Sulforaphane Mitigates High-Fat Diet-Induced Obesity by Enhancing Mitochondrial Biogenesis in Skeletal Muscle via the HDAC8-PGC1α Axis.

SCOPE: Histone deacetylases (HDACs) play a crucial role in the transcriptional regulation of various genes which can contribute to metabolic disorders. Although sulforaphane (SFN), a natural HDAC inhibitor, has been reported to alleviate obesity in humans and mice, the specific mechanisms and how HDACs contribute to SFN's anti-obesity effects remain unclear. METHODS AND RESULTS: Oral administration of SFN in mice fed high-fat diet increases peroxisome proliferator activating receptor γ coactivator (PGC1α)-induced mitochondrial biogenesis in skeletal muscle. Among HDACs, SFN specifically inhibits HDAC8 activity. SFN enhances mitochondrial DNA and adenosine triphosphate (ATP) production in C2C12 myotubes, similar to the action of PCI34051, a synthetic HDAC8-specific inhibitor. These effects are mediated by increased expression of PGC1α via upregulation of cAMP response element binding (CREB, Ser133 ) phosphorylation and p53 (Lys379 ) acetylation. These SFN-induced effects are not observed in cells with a genetic deletion of HDAC8, suggesting the existence of a regulatory loop between HDAC8 and PGC1α in SFN's action. CONCLUSION: SFN prevents obesity-related metabolic dysregulation by enhancing mitochondrial biogenesis and function via targeting the HDAC8-PGCα axis. These results suggest SFN as a beneficial anti-obesity agent providing new insight into the role of HDAC8 in the PGC1α-mediated mitochondrial biogenesis, which may be a novel and promising drug target for metabolic diseases.

Micro-grinding-based production for sulforaphene-enriched radish seeds extract via facilitating glucosinolates-myrosinase reaction, and evaluation of its anti-adipogenic effects.

Sulforaphene (SFEN), an isothiocyanate (ITC) abundant in radish (Raphanus sativus) seeds (RS), has many health benefits, including anti-obesity effects. SFEN content is affected by multiple factors during processing, such as glucoraphenin (GLE) (the precursor of SFEN) availability, myrosinase (essential for conversion from GLE to SFEN) activity, and SFEN stability. We examined the physiochemical-properties and anti-adipogenic effects of SFEN-enriched RSE produced by two processes, roasting and micro-grinding. The roasting process lowered SFEN content and myrosinase activity over 50 °C. However, among micro-grinding conditions, smaller particle size (#2 grind, ≈11.31 µm) more effectively increased SFEN content in RS compared to larger particles (#1 grind, ≈ 179.50 µm) by accelerating available GLE and myrosinase release from RS. Grind #2 also effectively inhibited the adipogenesis of 3T3-L1 pre-adipocytes compared to #1. Thus, micro-grinding can be suggested for producing SFEN-enriched RSE with anti-adipogenic activity as a functional material for obesity prevention or treatment.

Enhancing stability and bioavailability of sulforaphene in radish seed extracts using nanoemulsion made with high oleic sunflower oil.

The effect of nanoemulsions on the stability and bioavailability of sulforaphene (SFEN) in radish seed extract (RSE) was investigated. Four types of oil were used as lipid ingredients of the nanoemulsions: soybean, high oleic acid sunflower, coconut, and hydrogenated palm oils. SFEN in RSE nanoemulsions showed greater stability to temperature, acid, and alkaline conditions than SFEN in RSE suspended in water (RSE-S). Particularly under alkaline conditions, the half-life of SFEN in the nanoemulsion with high oleic sunflower oil (RSE-HOSO) was 8 times longer than that of RSE-S. Furthermore, in the pharmacokinetics study, it was observed that AUC0-8 increased and oral clearance (CL/F) decreased significantly in rats orally administered RSE-HOSO compared with RSE-S (p < 0.05). This study indicates that the type of oil used in nanoemulsions affects the stability and bioavailability of SFEN in RSE. These results may provide a guideline for the development of functional foods containing RSE. Supplementary Information: The online version contains supplementary material available at 10.1007/s10068-023-01304-2.

A machine learning-integrated stepwise method to discover novel anti-obesity phytochemicals that antagonize the glucocorticoid receptor.

As a type of stress hormone, glucocorticoids (GCs) affect numerous physiological pathways by binding to the glucocorticoid receptor (GR) and regulating the transcription of various genes. However, when GCs are dysregulated, the resulting hypercortisolism may contribute to various metabolic disorders, including obesity. Thus, attempts have been made to discover potent GR antagonists that can reverse excess-GC-related metabolic diseases. Phytochemicals are a collection of valuable bioactive compounds that are known for their wide variety of chemotypes. Recently, various computational methods have been developed to obtain active phytochemicals that can modulate desired target proteins. In this study, we developed a workflow comprising two consecutive quantitative structure-activity relationship-based machine learning models to discover novel GR-antagonizing phytochemicals. These two models collectively identified 65 phytochemicals that bind to and antagonize GR. Of these, nine commercially available phytochemicals were validated for GR-antagonist and anti-obesity activities. In particular, we confirmed that demethylzeylasteral, a phytochemical of the Tripterygium wilfordii Radix, exhibits potent anti-obesity activity in vitro through GR antagonism.

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

Adipocyte differentiation (adipogenesis) is a crucial process that determines the total number and size of mature adipocytes that will develop. In this study, the anti-adipogenic effect of sulforaphene (SFEN), a dietary isothiocyanate (ITC) derived from radish, is investigated both in 3T3-L1 pre-adipocytes and in human adipose tissue-derived stem cells. The results revealed that SFEN significantly inhibit adipogenic cocktail-induced adipocyte differentiation and lipid accumulation at the early stage of adipogenesis. Additionally, the effects are more potent compared to those of other ITCs derived from various cruciferous vegetables. As a related molecular mechanism of action, SFEN promotes the post-translational degradation of CCAAT/enhancer-binding protein (C/EBP) ß by decreasing the stability of C/EBPß, which is responsible for decreasing the expression of master regulatory proteins such as peroxisome proliferator-activated receptor γ and C/EBPα. Collectively, these results suggest that the intake of SFEN-enriched natural materials could be helpful as a strategy for preventing obesity.

5-(3',4'-Dihydroxyphenyl)-γ-valerolactone, a metabolite of procyanidins in cacao, suppresses MDI-induced adipogenesis by regulating cell cycle progression through direct inhibition of CDK2/cyclin O.

Cacao (Theobroma cacao) has a significant polyphenol content and has been reported to elicit anti-obesity effects. Previous studies have focused on the properties of cacao extract and procyanidins, while the potential mechanisms have not been fully elucidated. Here, we investigated the inhibitory effects of procyanidin metabolites on adipogenic cocktail-induced adipogenesis and lipogenesis in 3T3-L1 preadipocytes. It was observed that 5-(3',4'-dihydroxyphenyl)-γ-valerolactone (DHPV), a major procyanidin metabolite, exhibited the greatest inhibitory effects on adipogenesis and lipogenesis. DHPV dose-dependently reduced the expression levels of proteins involved in adipogenesis including peroxisome proliferator-activated receptor γ (PPAR γ) and CCAT/enhancer-binding protein α (C/EBP α), as well as lipogenesis-related factors such as fatty acid synthase and acetyl-CoA carboxylase. These inhibitory effects were primarily due to G1 phase arrest and the suppression of cell proliferation during mitotic clonal expansion, the early stage of adipogenesis. In an extensive kinase array, DHPV directly suppressed activation of the CDK2/cyclin O complex, and inhibited the phosphorylation of C/EBP ß, which is responsible for the induction of PPAR γ and C/EBP α. Taken together, these findings suggest that DHPV is a highly biologically active compound with potential anti-obesity effects and works by inhibiting the intracellular lipid content and cell differentiation.