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. 2022 Jul 16;31(11):1473–1480. doi: 10.1007/s10068-022-01130-y

1,3,5,8-Tetrahydroxyxanthone suppressed adipogenesis via activating Hedgehog signaling in 3T3-L1 adipocytes

Yimeng Zhou 1, Jin Tae Kim 1, Shuai Qiu 1, Seung Beom Lee 1, Ho Jin Park 1, Moon Jeong Soon 1, Hong Jin Lee 1,✉
PMCID: PMC9433504  PMID: 36060569

Abstract

In this study, we investigated the effect of 1,3,5,8-tetrahydroxyxanthone (THX) on the adipogenesis of 3T3-L1 adipocytes. THX, a xanthone isolated from Gentianella acuta, inhibited lipid accumulation in 3T3-L1 adipocytes and reduced the protein levels of the key adipogenic transcriptional factors, peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding protein α (C/EBPα), in a dose-dependent manner. In addition, THX enhanced the transcriptional activity of Gli1 known as the key indicator of Hedgehog (Hh) signaling activity and increased the expression of Gli1 and its upstream regulator Smo. The Smo activator SAG exerted the similar effect with THX on regulating Gli1, Smo, PPARγ and C/EBPα expression, which led to the suppression of fat formation in 3T3-L1 adipocytes. Furthermore, we found that the inhibitory effect of THX on adipogenesis was derived from regulation of the early stage of adipogenesis. These results suggest that THX suppresses the differentiation of adipocyte through Hh signaling and may be considered as a potent agent for the prevention of obesity.

Keywords: Adipogenesis; 1,3,5,8-Tetrahydroxyxanthone; Hedgehog signaling; Gli1; 3T3-L1 adipocytes

Introduction

Obesity has attracted increasing attention due to the association with the different chronic diseases (Loos and Yeo, 2022). Obese adults were reported to be at least 3.5, 2.0, and 3.7 times more likely to develop type 2 diabetes mellitus (Field et al., 2001), heart failure (Kenchaiah et al., 2002), osteoarthritis (Reyes et al., 2016) than people of normal weight, respectively. Obesity is associated to the energy imbalance between calories consumed and expended, characterized by increased accumulation of white adipose tissue (WAT), where excess energy is stored as fat (Rosen and Spiegelman, 2006). Abnormal WAT expansion involved in obesity includes the size increase of adipocyte size, hypertrophy and the number increase of adipocyte, hyperplasia (Haider and Larose, 2019). Adipogenesis, the process of hyperplasia, has been reported to be associated with obesity in high-fat diet (HFD) induced obese mice (Seo et al., 2018). Therefore, understanding the effect on adipogenesis may be a key issue in combating obesity.

Adipogenesis generally involves the formation of preadipocytes from fibroblast-like cells such as mesenchymal precursors and the differentiation of specified preadipocytes, which eventually generate triglyceride-filled functional and insulin-responsive mature adipocytes (Lefterova and Lazar, 2009). The essential regulators in adipogenesis include peroxisome proliferator-activated receptor gamma (PPARγ) and CCAAT/enhancer-binding proteins α (C/EBPα), which interact with each other and form a positive feedback to modulate adipocyte differentiation (Tang et al., 2004; Zuo et al., 2006). Genome-wide profiling figured out a significant overlap between PPARγ and C/EBPα binding in adipocytes (Madsen et al., 2014).

Hedgehog (Hh) signaling is one of the crucial pathways in mammalian embryonic development and tissue hemostasis, which plays a biological role through a signaling cascade (Skoda et al., 2018). The mechanism of Hh signaling pathway has been widely reported. Briefly, the bind of Hh ligands Sonic hedgehog (Shh), Indian hedgehog, and Desert hedgehog to the receptor Patched 1 (Ptch1) will release the G protein-coupled receptor Smoothened (Smo), which relocalizes to the tip of the cilium and further activate downstream transcription factors Gli1, Gli2, and Gli3, among which Gli1 is the key mediator of the Hh pathway (Briscoe and Therond, 2013). Previous studies revealed that Shh ligand significantly reduced the PPARγ2 promoter activity induced by C/EBPα in progenitors of adipocytes (Kim et al., 2007). Therefore, targeting Hh pathway may be a promising strategy to modulate adipogenesis.

Recently, the effects of anti-obesity by xanthones have been reported (Choi et al., 2015; Zheng et al., 2014). We have chosen 7 different xanthones (Table 1) for Hh signaling activation effects. Among them, tetrahydroxyxanthone isolated from Gentianella acuta has been used as a native Mongolian medicine treating diarrhea, arrhythmia, and jaundice (Ding et al., 2017; Wang et al., 2017). The health beneficial efficacy of 1,3,5,8-tetrahydroxyxanthone (THX) is more widely studied than other tetrahydroxyxanthones including the effects on attenuating colitis in rats by reducing inflammatory responses, colonic muscle spasm (Ni et al., 2019), antiaging, and anti-ketosis (Tang et al., 2019; Xiao et al., 2012). However, the effect of THX on adipogenesis has not been investigated. Here, we screened the effect of xanthones on Hh signaling activation and elucidated its regulation in adipogenesis using 3T3-L1 adipocytes.

Table 1.

Relative Gli1 transcriptional activity by the treatment of xanthones

No. Xanthones Relative Gli1 transcriptional activity
0.1 μg/mL 1 μg/mL 10 μg/mL
1 α-Mangostin 0.57 ± 0.02 0.32 ± 0.01 0.65 ± 0.03
2 Garcinone C 0.67 ± 0.02 0.50 ± 0.03 0.75 ± 0.02
3 γ-Mangostin 0.72 ± 0.07 0.55 ± 0.02 0.65 ± 0.01
4 Fuscaxanthone C 0.78 ± 0.01 0.80 ± 0.03 0.85 ± 0.02
5 Cowaxanthone B 1.17 ± 0.01 1.36 ± 0.01a 1.18 ± 0.01
6 β-Mangostin 1.29 ± 0.11 1.56 ± 0.04b 2.10 ± 0.05a
7 1,3,5,8-Tetrahydroxyxanthone 1.50 ± 0.09b 1.46 ± 0.02b 3.15 ± 0.11a
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a,bThe letter indicate the statistically significant effect on enhancing Gli1 transcriptional activity at p < 0.05 determined by one-way ANOVA followed by Duncan’s test

Materials and methods

Reagents and cell culture

α-Mangostin, garcinone C, γ-mangostin, fuscaxanthone C, cowaxanthone B, β-mangostin, and 1,3,5,8-tetrahydroxyxanthone (purity ≥ 95%, HPLC) were obtained from Chengdu Alfa Biotechnology Co., Ltd (Chengdu, China). 3-(4,5-Dimethylthiazol-2-yl)-2,5-Diphenyltetrazolium Bromide (MTT) and isobutylmethylxanthine (IBMX), dexamethasone (DEX), and Oil Red O solution were purchased from Sigma-Aldrich (St. Louis, MO, USA). Insulin was bought from Gibco (Billings, MT, USA). Shh Light II cell line was kindly provided from Dr. Ko at Yonsei University (Seoul, Korea). 3T3-L1 preadipocytes were purchased from the American Type Culture Collection (ATCC, Manassas, Virginia, USA). Both cell lines were cultured in Dulbecco's modified Eagle medium (DMEM, Gibco) supplemented with 10% bovine calf serum (Gibco) and 1% penicillin/streptomycin (Gibco) at 37 °C and 5% CO2.

Dual-luciferase assay

Shh Light II cells (10,000 cells/well) were seeded in 96-well plate and starved with serum free media for 6 h. Then, it was treated with different concentrations of THX for 24 h. After treatment, the cells were washed once with PBS and harvested with passive lysis buffer (Promega, Madison, WI, USA) for 30 min. Gli1 transcriptional activities were detected with firefly and Renilla dual luciferase kit (Promega, Madison, WI, USA) by a Veritas luminometer (Turner Biosystems, Sunnyvale, CA, USA).

Cell viability assay

3T3-L1 cells (3,000 cells/well) were seeded in 96-well plate and incubated 24 h. Then, it was treated with several concentrations of THX for 24 and 48 h. 4 h before the endpoint, 10% MTT (5 mg/mL) was added to each well. After removal of the media, DMSO (150 μL) was added to dissolve the formazan crystals. The absorbance was determined at 570 nm using the ELISA plate reader (BioTek, Winooski, VT, USA). Calculate the cell viability by comparing with control group.

Adipocyte differentiation

3T3-L1 adipocyte differentiation was performed as mentioned previously (Qiu et al., 2021). Briefly, 3T3-L1 cells (1 × 105 cells/well) were seeded in 3.5 cm dish and incubated for 48 h at 37 °C, 5% CO2. Next, it was changed with the media containing 10% FBS, 1% P/S (Gibco) for 48 h to reach confluence (day 0). Then, to induce differentiation, the cells were incubated with the media containing 10% FBS, 1% P/S with 0.5 mM 3-isobutyl-1-methylxanthine (IBMX), 1 μM dexamethasone (DEX), and 10 μg/mL insulin- (MDI) for 48 h (day 2). At day 4 and day 6, the media containing 10% FBS, 1% P/S with 10 μg/mL insulin was used. Different concentrations of THX (1, 5, 10 μM) was treated from day 0 to day 8. In the experiment of stage-dependent differentiation, THX was treated at day 6 (S1), day 4 (S2), day 2 (S3), and day 0 (S4) as shown in Fig. 4A.

Fig. 4.

Fig. 4

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Inhibitory effect of THX on early stage of adipogenesis in 3T3-L1 cells. A Lipid accumulation of 3T3-L1 adipocytes treated with THX at different stage of adipogenesis by Oil Red O staining. B Protein levels of adipogenic transcription factors (PPARγ and C/EBPα) and Hh mediators (Gli1 and Smo) in 3T3-L1 adipocytes treated with THX at different stage of adipogenesis. β-Actin was used as a control. Data are presented as means ± SD. The letters a–d indicate statistically significant differences at p < 0.05 determined by one-way ANOVA followed by Duncan’s test

Oil red O staining

To evaluate the lipid formation, 3T3-L1 cells (1 × 105 cells/well) were seeded in 3.5 cm dish. After differentiation, the cells were washed with PBS for one time and fixed with 10% formalin for 1 h. After fixation, the cells were washed with 60% isopropanol and stained with Oil Red O solution for 5 min. Then, Oil Red O solution was removed with distilled water and take pictures under the microscope (Olympus, Tokyo, Japan). For quantification, the lipid droplets was dissolved in 100% isopropanol and the absorbance was determined in the ELISA plate reader (BioTek, Winooski, VT, USA) at 518 nm was measured.

Protein extraction and western blot

After treatment, the cells were lysed with RIPA buffer containing protease inhibitors at 4 °C for 30 min. Then, the supernatant was collected by centrifugation for 15 min at 4 °C, 13,000 rpm. The protein concentrations were determined by BCA assay and same amounts of proteins were loaded to the SDS-PAGE gels. After running, the proteins were transfered into the PVDF membrane (Millipore, Billerica, MA, USA) and the membrane was blocked at room temperature for 1 h. Then, it was incubated with primary antibodies at 4 °C overnight and secondary antibodies at room temperature for 2 h. The primary antibodies against Gli1, Smo, PPARγ, C/EBPα were from Cell Signaling Technology (Boston, MA, USA). The secondary antibodies were from Santa Cruz Biotechnology (Santa Cruz, CA, USA).

Statistical analyses

All data were shown as mean ± SD and processed statistically using an analysis of variance (ANOVA) with Duncan’s post hoc test in SPSS 21. Values with p < 0.05 were considered statistically significant.

Results and discussion

THX suppressed the adipogenesis of 3T3-L1 adipocytes

Previous studies showed that phytochemicals such as caudatin and sulforaphene, activated Hh signaling and significantly inhibited adipogenesis in 3T3-L1 cells (Chen et al., 2018; Qiu et al., 2021). In this study, we screened 7 different xanthones to determine their effects on transcriptional activity of Gli1 in Shh Light II cells, and found that cowaxanthone B, β-mangostin, and THX exerted the significant induction of Gli1 transcriptional activity (Table 1). At 10 μg/mL, THX (Fig. 1A) showed 3.2 ± 0.1 times stronger effect on Gli1 transcriptional activity compared to the control whereas others exerted less or no effect (Table 1). These results led us to pursue the study of THX on Hh signaling and adipogenesis.

Fig. 1.

Fig. 1

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Inhibitory effects of THX on adipogenesis in 3T3-L1 adipocytes. A Structure of THX. B Cell viability of 3T3-L1 cells treated with THX. C Lipid accumulation of 3T3-L1 adipocytes treated with THX evaluated by Oil Red O staining. D Protein levels of adipogenic transcription factors (PPARγ and C/EBPα) in 3T3-L1 cells adipocytes after THX treatment. β-Actin was used as a control. Data are presented as means ± SD. The letters a–d indicate statistically significant differences at p < 0.05 determined by one-way ANOVA followed by Duncan’s test

We first examined the toxicity of THX in 3T3-L1 cells, a widely used in in vitro experiment of adipogenesis (Ali et al., 2013). As shown in Fig. 1B, THX up to 40 μM had no toxicity on 3T3-L1 cells at 24 h and 48 h. Considering the screening data, we chose 10 μM as the highest concentration for further experiments. THX remarkably reduced the lipid formation in a dose-dependent manner. Especially, THX at 10 μM decreased lipid accumulation by about two-fold compared to the MDI group (Fig. 1C). In addition, PPARγ and C/EBPα were significantly suppressed by THX treatment with decrease of about 35% and 38% at 10 μM of THX, respectively, compared to the MDI group (Fig. 1D). PPARγ is a nuclear receptor activated by fatty acids and eicosanoids (de Sa et al., 2017). Lack of PPARγ prevented the differentiation of preadipocytes (Rosen et al., 1999). C/EBPα, another essential transcriptional factor in adipogenesis, is induced at the later stage of adipogenesis and most abundant in mature adipocytes (Lefterova and Lazar, 2009). It was reported that one week-old transgenic C/EBPα−/− mice showed no perirenal, subcutaneous, and epididymal white fat although there were excess lipid substrate in the serum (Linhart et al., 2001). In addition, C/EBPα requires PPARγ to drive the adipogenic program, while C/EBPα is required to sustain PPARγ expression in the mature adipocytes (Rosen et al., 2002; Zhi et al., 1999). These suggest that THX suppressed fat accumulation of 3T3-L1 adipocytes via suppressing the expression of PPARγ and C/EBPα.

THX recovered the activity of Hh signaling in 3T3-L1 adipocytes

It was reported that white fat compartments almost completely disappeared and white adipocytes differentiation was blocked in fat-specific Hh signaling activation mutated mice (Pospisilik et al., 2010). We conducted experiments to explore the role of Hh signaling in the inhibitory effects of THX on adipogenesis. The regulation of crucial Hh signaling regulators, Gli1 and Smo, by THX treatment was evaluated in 3T3-L1 adipocytes. The reduced protein levels of Gli1 and Smo by MDI during adipogenesis was significantly recovered to 86.5 ± 7.3% and 99.1 ± 2.1% level of Gli1 and Smo, respectively (Fig. 2). Several studies have indicated a connection between obesity and primary cilia, which specifically transduces Hedgehog (Hh) signaling (Vaisse et al., 2017). Generalized ciliary dysgenesis resulted in hyperphagic obesity in adult mice (Davenport et al., 2007). Obese adipose-derived mesenchymal stem cells have defective primary cilia (Ritter et al., 2019). THX may decreased the defective primary cilia in adipocytes, then Smo re-localized to the tip of the cilium and further activated the transcription of Gli1 into nucleus, finally increased the protein level of Gli1 and Smo. Gli1-positive mesenchymal fibro-adipogenic progenitors (FAPs) was reported to have the lower adipogenic ability than Gli1-negative FAPs (Yao et al., 2021). Long-term activation of Smo was also found to significantly reduce the fat accumulation and improve glucose metabolism in high fat diet mice, accompanied by a remarkable decrease of PPARγ and C/EBPα (Shi and Long, 2017). In line with the previous studies, THX activated Hh signaling, possibly resulting in suppression of adipogenesis and fat accumulation in 3T3-L1 adipocytes.

Fig. 2.

Fig. 2

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Effect of THX on Hh signaling mediators, Gli1 and Smo. Protein levels of Hh mediators (Gli1 and Smo) in 3T3-L1 adipocytes after THX treatment. β-Actin was used as a control. Data are presented as means ± SD. The letters a–d indicate statistically significant differences at p < 0.05 determined by one-way ANOVA followed by Duncan’s test

Hh activator SAG suppressed lipid formation and regulated adipogenic factors in 3T3-L1 adipocytes

Hh activator SAG targeting Smo was evaluated in 3T3-L1 adipocytes and found that SAG at 5 μM significantly reduced the fat accumulation by 57.5 ± 5.3%, which was the similar reduction with THX at 10 μM, 56.1 ± 8.1%, compared to the MDI control (Fig. 3A). As we expect, SAG significantly enhanced the expression of target protein Smo as well as its downstream mediator Gli1 by 2.2 ± 0.1 and 2.4 ± 0.6 folds, respectively (Fig. 3B). In addition, after SAG treatment, the protein level of PPARγ and C/EBPα was reduced by 0.7 ± 0.04 and 0.6 ± 0.03 folds, compared to the MDI control in 3T3-L1 adipocytes, respectively, (Fig. 3B). The effect of SAG on Hh signaling mediators and adipogenic markers showed the similar trend with THX, indicating that THX may regulate adipogenesis via Hh signaling in 3T3-L1 adipocytes.

Fig. 3.

Fig. 3

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Inhibitory effect of THX and SAC on adipogenesis. A Lipid accumulation of 3T3-L1 adipocytes treated by THX and SAG by Oil Red O staining. B Protein levels of Hh mediators (Gli1 and Smo) and adipogenic transcription factors (PPARγ and C/EBPα) in 3T3-L1 adipocytes after THX and SAG treatment. β-Actin was used as a control. Data are presented as means ± SD. The letters a–d indicate statistically significant differences at p < 0.05 determined by one-way ANOVA followed by Duncan’s test

THX suppressed adipogenesis at the early stage in 3T3-L1 adipocytes

During differentiation from preadipocytes to mature adipocytes, preadipocytes have the serial processes including growth arrest, mitotic clonal expansion, and terminal differentiation (Lefterova and Lazar, 2009). To determine which stages of adipogenesis affected by THX, we treated 3T3-L1 cells with THX at different time points. The treatment of THX at day 0 (S4) mimics the regulatory effect of THX on growth arrest stage, and its treatment at day 2 (S3) does on mitotic clonal expansion stage. The regulatory effect on terminal differentiation stage can be determined by THX treatment at day 4 (S2) and day 6 (S1) (Fig. 4A). Overall, the earlier THX was treated during the adipogenesis, the more regulatory effect of THX was determined. Especially, THX treatment at S4 and S3 stages, fat accumulation in 3T3-L1 adipocytes was significantly suppressed by 41.2 ± 9.6% and 25.7 ± 9.2%, compared to the MDI control, respectively (Fig. 4A). The levels of the adipogenic transcription factors PPARγ and C/EBPα were also decreased to 53.2 ± 2.5% and 42.4 ± 0.7% by THX treatment at S4 stage, and 58.2 ± 3.2% and 53.8 ± 2.9% by its treatment at S3 stage, respectively (Fig. 4B). In Hh signaling mediators, Gli1 and Smo expression was recovered by THX treatment to 1.78 ± 0.1 and 1.59 ± 0.2 folds at S4 stage, and 1.49 ± 0.06 and 1.59 ± 0.03 folds at S3 stage, respectively (Fig. 4B). In the previous studies, the root extract of Heracleum moellendorffii and β-carboline alkaloids were also reported to regulate the early stage of adipogenesis in 3T3‐L1 cells (Baek et al., 2019; Geum et al., 2021), which is in line with our findings. Taken together, these results support that THX regulates the adipogenesis at the early stage through activating Hh signaling, resulting in reduction of lipid formation in 3T3-L1 adipocytes.

In conclusion, THX suppressed adipogenesis of 3T3-L1 adipocyte by enhancing the Hh signaling pathway, and inhibiting the expression of the key adipogenic markers, PPARγ and C/EBPα, leading to the decrease of lipid accumulation. Although further experiments are needed to determine whether Hh signaling is a direct target of THX in regulating adipogenesis, THX can be considered as a potential candidate for modulating adipogenesis and preventing obesity.

Acknowledgements

This study was funded by the National Research Foundation of Korea (NRF-2021R1F1A1063279) and the Bio-Synergy Research Project (NRF-2013M3A9C4078156) of the Ministry of Science, ICT, and Future Planning. This study was also supported by the Chung-Ang University Graduate Research Scholarship (Academic Scholarship for the College of Biotechnology and Natural Resources) in 2022.

Declarations

Conflict of interest

The authors declare no conflict of interest.

Footnotes

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Change history

4/29/2023

A Correction to this paper has been published: 10.1007/s10068-023-01323-z

Contributor Information

Yimeng Zhou, Email: zym95@cau.edu.cn.

Jin Tae Kim, Email: jiny-1001@nate.com.

Shuai Qiu, Email: qsly2018@naver.com.

Seung Beom Lee, Email: lsbeee99@naver.com.

Ho Jin Park, Email: 1108ghwls@naver.com.

Moon Jeong Soon, Email: smj990916@naver.com.

Hong Jin Lee, Email: hongjin@cau.ac.kr.

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