Benzyl Isothiocyanate and Phenethyl Isothiocyanate Inhibit Adipogenesis and Hepatosteatosis in Mice with Obesity Induced by a High-Fat Diet

Abstract

Benzyl isothiocyanate (BITC) and phenethyl isothiocyanate (PEITC) are organosulfur phytochemicals rich in cruciferous vegetables. We investigated the antiobesity and antihepatosteatosis activities of BITC and PEITC and the working mechanisms involved. C57BL/6J mice were fed a low-fat diet (LFD), a high-fat diet (HFD), or a HFD supplemented with 0.5 (L) or 1 g/kg (H) BITC or PEITC for 18 weeks. Compared with the HFD group, BITC or PEITC decreased the final body weight of mice in a dose-dependent manner [39.0 ± 3.1 (HFD), 34.4 ± 3.2 (BITC-L), 32.4 ± 2.8 (BITC-H), 36.2 ± 4.4 (PEITC-L), and 32.8 ± 2.9 (PEITC-H) g, p < 0.05], relative weight of epididymal fat [5.7 ± 0.4 (HFD), 4.7 ± 0.7 (BITC-L), 3.7 ± 0.3 (BITC-H), 4.4 ± 1.0 (PEITC-L), and 3.2 ± 0.6 (PEITC-H) %, p < 0.05], hepatic triglycerides [98.4 ± 6.0 (HFD), 81.0 ± 8.9 (BITC-L), 63.5 ± 5.6 (BITC-H), 69.3 ± 5.6 (PEITC-L), and 49.4 ± 2.9 (PEITC-H) mg/g, p < 0.05], and plasma total cholesterol [140 ± 21.3 (HFD), 109 ± 5.6 (BITC-L), 101 ± 11.3 (BITC-H), 126 ± 8.3 (PEITC-L), and 91.8 ± 12.7 (PEITC-H) mg/dL, p < 0.05]. Q-PCR and immunoblotting assays revealed that BITC and PEITC suppressed the expression of liver X receptor α, sterol regulatory element-binding protein 1c, stearoyl-CoA desaturase 1, fatty acid synthase, and acetyl-CoA carboxylase in both epididymal adipose and liver tissues. After a single oral administration of 85 mg/kg BITC or PEITC, the maximum plasma concentrations (C max ) of BITC and PEITC were 5.8 ± 2.0 μg/mL and 4.3 ± 1.9 μg/mL, respectively. In 3T3-L1 adipocytes, BITC and PEITC dose-dependently reduced adipocyte differentiation and cell cycle was arrested in G0/G1 phase. These findings indicate that BITC and PEITC ameliorate HFD-induced obesity and fatty liver by down-regulating adipocyte differentiation and the expression of lipogenic transcription factors and enzymes.

Sulforaphene Suppresses Adipocyte Differentiation via Induction of Post-Translational Degradation of CCAAT/Enhancer Binding Protein Beta (C/EBPβ)

“…However, Oil Red O staining indicated that different ITCs inhibited MDM-induced adipogenesis in different ways ( Figure 1B), even though they all had the N=C=S structure. Besides the N=C=S structure, the side chains of each ITC can also contribute to ITC bioactivity in terms of lipophilicity, side-chain length, molecular geometry, and chemical stability [27,55]. Given the results published in previous studies [56,57], our findings suggest that SFEN interacts with C/EBPβ at an earlier stage of adipogenesis than other ITCs ( Figure 1B).…”

“…We compared the ability of SFEN to inhibit adipogenesis to those of other ITCs, including SFN, IBR, ERC, AITC, BITC, and PEITC. The anti-adipogenic effects of these ITCs have been described previously [25][26][27]32]. To investigate whether SFEN exerts the strongest inhibitory effect against MDM-induced adipogenesis among this group of ITCs, we tested the effects of multiple ITCs at the same concentration (10 µM) in the presence of MDM, an adipogenic inducer.…”

“…SFEN has been reported to exhibit anti-mutagenic activity against food-derived mutagens [23] and anti-cancer activity in several cancer cell lines [24]. Many recent studies have reported that several ITCs, including ERC, SFN, AITC, and PEITC, exhibit strong anti-obesity effects, largely via anti-adipogenic activities [25][26][27][28]. However, the anti-adipogenic and anti-obesity effects of SFEN, and its underlying mechanisms of action, including which adipogenic transcription factors (e.g., C/EBPβ) are important, are still unclear.Herein, we compared the inhibitory effects of several ITCs on adipogenesis and found that SFEN was the most effective inhibitor of adipocyte differentiation and lipid accumulation in 3T3-L1 adipocytes.…”

Benzyl Isothiocyanate Induces Apoptosis via Reactive Oxygen Species-Initiated Mitochondrial Dysfunction and DR4 and DR5 Death Receptor Activation in Gastric Adenocarcinoma Cells

“…BITC has been studied in various cancers, such as oral cancer [10], pancreatic cancer [11], brain cancer [12], melanoma [13,14], and gastric cancer [15], to evaluate its potential for cytotoxic effects on cancer cells. Additionally, BITC has been shown to have anthelmintic [16], anti-inflammatory [17], and anti-adipogenic effects [18]. Due to the large number of therapeutic advantages that have been found in various studies, BITC has gained interest as a novel therapeutic candidate for gastric cancer, with potential chemopreventive effects.…”

Mechanisms Underlying Biological Effects of Cruciferous Glucosinolate-Derived Isothiocyanates/Indoles: A Focus on Metabolic Syndrome

“…Fat deposition decrease in WAT takes place through inhibition of C/EBPα and PPARγ and the suppression of lipogenesis via activation of the AMPKa pathway ( 268 ). In HFD fed mice, Chuang et al described that BITC and PEITC prevent body weight gain in a dose-dependent manner with diminishing adipogenesis and prevention of hepatosteatosis through inhibition of the lipogenic regulatory transcription factors PPARγ, LXRα, and SREBP1c, and a decrease in their regulated downstream enzymes ( 266 ). They also found that BITC and PEITC had similar effects and that 3T3-L1 cells were arrested in the G0/G1 phase.…”