Obesity is a medical condition of excess body fat negatively influencing morbidity and mortality via non-communicable disease risks. Adipogenesis, the process in which preadipocytes differentiate into adipocytes, plays a pivotal role in obesity. Our previous study proved that tannic acid (TA) showed anti-adipogenesis effect in 3T3-L1 preadipocytes. However, the precise mechanism involved in the inhibition in adipocytes differentiation by TA is unclear, and thus this is the subject of the present investigation. In this study, we determined the effect of TA on different stages of 3T3-L1 preadipocytes differentiation, and found that when treating in the early stage of differentiation, TA reduced lipid accumulation significantly. However, TA did not reduce lipid accumulation when treating in mid- and late-stages of adipocyte differentiation. To further study which gene TA had an impact on in the early stage of differentiation, we identified a number of genes associated with lipid metabolism. The results showed that compared to the control group, the mRNA levels of FAS, C/EBPα, and PPARγ were significantly decreased (p < 0.05), whereas the mRNA levels of adipsin, ap2 were increased (p < 0.05). However, TA had no effect on mRNA levels of ACC1 and ACC2. Western blot results showed that TA down-regulated the expression of PPARγ, which is a major factor in preadipocyte differentiation. In addition, TA did not affect the PI3 K/AKT pathway. These results indicate that the anti-adipogenesis effect of TA involves down-regulation of PPARγ in the early stage of 3T3-L1 preadipocyte differentiation. Some potential limitations of this study should be considered. All the results in this study were based on cell experiments. However, the human bioavailability of TA is not clear. In the present study, the concentration of TA was 5 μM; therefore, there were concerns about whether oral intake of TA could reach the effective concentrations. This important point needs to be clarified in vivo.

Dietary spices have been adopted in cooking since ancient times to enhance flavor and also as food preservatives and disease remedies. In China, the use of spices and other aromatic plants as food flavoring is an integral part of dietary behavior, but relatively little is known about their functions. Fatty acid synthase (FAS) has been recognized as a remedy target, and its inhibitors might be applied in disease treatment. The present work was designed to assess the inhibitory activities on FAS of spices extracts in Chinese menu. The in vitro inhibitory activities on FAS of 22 extracts of spices were assessed by spectrophotometrically monitoring oxidation of NADPH at 340 nm. Results showed that 20 spices extracts (90.9 %) exhibited inhibitory activities on FAS, with half inhibition concentration (IC50) values ranging from 1.72 to 810.7 μg/ml. Among them, seven spices showed strong inhibitory effect with IC50 values lower than 10 μg/ml. These findings suggest that a large proportion of the dietary spices studied possess promising inhibitory activities on FAS, and subsequently might be applied in the treatment of obesity and obesity-related human diseases.

Fatty acid synthase (FAS) has attracted more and more attention as a potential target for cancer treatment. Natural FAS inhibitors are emerging as potential therapeutic agents to treat cancer. Rheum tanguticum Maxim. ex Balf. (rhubarb) is a traditional Chinese nutritional food and has been reported to possess a variety of biological activities, including the ability to induce the apoptosis of cancer cells. This study indicates that desoxyrhaponticin (DC) and rhaponticin (RC), two stilbene glycosides from rhubarb, could be considered as promising FAS inhibitors. We found that both DC and RC could inhibit intracellular FAS activity and downregulate FAS expression in human breast cancer MCF-7 cells. In addition, the apoptotic effect of DC on human cancer cells was announced for the first time. Since FAS plays a key role in the biosynthesis pathway of fatty acids in cancer cells, these findings suggest that DC has potential applications in the prevention and treatment of cancer.

Fatty acid synthase (FAS) is highly expressed in many kinds of human cancers, including liver cancer. Curcumin is the major active ingredient of Curcuma longa and has long been used to treat a variety of maladies. In the present study, we investigated the potential use of curcumin as a kind of FAS inhibitor for chemoprevention of liver cancer. Curcumin induced HepG2 cell apoptosis with the IC50 value of 8.84 μg/ml. It inhibited intracellular FAS activity, and downregulated expression and mRNA level of FAS in a dose-dependent manner. In addition, sodium palmitate could rescue cell apoptosis induced by curcumin. Further studies reviewed that siRNA of FAS showed similar results as curcumin. These findings suggested that curcumin might be useful for preventing or treating liver cancer.

Fatty acid synthase (FAS) is overexpressed in many human cancers including breast cancer and is considered to be a promising target for therapy. Sea buckthorn has long been used to treat a variety of maladies. Here, we investigated the inhibitory effect of sea buckthorn procyanidins (SBPs) isolated from the seeds of sea buckthorn on FAS and FAS overexpressed human breast cancer MDA-MB-231 cells. The FAS activity and FAS inhibition were measured by a spectrophotometer at 340 nm of nicotinamide adenine dinucleotide phosphate (NADPH) absorption. We found that SBP potently inhibited the activity of FAS with a half-inhibitory concentration (IC50) value of 0.087 μg/ml. 3-4,5-Dimethylthiazol-2-yl-2,3-diphenyl tetrazolium bromide (MTT) assay was used to test the cell viability. SBP reduced MDA-MB-231 cell viability with an IC50 value of 37.5 μg/ml. Hoechst 33258/propidium iodide dual staining and flow cytometric analysis showed that SBP induced MDA-MB-231 cell apoptosis. SBP inhibited intracellular FAS activity with a dose-dependent manner. In addition, sodium palmitate could rescue the cell apoptosis induced by SBP. These results showed that SBP was a promising FAS inhibitor which could induce the apoptosis of MDA-MB-231 cells via inhibiting FAS. These findings suggested that SBP might be useful for preventing or treating breast cancer.

Fatty acid synthase (FAS) has been recognized as a potential therapeutic target for obesity. In this study, for the first time, the inhibitory effect of pomegranate husk extract, punicalagin and ellagic acid on FAS was investigated. We found them potently inhibiting the activity of FAS with half-inhibitory concentration values (IC50) of 4.1 μg/ml (pomegranate husk extract), 4.2 μg/ml (4.50 μM, punicalagin) and 1.31 μg/ml (4.34 μM, ellagic acid), respectively. Moreover, they all exhibited time-dependent inactivation of FAS. Punicalagin and ellagic acid inhibited FAS with different mechanisms compared to previously reported inhibitors, through inactivating acetyl/malonyl transferase and β-ketoacyl synthase domains, respectively. Additionally, 100 μg/ml pomegranate husk extract, 5.24 μg/ml (5 μM) punicalagin and 4.5 μg/ml (15 μM) ellagic acid effectively reduced lipid accumulation inside FAS over-expressed 3T3-L1 adipocytes. Since FAS plays a key role in the biosynthesis pathway of fatty acid, these findings suggest that pomegranate husk extract, punicalagin and ellagic acid have potential in the prevention and treatment of obesity.Highlights► Discover novel and high active FAS inhibitors isolated from pomegranate. ► The inhibitors obviously inhibited the lipid accumulation of 3T3-L1 pre-adipocytes. ► The inhibitory activity is rather than protein precipitation by tannin.

•We put forward a new hypothesis about the mechanism of fatty acid production ratio.•The geometric shape of KS domain active site is speculated as one of the determinates of fatty acid production ratio.•The binding site between KS domain and its substrate was analyzed by energy calculation and access tunnel analysis.•The most possible shape of fatty acid pathway in KS domain is a narrow channel.•The binding free energy between C16 acyl tail fatty acid and KS domain is lower than that of any other substrate analogs.Fatty acid synthase (FAS) is a multifunctional homodimeric protein, and is the key enzyme required for the anabolic conversion of dietary carbohydrates to fatty acids. FAS synthesizes long-chain fatty acids from three substrates: acetyl-CoA as a primer, malonyl-CoA as a 2 carbon donor, and NADPH for reduction. The entire reaction is composed of numerous sequential steps, each catalyzed by a specific functional domain of the enzyme. FAS comprises seven different functional domains, among which the β-ketoacyl synthase (KS) domain carries out the key condensation reaction to elongate the length of fatty acid chain. Acyl tail length controlled fatty acid synthesis in eukaryotes is a classic example of how a chain building multienzyme works. Different hypotheses have been put forward to explain how those sub-units of FAS are orchestrated to produce fatty acids with proper molecular weight. In the present study, molecular dynamic simulation based binding free energy calculation and access tunnels analysis showed that the C16 acyl tail fatty acid, the major product of FAS, fits to the active site on KS domain better than any other substrates. These simulations supported a new hypothesis about the mechanism of fatty acid production ratio: the geometric shape of active site on KS domain might play a determinate role.