the groups were detected by
one-way factorial ANOVA, Turkey’s test was used. A level of
significance of P<0.05 was chosen for all statistical comparisons.
Data are presented as means ± SEM.
Effects of THI on body weight and food intake
Many herbal extracts were screened for the inhibition of fat
accumulation in 3T3-L1 cells (data not shown). Two herbs,
Scutellariae Radix and Platycodi Radix, were finally selected due
to their strong activities. In this study, we examined the effects
of the mixed extract of these two herbs, named THI, on metabolic
abnormality in mice fed a high-fat diet. There are two types of
obesity animal models available. One includes genetic models
such as the leptin-deficient ob/ob mouse model and the leptin
receptor deficient db/db mouse model. The other type includes
the DIO model. In this study, we used the DIO model to
determine the effects of THI on obesity since DIO is an
experimental model with much higher applicability to human
obesity. Mice were subdivided into three groups: the normal diet
group with vehicle treatment, the 60% HFD group with vehicle
treatment, and the 60% HFD group with THI treatment. There
were significant differences in body weight between the HFD
and normal diet groups from the first week of the experiment.
The THI-administered mice showed a more modest increase in
size and body weight than did the HFD group, although food
intake was the same for both groups (Fig. 1A and 1B).
Weight of epididymal white adipose tissue was highly
increased in the HFD group compared with the normal diet group,
Sora Han et al.
Fig. 2. THI administration decreases weights of epididymal adipose tissues. (A)
Weights of two epididymal adipose tissues were measured after 10 weeks of high-fat
diet and expressed as g/100 g of body weight. (B) Whole liver weights were
measured and expressed as g/100 g of body weight. **P< 0.01 indicates statistical
significance between HFD-Veh, high-fat diet with water administration and HFD-THI,
high-fat diet with THI administration. All values are given as mean ±SEM (n= 7)
for all groups.
Fig. 3. THI reduces total cholesterol levels. (A) Serum triglyceride levels were measured (n = 7). (B) Serum total cholesterol levels were measured (n= 7). (C-F) Relative
expression levels of hormone-sensitive lipase (HSL), adipose triglyceride lipase (ATGL), mitochondrial uncoupling protein 2 (UCP2), and carnitine palmitoyltransferase 1a (CPT1a)
mRNA in epididymal white adipose tissues and skeletal muscle tissues were determined using RT-PCR (n = 3). Values are given as mean ±SEM **P < 0.01.
Fig. 4. THI reduces adipogenic differentiation of 3T3-L1 cells in vitro. (A)
Intracellular fat droplets in 3T3-L1 cells were stained with Oil red O dye after
adipogenic differentiation for 7 days. (B) Intracellular fat content was compared in
3T3-L1 cells after treatment with various concentrations of THI. (C) Protein
expression levels of adipogenic transcription factors, C/EBPα, C/EBPβ, and PPAR
γ, were measured in 3T3-L1 cells. β-actin was used as a loading control. *P <
0.05, **P < 0.01, ***P < 0.001 compared with untreated sample.
and the THI-administered HFD group showed a significant
decrease in adipose tissue weight by as much as 40% compared
with the HFD group (Fig. 2A). However, liver tissue weights
were not significantly different among the three groups (Fig. 2B).
Effects of THI on serum levels of triglycerides, total cholesterol,
Since THI administration reduced adipose tissue weight, we
wondered whether or not THI could induce changes in the serum
levels of triglycerides and total cholesterol. The level of total
cholesterol was lower compared with the HFD group (Fig. 3A
and 3B), whereas the triglyceride level was not reduced to a
statistically significant level. Next, to determine whether or not
administration of THI enhances energy expenditure, total RNA
was isolated from epididymal white adipose tissues. The mRNA
THI improves metabolic abnormality
Fig. 5. THI administration improves glucose tolerance. Mice were fasted for 14
hr before OGTT. Blood glucose levels were measured every 30 min for 120 min,
and relative areas under curves (AUC) were calculated. Data are expressed as mean
±SEM (n = 7). *P < 0.05, **P < 0.01, ***P < 0.001 indicate statistical significance
between HFD-Veh, high-fat diet with water administration and HFD-THI, high-fat diet
with THI administration groups.
Fig. 6. THI administration with swimming exercise synergistically decreases total serum cholesterol levels. (A) Body weight changes were measured 10 weeks after
high-fat diet (S/HFD-Veh, sedentary high-fat diet with water administration), swimming exercise (E/HFD-Veh, exercising high-fat diet with water administration), and combination
of THI administration and swimming exercise (E/HFD-Veh, exercising high-fat diet with THI administration) (n = 7 for each group). (B) Food intake per mouse per day was
measured. (C) Epididymal white adipose tissue weight was measured and expressed as g/100 g of body weight. ***P < 0.001 indicates statistical significance of each group
versus the S/HFD-Veh group. (D) Serum triglycerides levels were measured (n = 5). (E) Total serum cholesterol levels were measured (n = 5). ***P < 0.001 indicates statistical
significance between indicated groups. (F) Oral glucose tolerance test was performed (n = 7, left), and relative areas under curves (AUC) were calculated. All values are given
as mean ±SEM.
levels of hormone-sensitive lipase (HSL) and adipose triglyceride
lipase (ATGL), which are involved in the mobilization of free
fatty acids from adipose triacylglycerol stores, were analyzed by
RT-PCR. There was no significant increase in HSL and ATGL
mRNA expression (Fig. 3C). The mRNA levels of mitochondrial
uncoupling protein 2 (UCP2) and carnitine palmitoyltransferase
1a (CPT1a), which are responsible for energy expenditure, were
also analyzed by RT-PCR. The levels of UCP2 and CPT1a
mRNA in adipose and muscle tissues were not changed
statistically (Fig. 3E and 3F).
THI was also found to inhibit Oil red O-stained fat droplet
formation, which is a marker of adipogenesis, during adipogenic
differentiation of 3T3-L1 cells in vitro (Fig. 4A). THI also
significantly reduced the intracellular fat content in a dose-
dependent manner (Fig. 4B). To elucidate the molecular mechanism
of THI action in vitro, the expression levels of major transcription
factors of adipogenesis were analyzed. It was found that THI
downregulated the expression of C/EBPα and PPARγ, whereas
C/EBPβ levels were not changed (Fig. 4C).
Next, we performed an oral glucose tolerance test. All groups
of mice were fasted during the night cycle, and glucose was orally
injected 14 hr after starvation. Blood glucose levels were
measured at the indicated time points. The THI-administered
group showed improved oral glucose tolerance compared with
the HFD group, although the glucose tolerance of the
THI-administered group was not improved to the levels of the
normal diet group (Fig. 5).
Effect of exercise on the THI-administered HFD group
Since it is well-known that exercise effectively improves the
metabolic index, we examined whether or not THI administration
Sora Han et al.
could act synergistically with exercise. The HFD group was
orally administered with THI and subjected to swimming exercise
for 10 weeks or swimming exercise without THI administration.
Exercise induced dramatic weight loss in the THI-administered
high-fat group (Fig. 6A) but did not alter the amount of food
intake (Fig. 6B). Weight loss in the THI-administered exercised
group was due to the dramatic reduction of adipose tissue (Fig.
6C) and triglyceride levels (Fig. 6D). The simultaneous combina-
tion of exercise and THI administration induced lower levels of
total cholesterol compared with the group that only exercised
(Fig. 6E). These results indicate that the simultaneous combinat-
ion of exercise and THI administration has a synergistic effect
on the reduction of total cholesterol levels and that THI does
not affect the beneficial effect of exercise. In addition, the results
also confirm an improvement in fasting blood glucose levels and
oral glucose tolerance (Fig. 6F).
Herbal extracts have been widely used for the treatment of
metabolic diseases, including obesity, type II diabetes, and
hyperlipidemia. The effects of THI on metabolic diseases were
examined using a DIO mouse model. In our system, although
the concentration of THI required for inhibition of adipogenesis
was quite high in vitro, potent THI metabolite was generated
in vivo and thus may be involved in the reduction of adipose
tissue. It is also conceivable that the reduction of body weight
was due to reduced adipose tissue weight, as THI effectively
inhibited adipogenesis in 3T3-L1 preadipocytes through the
downregulation of C/EBPα and PPARγ, which are the main
transcription factors involved in adipogenesis. We also examined
the possibility that THI reduced adipose tissue weight through
increased fatty acid oxidation. However, the levels of HSL,
ATGL, UCP-2, and CPT1a, which are involved in lipid
mobilization and fatty acid oxidation, were not significantly
changed. However, we cannot rule out the possibility that THI
increases the consumption of fatty acids through another
mechanism involving PPARδ or AMPK activation, as reduced
adipogenesis could increase the level of fatty acids.
The anti-obesity effects of many natural compounds are
reported to be mediated by inhibition of adipogenesis. For
instance, epigallocatechin gallate (EGCG), genistein, esculetin,,
berberine, resveratrol, guggulsterone, conjugated linoleic acid,
capsaicin, baicalein, and procyanidins are all reported to inhibit
adipogenesis . Among these, genistein, EGCG, and capsaicin
have been shown to inhibit adipogenesis by activating AMP-
activated protein kinase , and resveratrol was reported to
increase the expression of sirtuin 1, a gene that represses expression
of PPARγ . It may be very difficult to identify every
molecular target of a multi-component herbal composition like
THI, but the combined effects of its diverse actions are clearly
the downregulation of PPARγ and C/EBPα, major transcription
factors, as shown in Fig. 4C. PPARγ, a transcription factor of
the nuclear-receptor superfamily, is known to be the master
regulator of adipogenesis since it is both necessary and sufficient
for adipogenesis . The expression of PPARγ alone has been
shown to induce adipogenesis in fibroblasts . PPARγ is also
known to induce the expression of C/EBPα by binding to its
promoter region , and the THI-induced reduction of C/EBPα
expression may be the result of decreased PPARγ expression.
The results of this study suggest that the combined effects of
THI are mediated through the downregulation of the major
transcription factors of adipogenesis, PPARγ and C/EBPα.
Orally administered THI markedly reduced serum cholesterol
levels and fasting glucose levels while improving glucose
tolerance. Reportedly, Scutellariae Radix contains wogonin, a
flavone that is known to have anxiolytic properties in mice 
and potentiate the anti-tumor action of etoposide by ameliorating
adverse effects . However, there has been report that
Scutellariae Radix has any anti-adipogenic effects. On the other
hand, Scutellariae Radix contains baicalin , which is known
to exhibit anti-inflammatory activity by binding to chemokines
 or by inhibiting NF-kB . Baicalin suppresses lung
carcinoma and lung metastasis by SOD mimic and HIF-1alpha
inhibition  and exerts anti-adipogenic functions through the
maintenance of β-catenin expression . Therefore, the
observed effects of the THI extracts, such as loss of body weight
and improved glucose tolerance, may be attributed to baicalin.
Although platycodin saponins are known to ameliorate obesity
and hyperlipidemia  as well as reduce serum triglyceride levels
in HFD rats , the administration of THI-containing platycodin
saponins did not result in decreased serum triglyceride levels.
In the case of cholesterol, the exercised THI-administered
high-fat group showed a decrease in cholesterol levels compared
with the exercised high-fat group. This implies that when exercise
and THI administration are performed simultaneously, the
metabolic index can be improved compared to that obtained with
only THI administration. Although it was reported that swimming
exercise does not significantly increase glucose uptake in isolated
skeletal muscles , swimming exercise alone or in combination
with THI administration markedly improved HFD-induced
glucose intolerance in vivo.
In conclusion, THI administration effectively reduced body
weight, improved cholesterol level typically increased by a HFD,
decreased fasting glucose levels, and enhanced glucose tolerance.
Exercise training combined with THI administration also
synergistically enhanced the effect of THI on cholesterol levels.
These results show that THI has potential as a powerful health
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