Synergistic Effect of Bupleuri Radix and Scutellariae Radix on Adipogenesis and AMP-Activated Protein Kinase: A Network Pharmacological Approach

Lee, Jueun; Park, Jinbong; Park, Hyewon; Youn, Dong-Hyun; Lee, Jaehoon; Hong, Seokbeom; Um, Jae-Young

doi:https://doi.org/10.1155/2018/5269731

Evidence-Based Complementary and Alternative Medicine

On this page

Abstract Introduction Materials and Methods Results Discussion Conclusion Data Availability Conflicts of Interest Authors’ Contributions Acknowledgments References Copyright Related Articles

Special Issue

Diabetes and Metabolism Disorders Medicinal Plants: A Glance at the Past and a Look to the Future 2018

View this Special Issue

Research Article | Open Access

Volume 2018 | Article ID 5269731 | https://doi.org/10.1155/2018/5269731

Synergistic Effect of Bupleuri Radix and Scutellariae Radix on Adipogenesis and AMP-Activated Protein Kinase: A Network Pharmacological Approach

Jueun Lee,¹Jinbong Park,^1,2Hyewon Park,³Dong-Hyun Youn,^1,2Jaehoon Lee,⁴Seokbeom Hong,⁴and Jae-Young Um^1,2

Academic Editor: Hilal Zaid

Received20 Apr 2018

Revised11 Jul 2018

Accepted26 Jul 2018

Published23 Aug 2018

Abstract

Obesity has become a major health threat in developed countries. However, current medications for obesity are limited because of their adverse effects. Interest in natural products for the treatment of obesity is thus rapidly growing. Korean medicine is characterized by the wide use of herbal formulas. However, the combination rule of herbal formulas in Korean medicine lacks experimental evidence. According to Shennong’s Classic of Materia Medica, the earliest book of herbal medicine, Bupleuri Radix (BR) and Scutellariae Radix (SR) possess the Sangsoo relationship, which means they have synergistic features when used together. Therefore these two are frequently used together in prescriptions such as Sosiho-Tang. In this study, we used the network pharmacological method to predict the interaction between these two herbs and then investigated the effects of BR, SR, and their combination on obesity in 3T3-L1 adipocytes. BR, SR, and BR-SR mixture significantly decreased lipid accumulation and the expressions of two major adipogenic factors, peroxisome proliferator-activated receptor-gamma (PPARγ) and CCAAT/enhancer-binding protein-alpha (C/EBPα), and their downstream genes, Adipoq, aP2, and Lipin1 in 3T3-L1 cells. In addition, the BR-SR mixture had synergistic effects compared with BR or SR on inhibition of adipogenic-gene expressions. BR and SR also inhibited the protein expressions of PPARγ and C/EBPα. Furthermore, the two extracts successfully activated AMP-activated protein kinase alpha (AMPK α), the key regulator of energy metabolism. When compared to those of BR or SR, the BR-SR mixture showed higher inhibition rates of PPARγ and C/EBPα, along with higher activation rate of AMPK. These results indicate a new potential antiobese pharmacotherapy and also provide scientific evidence supporting the usage of herbal combinations instead of mixtures in Korean medicine.

1. Introduction

The epidemiology of obesity is constantly increasing, becoming a health threat all over the world. The World Health Organization has reported that over 1.4 billion adults worldwide are overweight (BMI ≥ 25 kg/m²) or obese (BMI ≥ 30 kg/m²) [1]. However, there are only 5 treatments (orlistat, lorcaserin, liraglutide, phentermine/topiramate, and bupropion/naltrexone) approved by the United States Food and Drug Administration. Despite their efficacies, adverse effects of these drugs lead to search for other options [2].

Obesity is caused by a simple process: when energy intake exceeds expenditure, the excess energy is saved in as a form of lipid. On the other hand, in the perspective of selecting treatments, there are more than pathways to resolve this metabolic syndrome. Pharmacological approach for obesity treatment can be subcategorized into two methods: inhibiting lipid accumulation or consuming accumulated lipids. Former method inhibits lipid accumulation in adipose tissues by decreasing appetite, lowering fat absorption, and inhibiting adipogenesis, and the latter is by increasing energy expenditure via fatty acid oxidation or brown adipose tissue- (BAT-) related thermogenesis [3]

Network pharmacology is a system biology-based methodology for pharmacological research [4, 5]. Network pharmacological research replaces the dominant paradigm of drug design based on “one gene, one drug, one disease,” into multitarget drugs that act on biological networks. These unique characteristics of network pharmacology expand the potential use of traditional herbal medicine including Korean medicine, Japanese Kampo medicine, and Traditional Chinese Medicine [6]. In this premise, as obesity is a multipathway-involved disease, and the multicomponent-multitarget herbal drugs may provide an answer to its treatment.

Bupleuri Radix (BR) and Scutellariae Radix (SR) are both components of Sosiho-Tang, a traditional Korean herbal formula which is originally used to treat chronic herbal diseases. The antiobese effect of Sosiho-Tang is reported in a study using 3T3-L1 adipocytes and high fat diet- (HFD-) induced obese C57BL/6J mice [7]. In the current study, Yoo et al. show Sosiho-Tang can inhibit adipogenesis by suppressing CCAAT/enhancer-binding protein-alpha (C/EBPα) and peroxisome proliferator-activated receptor-gamma (PPARγ), two key regulators of adipogenesis in vivo and in vitro. Furthermore, other studies demonstrate that BR can attenuate obesity in rats by regulating adipogenic factors [8], while its active compound saikosaponin A inhibits inflammatory markers in adipocytes [9]. Several reports also demonstrate the antiobese and antiadipogenic effect of SR [10] and its active compounds such as baicalin [11–14], baicalein [15, 16], and wogonin [17–19].

Based on these studies, we expected that BR and SR are the major components of Sosiho-Tang responsible for antiobese effects. They are used for specific types of obesity patients after diagnosis by a Korean medicine practitioner, and, in addition, several experimental studies also report the possibility. According to Shennong’s Classic of Materia Medica, a classic of oriental medicine introducing 365 kinds of herbs and their features [20], BR and SR are Sangsoo (synergistic) pairs. As a pair of Sangsoo (synergism), our hypothesis herein is that BR and SR may show synergistic effects in obesity-related mechanisms. Therefore, in this study, we evaluate the synergistic potential between BR and SR by the network pharmacological approach and assess their effects on obesity by investigating related mechanisms.

2. Materials and Methods

2.1. Reagents

3-Isobutylmethylxanthine (IBMX), dexamethasone (Dex), and Insulin were purchased from Sigma Chemicals (St Louis, MO, USA). Dulbecco’s modified Eagle’s medium (DMEM), penicillin-streptomycin, bovine serum (BS), and fetal bovine serum (FBS) were purchased from Gibco BRL (Grand Island, NY, USA).

2.2. Preparation of Water Extracts of BR and SR

BR (the root of Bupleurum falcatum Linne) and SR (the root of Scutellaria baicalensis Georgi), both originated from China, were purchased from Omniherb Co. (Daegu, Republic of Korea) identified by a specialist of herbs. 100 g of BR was extracted in 1000 ml of distilled water at 100°C for 4 h. 100 g of SR was extracted by the same method. Then, the water extracted BR and SR were freeze dried. The yields were 15.9% and 17.6% for BR and SR, respectively. The same amounts of BR and SR were mixed to prepare the BR-SR mixture.

2.3. Network Pharmacological Analysis

The herbal compound-target gene information was analyzed using the Traditional Chinese Medicine Systems Pharmacology Database (TCMSP). The major chemical components of SR and BR were collected and extracted from TCMSP. We collected each 99 and 147 compounds that encompassed the main components of SR and BR, taking into account the relevant reports. Then we selected the 9 and 10 chemical compounds that satisfied an oral bioavailability (OB) ≥ 10% and drug-likeness (DL) ≥ 0.04 and provide further extraction and optimization of the medicinal ingredients. Nineteen pharmacological ingredients that satisfied the above conditions are showed in Table 1. In a biological network, nodes are visual representations proteins, genes, or metabolites. An edge is a visual representation of a relation. It is a line that connects two nodes and represents biological relationships, such as physical interactions or gene expression regulation [21]. In this study, nodes mean compounds and targets, and edges are relationships between compounds and target. Degree is the number of connected nodes.

To construct a compound-target network, we used Cytoscape 3.6.0 software. By compound-target network, we studied Sangsoo relationships between SR and BR. Multiple targets that participate in 3T3-L1 adipocytes were shared by each compound of SR and BR.

2.4. Cell Culture and Adipocyte Differentiation

3T3-L1 preadipocytes (American Type Culture Collection, Rockville, MD, USA) was cultured and differentiated as previously described [22]. Briefly, 3T3-L1 preadipocytes were cultured in DMEM containing 1% penicillin-streptomycin and 10% BS in 6-well plates until confluence at 37°C. Two days after 100% confluence (day 0), cells were differentiated for 48 h in differentiation medium composed of DMEM containing 10% FBS and differentiation inducers (MDI: 0.5 mM IBMX, 1 μM Dex, and 1 μg/ml insulin). From day 2 to day 4, the cells were incubated in culture medium (DMEM plus 10% FBS and 1 μg/ml insulin) supplemented with BR, SR, or BR-SR mixture. Then, at day 4, the medium was changed into fresh culture medium and the cells were cultured for 48 h.

2.5. Cell Viability Assay

Cytotoxicity of BR, SR, and BR-SR mixture was evaluated using the MTS assay, as previously described [23]. The absorbance was measured at 490 nm using a VERSAmax microplate reader (Molecular Devices, Sunnyvale, CA, USA).

2.6. Oil Red O Staining

Intracellular lipid accumulation was measured by Oil Red O staining as previously described [24]. The absorbance, which is proportional to intracellular lipid, was measured at 500 nm with a VERSAmax microplate reader (Molecular Devices, Sunnyvale, CA, USA).

2.7. RNA Isolation and Real-Time Reverse-Transcription Polymerase Chain Reaction (RT-PCR)

Total RNA was extracted from BR, SR, or BR-SR mixture-treated cells using QIAzol lysis reagent (Qiagen Sciences Inc., Germantown, MD, USA) and GeneAll RiboEx Total RNA extraction kit (GeneAll Biotechnology, Seoul, Republic of Korea) as previously described [25]. mRNA evaluation was performed using a StepOnePlus Real-time RT-PCR System (Applied Biosystems, Foster City, CA, USA). Primer sequences used in this study are described in Table 2.

2.8. Protein Extraction and Western Blot Analysis

BR, SR, or BR-SR mixture-treated cells were harvested and lysed in Cell Lysis Buffer (Cell Signaling Technology Inc., Danvers, MA, USA). Determination of total protein concentration and western blot analysis were performed as described previously [25, 26].

2.9. Statistical Analysis

Results are expressed as mean ± standard error mean (SEM). Student t-test was used to determine statistical relevance. All statistical analyses were performed using GraphPad Prism 5 (GraphPad Software, La Jolla, CA, USA).

3. Results

3.1. Compound-Compound Target Network Analysis of BR and SR

For prediction analysis of Sangsoo relationship between BR and SR, we constructed the compound-target network (Figure 1(a)) based on data mining. This network consists of 19 compounds and 504 candidate targets in which pink circles and blue ones correspond to active components and targets, respectively. In the relationships between compounds and targets, we found 265 nodes and 504 edges. The means of degree value (the number of associated targets) of the compounds were 18, indicating that most of the compounds regulated multiple targets to exert various therapeutic effects. The mean compounds of each target were 6, showing that most of the targets can interact with multiple compounds simultaneously.

(a)

(b)

Among the active compounds, quercetin of BR exhibits the highest number of target candidate target interactions (degrees =154), followed by apigenin from SR (degrees = 80), kaempferol from BR (degrees = 59), and wogonin from SR (degrees = 52).

In the 504 targets of active compounds, prostaglandin G/H syntheses 2 showed the highest degree (degrees = 12), which was followed by apoptosis regulator Bcl-2 and caspase-3 (degrees = 10), prostaglandin G/H synthase 1 and phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit, and gamma isoform (degrees = 9). The network pharmacological analysis result demonstrates the potential synergistic effect of SR and BR on adipogenesis and energy expenditure through modulating these relevant proteins.

3.2. BR and SR Inhibit Lipid Accumulation in 3T3-L1 Adipocytes

First, we evaluated the cytotoxicity of BR and SR on 3T3-L1 adipocytes. As shown in Figure 2(a), BR and SR did not affect cell viability up to concentration of 10 μg/ml and 1 μg/ml, respectively, when analyzed by an MTS assay. Further experiments were conducted using concentrations which did not decrease cell viability. Next, to evaluate the effect of BR and SR on lipid accumulation, Oil Red O staining assay was performed. Adipocytes treated with BR and SR both showed concentration-dependent decrease of intracellular lipids (Figure 2(b)).

(a)

(b)

(c)

Figure 2

BR and SR inhibit lipid accumulation in 3T3-L1 adipocytes. (a) An MTS assay was performed in order to measure the effects of Bupleuri Radix and Scutellariae Radix on cell viability in 3T3-L1 cells. (b) An Oil Red O assay was performed in order to measure the effect of Bupleuri Radix and Scutellariae Radix on lipid accumulation in 3T3-L1 cells. (c) A Real-Time RT-PCR assay was performed in order to measure the effect of Bupleuri Radix and Scutellariae Radix on mRNA expressions of AdipoQ, aP2, and Lipin1. Gapdh mRNA was analyzed as an internal control. Experiments were repeated at least three times. Data represented are the relative expression. All values are mean ± SEM. , significantly different from untreated adipocytes. BR, Bupleuri Radix; SR, Scutellariae Radix.

3.3. BR and SR Decrease Adipokines in 3T3-L1 Adipocytes

Real-time RT-PCR assays revealed adipokine genes including Adipoq, aP2, and Lipin1 were decreased as well (Figure 2(c)). Adiponectin, an adipokine transcripted by the Adipoq gene, promotes adipocyte differentiation by increasing C/EBPα and PPARγ in 3T3-L1 adipocytes [27], and also secreted adiponectins are considered as a marker to evaluate adipogenic differentiation [28]. Adipocyte protein 2 (aP2) is a mediator of intracellular transport of fatty acids which is primarily expressed in adipocytes and macrophages [29]. Inhibition of this protein leads to a potential amelioration of obesity [30]. The role of Lipin-1, a protein with the most prominent expression in adipose tissue, skeletal muscle, and testis [31], in adipogenesis is complex. Several studies indicate its importance since the lack of Lipin-1 results in disturbed adipogenesis both in vivo and in vitro [32–34].

3.4. BR and SR Suppress Adipogenesis and Increase Energy Expenditure in 3T3-L1 Adipocytes

To investigate the action mechanism in lipid inhibition by BR and SR, we assessed the change in adipogenic factors. Two major controllers in adipogenesis, C/EBPα and PPARγ, were significantly decreased by BR and SR treatment at mRNA level and protein level both (Figures 3(a) and 3(b)), suggesting suppressed adipogenesis was responsible for the antilipogenic effect of BR. Then, we evaluated the effect of BR and SR on AMP-activated protein kinase alpha (AMPKα). As a result, we observed concentration-dependent increase in phosphorylation of AMPKα in BR- and SR-treated adipocytes (Figure 3(c)). Through these results, we could conclude that BR and SR suppress lipid accumulation in 3T3-L1 adipocytes by two action mechanisms: inhibition of adipogenesis and increase of energy expenditure.

(a)

(b)

(c)

Figure 3

BR and SR suppress adipogenesis and increase energy expenditure in 3T3-L1 adipocytes. (a) A real-time RT-PCR assay was performed in order to measure the effect of Bupleuri Radix and Scutellariae Radix on mRNA expressions of Cebpa and Pparg. (b) A western blot assay was performed in order to measure the effect of Bupleuri Radix Scutellariae Radix on protein expressions of C/EBPα, PPARγ, and (c) p-AMPKα. Gapdh mRNA was analyzed as an internal control for Real-Time RT-PCR assays. Experiments were repeated at least three times. Data represented are the relative expression. All values are mean ± SEM. , significantly different from untreated adipocytes. BR, Bupleuri Radix; SR, Scutellariae Radix.

3.5. BR-SR Mixture Synergistically Suppress Lipid Accumulation in 3T3-L1 Adipocytes

To confirm whether our hypothesis is correct or not, we then performed experiments to evaluate the synergism between BR and SR. BR and SR are contained in Sosiho-Tang at a 3:2 ratio (12 g and 8 g, respectively), and our results on separate extracts showed 1 μg/ml was the most efficient concentration of SR while 1 μg/ml and 10 μg/ml of BR did not differ significantly. Therefore, we used BR-SR mixture at 1 μg/ml of which extracts were mixed at 1:1 ratio. As shown in Figure 4(a), BR-SR 1:1 mixture suppressed lipid accumulation in 3T3-L1 adipocytes, whose inhibition rate was higher than BR 1 μg/ml or SR 1 μg/ml (p < 0.05 and p = 0.06, respectively). Further qPCR results indicated synergistic inhibition of adipokine genes such as Adipoq, aP2, and Lipin1 (Figure 4(b)).

(a)

(b)

Figure 4

BR-SR mixture synergistically suppresses lipid accumulation in 3T3-L1 adipocytes. (a) An Oil Red O assay was performed in order to measure the effect of Bupleuri Radix, Scutellariae Radix, and their 1:1 mixture on lipid accumulation in 3T3-L1 cells. (b) A Real-Time RT-PCR assay was performed in order to measure the effect of Bupleuri Radix, Scutellariae Radix, and their 1:1 mixture on mRNA expressions of AdipoQ, aP2, and Lipin1. Gapdh mRNA was analyzed as an internal control. Experiments were repeated at least three times. Data represented are the relative expression. All values are mean ± SEM. , significantly different from untreated adipocytes. BR, Bupleuri Radix; SR, Scutellariae Radix.

3.6. BR-SR Mixture Synergistically Inhibits Adipogenesis and Increases Energy Expenditure

To investigate the effect of BR-SR mixture on adipogenesis, we analyzed expression levels of Cebpa and Pparg using Real-Time RT-PCR. As in Figure 5(a), BR-SR 1:1 mixture showed higher inhibition rate in the two factors when compared to separate extracts at the same concentration. Consistently, BR-SR mixture showed synergistic inhibitory effect on protein levels of C/EBPα and PPARγ as well (Figure 5(b)). Mixture of BR and SR also enhanced the activation of AMPKα (Figure 5(c)), implying that these two herbal extracts synergistically interact in two different pathways of obesity treatment: inhibiting adipogenesis and increasing energy expenditure.

(a)

(b)

(c)

Figure 5

BR-SR mixture synergistically inhibits adipogenesis and increases energy expenditure. (a) A real-time RT-PCR assay was performed in order to measure the effect of Bupleuri Radix, Scutellariae Radix, and their 1:1 mixture on mRNA expressions of Cebpa and Pparg. (b) A western blot assay was performed in order to measure the effect of Bupleuri Radix, Scutellariae Radix, and their 1:1 mixture on protein expressions of C/EBPα, PPARγ, and (c) p-AMPKα. Gapdh mRNA was analyzed as an internal control for Real-Time RT-PCR assays. Experiments were repeated at least three times. Data represented are the relative expression. All values are mean ± SEM. , significantly different from untreated adipocytes. BR, Bupleuri Radix; SR, Scutellariae Radix.

4. Discussion

The emerging crisis of obesity impacts the world. A more serious problem is that obesity can lead to other metabolism-related diseases, such as diabetes, cardiovascular diseases, and even cancer [35]. Current available medications for obesity are however limited; therefore the necessity of new options are growing. Nature-derived materials, in this case, have gained interest in the field of obesity treatment due to their positive effects with pharmacological safety [36]. Sosiho-Tang is a Korean medical formula composed of seven herbs: BR (12 g), SR (8 g), Pinelliae Tuber (4 g), Ginseng Radix (4 g), Zizyphi Fructus (4 g), Zingiberis Rhizoma (4 g), and Glycyrrhizae Radix (2 g). This herbal formula is a candidate for optional treatments as Yoo et al. reported its show antiobese effects in vivo and in vitro [7].

Several studies report the synergistic interaction in nature-derived materials. Our previous study has reported synergistic effect of two herbal pairs, Vertrum nigrum and Panax ginseng [37]. Zhao et al. used HFD-induced rats to show synergism between quercetin and resveratrol [38]. Another group has also reported the synergistic effect of this pair “browning” of white adipose tissue [39]. In this study, we first analyzed the possible synergy of BR-SR pair by a network pharmacological approach. In the compound-target analysis, we observed several active compounds of BR and SR regulate targets related to adipogenesis and energy expenditure.

Obesity results from accumulation of excess energy in the form of lipid in adipocytes. Adipogenesis is a process of differentiation of preadipocyte into adipocytes. Numerous transcriptional factors form a complex cascade of adipogenesis, of which process changes in shape, genes, proteins, and hormones are accompanied [40, 41]. Among them, C/EBPα and PPARγ are considered to be the master regulators in adipogenesis [42]. In the current study, BR-SR mixture showed significant synergism on the inhibition of these two key adipogenic factors.

In addition to inhibiting adipogenesis, pharmacological activation of AMPKα is another potential pathway for obesity treatment. The energy storing WAT expresses AMPK, a serine/threonine protein kinase complex composed of three subunits (AMPKα, β and γ) which is activated in low energy-conditions [43]. Activated AMPK induces catalytic ATP generation while inhibiting anabolic process of energy consumption in order to maintain cellular energy homeostasis [44]. Thus, AMPK is one of the key regulators in energy homeostasis that mediate glucose and lipid metabolism to modulate energy levels [45]. Although previous studies allow the anticipation of AMPK elevation by BR [46] and SR [47, 48], the significance of our study was that, by network pharmacological analysis, a possible synergy mechanism on AMPK induction could be expected. Our results show that BR and SR extracts can activate AMPKα, suggesting their ability to increase energy expenditure. Furthermore, the 1:1 mixture of these two herbs interacted synergistically, phosphorylating AMPKα at a higher level.

Besides energy expenditure, AMPKα is also a regulator of adipogenesis by suppressing C/EBPα and PPARγ [49]. These reports again provide substantial evidence of synergy between BR and SR on adipogenesis. However, further study is required to fully understand the synergy mechanism of this Sangsoo pair of BR and SR.

5. Conclusion

Taken together, we analyzed the network pharmacological action of the Sangsoo herbal pair BR and SR, the two major components of Sosiho-Tang to predict their synergistic possibility. The compound-target relevance showed that these two herbs share two major antiobese targets: adipogenesis and energy expenditure. Then we used 3T3-L1 adipocytes to investigate whether the herbal pair do synergistically interact. As expected, BR-SR mixture showed synergism on suppressing intracellular lipid accumulation and adipokine genes, which resulted from inhibition of adipogenic factors, C/EBPα and PPARγ, and activation of the key regulator of energy metabolism, AMPKα. Despite the fact that further mechanism study is required and that our results lack in vivo effects of BR-SR herbal pair, our results provide experimental evidence for the Korean medical theory of Sangsoo and also suggest this herbal pair BR and SR may benefit as a potential antiobese therapeutic agent.

Data Availability

The authors will retain all data and can provide it when requested.

Conflicts of Interest

The authors declare that they have no conflicts of interest.

Authors’ Contributions

The first three authors (Jueun Lee, Jinbong Park, and Hyewon Park) contributed equally to this paper and share first authorship. Jae-Young Um developed the experimental design and conducted all of the manuscript. Jueun Lee performed the network pharmacology analysis. Hyewon Park and Dong-Hyun Youn performed the in vitro experiments. Jaehoon Lee and Seokbeom Hong provided technical and material support. Jinbong Park wrote the manuscript. All authors read and approved the final manuscript for submission.

Acknowledgments

This study was supported by the National Research Foundation of Korea (NRF-2015R1A41042399 and 2018R1D1A1B07049882) and Kyung Hee University in 2018 (KHU-1051).

References

World Health Organization Media Centre, WHO Media Centre Fact Sheets: Obesity and Overweight, World Health Organization Media Centre, 2015.
M. Solas, F. I. Milagro, D. Martínez-Urbistondo, M. J. Ramirez, and J. A. Martínez, “Precision obesity treatments including pharmacogenetic and nutrigenetic approaches,” Trends in Pharmacological Sciences, vol. 37, no. 7, pp. 575–593, 2016.
View at: Publisher Site | Google Scholar
H. R. Wyatt, “Update on treatment strategies for obesity,” The Journal of Clinical Endocrinology & Metabolism, vol. 98, no. 4, pp. 1299–1306, 2013.
View at: Publisher Site | Google Scholar
A. L. Hopkins, “Network pharmacology,” Nature Biotechnology, vol. 25, no. 10, pp. 1110-1111, 2007.
View at: Publisher Site | Google Scholar
A. L. Hopkins, “Network pharmacology: the next paradigm in drug discovery,” Nature Chemical Biology, vol. 4, no. 11, pp. 682–690, 2008.
View at: Publisher Site | Google Scholar
G.-b. Zhang, Q.-y. Li, Q.-l. Chen, and S.-b. Su, “Network pharmacology: a new approach for chinese herbal medicine research,” Evidence-Based Complementary and Alternative Medicine, vol. 2013, Article ID 621423, 9 pages, 2013.
View at: Publisher Site | Google Scholar
S.-R. Yoo, M.-Y. Lee, B.-K. Kang, H.-K. Shin, and S.-J. Jeong, “Soshiho-tang aqueous extract exerts antiobesity effects in high fat diet-fed mice and inhibits adipogenesis in 3T3-L1 adipocytes,” Evidence-Based Complementary and Alternative Medicine, vol. 2016, Article ID 2628901, 2016.
View at: Google Scholar
T. F. Tzeng, H. J. Lu, S. S. Liou, C. J. Chang, and I. M. Liu, “Vinegar-baked radix bupleuri regulates lipid disorders via a pathway dependent on peroxisome-proliferator-activated receptor-alpha in high-fat-diet-induced obese rats,” Evidence-Based Complementary and Alternative Medicine, vol. 2012, Article ID 827278, 12 pages, 2012.
View at: Publisher Site | Google Scholar
S. O. Kim, J. Y. Park, S. Y. Jeon, C. H. Yang, and M. R. Kim, “Saikosaponin a, an active compound of Radix Bupleuri, attenuates inflammation in hypertrophied 3T3-L1 adipocytes via ERK/NF-κB signaling pathways,” International Journal of Molecular Medicine, vol. 35, no. 4, pp. 1126–1132, 2015.
View at: Publisher Site | Google Scholar
S.-J. Hong, J. C. Fong, and J.-H. Hwang, “Effects of crude drugs on glucose uptake in 3T3-L1 adipocytes,” Kaohsiung Journal of Medical Sciences, vol. 16, no. 9, pp. 445–451, 2000.
View at: Google Scholar
H. Lee, R. Kang, Y. Hahn et al., “Antiobesity effect of baicalin involves the modulations of proadipogenic and antiadipogenic regulators of the adipogenesis pathway,” Phytotherapy Research, vol. 23, no. 11, pp. 1615–1623, 2009.
View at: Publisher Site | Google Scholar
D. H. Kwak, J.-H. Lee, K. H. Song, and J. Y. Ma, “Inhibitory effects of baicalin in the early stage of 3T3-L1 preadipocytes differentiation by down-regulation of PDK1/Akt phosphorylation,” Molecular and Cellular Biochemistry, vol. 385, no. 1-2, pp. 257–264, 2014.
View at: Publisher Site | Google Scholar
L.-L. Yang, N. Xiao, J. Liu et al., “Differential regulation of baicalin and scutellarin on AMPK and Akt in promoting adipose cell glucose disposal,” Biochimica et Biophysica Acta, vol. 1863, no. 2, pp. 598–606, 2017.
View at: Publisher Site | Google Scholar
P. Fang, M. Yu, W. Min et al., “Beneficial effect of baicalin on insulin sensitivity in adipocytes of diet-induced obese mice,” Diabetes Research and Clinical Practice, vol. 139, pp. 262–271, 2018.
View at: Publisher Site | Google Scholar
M.-H. Cha, I.-C. Kim, B.-H. Lee, and Y. Yoon, “Baicalein inhibits adipocyte differentiation by enhancing COX-2 expression,” Journal of Medicinal Food, vol. 9, no. 2, pp. 145–153, 2006.
View at: Publisher Site | Google Scholar
Y. Nakao, H. Yoshihara, K. Fujimori, and H. Xu, “Suppression of very early stage of adipogenesis by baicalein, a plant-derived flavonoid through reduced Akt-C/EBPα-GLUT4 signaling-mediated glucose uptake in 3T3-L1 adipocytes,” PLoS ONE, vol. 11, no. 9, Article ID e0163640, 2016.
View at: Publisher Site | Google Scholar
E.-J. Bak, J. Kim, Y. H. Choi et al., “Wogonin ameliorates hyperglycemia and dyslipidemia via PPARα activation in db/db mice,” Clinical Nutrition, vol. 33, no. 1, pp. 156–163, 2014.
View at: Publisher Site | Google Scholar
T. Yang, H. Liu, B. Zhao et al., “Wogonin enhances intracellular adiponectin levels and suppresses adiponectin secretion in 3T3-L1 adipocytes,” Endocrine Journal, vol. 64, no. 1, pp. 15–26, 2017.
View at: Publisher Site | Google Scholar
J. Chen, J. Liu, and Y. Wang, “Wogonin mitigates nonalcoholic fatty liver disease via enhancing PPARα/AdipoR2, in vivo and in vitro,” Biomedicine & Pharmacotherapy, vol. 91, pp. 621–631, 2017.
View at: Google Scholar
R. Jin, B. Zhang, C.-M. Xue, S.-M. Liu, Q. Zhao, and K. Li, “Classification of 365 Chinese medicines in Shennong’s Materia Medica Classic based on a semi-supervised incremental clustering method,” Journal of Chinese Integrative Medicine, vol. 9, no. 6, pp. 665–674, 2011.
View at: Publisher Site | Google Scholar
D. Merico, D. Gfeller, and G. D. Bader, “How to visually interpret biological data using networks,” Nature Biotechnology, vol. 27, no. 10, pp. 921–924, 2009.
View at: Publisher Site | Google Scholar
J. Park, Y.-D. Jeon, H.-L. Kim et al., “Veratri Nigri Rhizoma et Radix (Veratrum nigrum L.) and its constituent jervine prevent adipogenesis via activation of the LKB1-AMPKalpha-ACC axis in vivo and in vitro,” Evidence-Based Complementary and Alternative Medicine, vol. 2016, Article ID 8674397, 12 pages, 2016.
View at: Publisher Site | Google Scholar
Y. Jung, J. Park, H. Kim et al., “Vanillic acid attenuates obesity,” The FASEB Journal, vol. 32, no. 3, pp. 1388–1402, 2018.
View at: Publisher Site | Google Scholar
M.-Y. Jeong, H.-L. Kim, J. Park et al., “Rubi Fructus (Rubus coreanus) activates the expression of thermogenic genes in vivo and in vitro,” International Journal of Obesity, vol. 39, no. 3, pp. 464–456, 2015.
View at: Publisher Site | Google Scholar
M.-Y. Jeong, J. Park, D.-H. Youn et al., “Albiflorin ameliorates obesity by inducing thermogenic genes via AMPK and PI3K/AKT in vivo and in vitro,” Metabolism - Clinical and Experimental, vol. 73, pp. 85–99, 2017.
View at: Publisher Site | Google Scholar
H. Kim, Y. Jung, J. Park et al., “Farnesol has an anti-obesity effect in high-fat diet-induced obese mice and induces the development of beige adipocytes in human adipose tissue derived-mesenchymal stem cells,” Frontiers in Pharmacology, vol. 8, article 654, 2017.
View at: Publisher Site | Google Scholar
Y. Fu, N. Luo, R. L. Klein, and W. Timothy Garvey, “Adiponectin promotes adipocyte differentiation, insulin sensitivity, and lipid accumulation,” Journal of Lipid Research, vol. 46, no. 7, pp. 1369–1379, 2005.
View at: Publisher Site | Google Scholar
E. Martella, C. Bellotti, B. Dozza, S. Perrone, D. Donati, and E. Lucarelli, “Secreted adiponectin as a marker to evaluate in vitro the adipogenic differentiation of human mesenchymal stromal cells,” Cytotherapy, vol. 16, no. 11, pp. 1476–1485, 2014.
View at: Publisher Site | Google Scholar
L. Sun, A. C. Nicholson, D. P. Hajjar, A. M. Gotto Jr., and J. Han, “Adipogenic differentiating agents regulate expression of fatty acid binding protein and CD36 in the J744 macrophage cell line,” Journal of Lipid Research, vol. 44, no. 10, pp. 1877–1886, 2003.
View at: Publisher Site | Google Scholar
K. Maeda, H. Cao, K. Kono et al., “Adipocyte/macrophage fatty acid binding proteins control integrated metabolic responses in obesity and diabetes,” Cell Metabolism, vol. 1, no. 2, pp. 107–119, 2005.
View at: Publisher Site | Google Scholar
M. Péterfy, J. Phan, P. Xu, and K. Reue, “Lipodystrophy in the fld mouse results from mutation of a new gene encoding a nuclear protein, lipin,” Nature Genetics, vol. 27, no. 1, pp. 121–124, 2001.
View at: Publisher Site | Google Scholar
K. Reue, P. Xu, X.-P. Wang, and B. G. Slavin, “Adipose tissue deficiency, glucose intolerance, and increased atherosclerosis result from mutation in the mouse fatty liver dystrophy (fld) gene,” Journal of Lipid Research, vol. 41, no. 7, pp. 1067–1076, 2000.
View at: Google Scholar
P. Zhang, K. Takeuchi, L. S. Csaki, and K. Reue, “Lipin-1 phosphatidic phosphatase activity modulates phosphatidate levels to promote peroxisome proliferator-activated receptor γ (PPARγ) gene expression during adipogenesis,” The Journal of Biological Chemistry, vol. 287, no. 5, pp. 3485–3494, 2012.
View at: Publisher Site | Google Scholar
H. Sembongi, M. Miranda, G.-S. Han et al., “Distinct roles of the phosphatidate phosphatases lipin 1 and 2 during adipogenesis and lipid droplet biogenesis in 3T3-L1 cells,” The Journal of Biological Chemistry, vol. 288, no. 48, pp. 34502–34513, 2013.
View at: Publisher Site | Google Scholar
NCD Risk Factor Collaboration, “Worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128.9 million children, adolescents, and adults,” Lancet, vol. 390, no. 10113, pp. 2627–2642, 2016.
View at: Google Scholar
Y. Liu, M. Sun, H. Yao, Y. Liu, and R. Gao, “Herbal medicine for the treatment of obesity: an overview of scientific evidence from 2007 to 2017,” Evidence-Based Complementary and Alternative Medicine, vol. 2017, Article ID 8943059, 17 pages, 2017.
View at: Publisher Site | Google Scholar
J. Park, Y.-D. Jeon, H.-L. Kim et al., “Interaction of Veratrum nigrum with Panax ginseng against obesity: A Sang-ban relationship,” Evidence-Based Complementary and Alternative Medicine, vol. 2013, Article ID 732126, 13 pages, 2013.
View at: Publisher Site | Google Scholar
L. Zhao, F. Cen, F. Tian et al., “Combination treatment with quercetin and resveratrol attenuates high fat diet-induced obesity and associated inflammation in rats via the AMPKα1/SIRT1 signaling pathway,” Experimental and Therapeutic Medicine, vol. 146, pp. 5942–5948, 2017.
View at: Publisher Site | Google Scholar
N. Arias, C. Picó, M. Teresa Macarulla et al., “A combination of resveratrol and quercetin induces browning in white adipose tissue of rats fed an obesogenic diet,” Obesity, vol. 25, no. 1, pp. 111–121, 2017.
View at: Publisher Site | Google Scholar
H. Koutnikova and J. Auwerx, “Regulation of adipocyte differentiation,” Annals of Medicine, vol. 33, no. 8, pp. 556–561, 2001.
View at: Publisher Site | Google Scholar
E. D. Rosen and O. A. MacDougald, “Adipocyte differentiation from the inside out,” Nature Reviews Molecular Cell Biology, vol. 7, no. 12, pp. 885–896, 2006.
View at: Publisher Site | Google Scholar
R. F. Morrison and S. R. Farmer, “Hormonal signaling and transcriptional control of adipocyte differentiation,” Journal of Nutrition, vol. 130, no. 12, pp. 3116S–3121S, 2000.
View at: Publisher Site | Google Scholar
M. C. Towler and D. G. Hardie, “AMP-activated protein kinase in metabolic control and insulin signaling,” Circulation Research, vol. 100, no. 3, pp. 328–341, 2007.
View at: Publisher Site | Google Scholar
D. G. Hardie, F. A. Ross, and S. A. Hawley, “AMPK: a nutrient and energy sensor that maintains energy homeostasis,” Nature Reviews Molecular Cell Biology, vol. 13, no. 4, pp. 251–262, 2012.
View at: Publisher Site | Google Scholar
R. B. Ceddia, “The role of AMP-activated protein kinase in regulating white adipose tissue metabolism,” Molecular and Cellular Endocrinology, vol. 366, no. 2, pp. 194–203, 2013.
View at: Publisher Site | Google Scholar
Z. Zhen, B. Chang, M. Li et al., “Anti-diabetic effects of a coptis chinensis containing new traditional Chinese medicine formula in type 2 diabetic rats,” American Journal of Chinese Medicine, vol. 39, no. 1, pp. 53–63, 2011.
View at: Publisher Site | Google Scholar
T. Wang, H. Jiang, S. Cao et al., “Baicalin and its metabolites suppresses gluconeogenesis through activation of AMPK or AKT in insulin resistant HepG-2 cells,” European Journal of Medicinal Chemistry, vol. 141, pp. 92–100, 2017.
View at: Publisher Site | Google Scholar
Q. Chen, M. Liu, H. Yu et al., “Scutellaria baicalensis regulates FFA metabolism to ameliorate NAFLD through the AMPK-mediated SREBP signaling pathway,” Journal of Natural Medicines, vol. 72, no. 3, pp. 655–666, 2018.
View at: Publisher Site | Google Scholar
Y. Dagon, Y. Avraham, and E. M. Berry, “AMPK activation regulates apoptosis, adipogenesis, and lipolysis by eIF2α in adipocytes,” Biochemical and Biophysical Research Communications, vol. 340, no. 1, pp. 43–47, 2006.
View at: Publisher Site | Google Scholar

Copyright

Copyright © 2018 Jueun Lee et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

PDF Download Citation

Download other formats

Order printed copies

Views

1194

Downloads

1036

Citations