In Vitro Screening and Lipid-Lowering Effect of Prickly Pear (Opuntia Ficus-Indica L. Mill.) Fruit Extracts in 3T3-L1 Pre-Adipocytes and Mature Adipocytes.

Opuntia ficus-indica fruits have been widely used due to their nutritional composition and beneficial effects on health, particularly against chronic diseases such as diabetes, obesity, cardiovascular diseases and cancer, among others. In recent years, prickly pear peel and pulp extracts have been characterised, and a high number of bioactive compounds have been identified. This study aimed to analyse the triglyceride-lowering effect of prickly pear peel and pulp extracts obtained from fruits of three varieties (Pelota, Sanguinos, and Colorada) in 3T3-L1 maturing and mature adipocytes. At a concentration of 50 µg/mL, peel extracts from Colorada reduced triglyceride accumulation in pre-adipocytes and mature adipocytes. Additionally, at 25 µg/mL, Pelota peel extract decreased triglyceride content in mature adipocytes. Moreover, maturing pre-adipocytes treated with 50 and 25 µg/mL of Sanguinos pulp extract showed a reduction of triglyceride accumulation. In addition, the lipid-lowering effect of the main individual betalain and phenolic compounds standards were assayed. Piscidic acid and isorhamnetin glycoside (IG2), found in Colorada peel extract, were identified as the bioactive compounds that could contribute more notably to the triglyceride-lowering effect of the extract. Thus, the betalain and phenolic-rich extracts from Opuntia ficus indica fruits may serve as an effective tool in obesity management.

Anti-Obesity Effects of Isorhamnetin and Isorhamnetin Conjugates.

Isorhamnetin is a plant-derived secondary metabolite which belongs to the family of flavonoids. This review summarises the main outcomes described in the literature to date, regarding the effects of isorhamnetin on obesity from in vitro and in vivo studies. The studies carried out in pre-adipocytes show that isorhamnetin is able to reduce adipogenesis at 10 µM or higher doses and that these effects are mediated by Pparγ and by Wnt signalling pathway. Very few studies addressed in rodents are available so far. It seems that treatment periods longer than two weeks are needed by isorhamnetin and its glycosides to be effective as anti-obesity agents. Nevertheless, improvements in glycaemic control can be observed even in short treatments. Regarding the underlying mechanisms of action, although some contradictory results have been found, reductions in de novo lipogenesis and fatty acid uptake could be proposed. Further research is needed to increase the scientific evidence referring to this topic; studies in animal models are essential, as well as randomised clinical trials to determine whether the positive results observed in animals could also be found in humans, in order to determine if isorhamnetin and its glycosides can represent a real tool against obesity.

Effects of Physiological Doses of Resveratrol and Quercetin on Glucose Metabolism in Primary Myotubes.

Phenolic compounds have emerged in recent years as an option to face insulin resistance and diabetes. The central aim of this study was: (1) to demonstrate that physiological doses of resveratrol (RSV) or quercetin (Q) can influence glucose metabolism in human myotubes, (2) to establish whether AMP-activated protein kinase (AMPK) and protein kinase B -PKB- (Akt) pathways are involved in this effect. In addition, the effects of these polyphenols on mitochondrial biogenesis and fatty acid oxidation were analysed. Myotubes from healthy donors were cultured for 24 h with either 0.1 µM of RSV or with 10 µM of Q. Glucose metabolism, such as glycogen synthesis, glucose oxidation, and lactate production, were measured with D[U-14C]glucose. ß-oxidation using [1-14C]palmitate as well as the expression of key metabolic genes and proteins by Real Time PCR and Western blot were also assessed. Although RSV and Q increased pgc1α expression, they did not significantly change either glucose oxidation or ß-oxidation. Q increased AMPK, insulin receptor substrate 1 (IRS-1), and AS160 phosphorylation in basal conditions and glycogen synthase kinase 3 (GSK3ß) in insulin-stimulated conditions. RSV tended to increase the phosphorylation rates of AMPK and GSK3ß. Both of the polyphenols increased insulin-stimulated glycogen synthesis and reduced lactate production in human myotubes. Thus, physiological doses of RSV or Q may exhibit anti-diabetic actions in human myotubes.

Effects of Quercetin Metabolites on Triglyceride Metabolism of 3T3-L1 Preadipocytes and Mature Adipocytes.

Quercetin (Q) has rapid metabolism, which may make it worthwhile to focus on the potential activity of its metabolites. Our aim was to evaluate the triglyceride-lowering effects of Q metabolites in mature and pre-adipocytes, and to compare them to those induced by Q. 3T3-L1 mature and pre-adipocytes were treated with 0.1, 1 and 10 µM of Q, tamarixetin (TAM), isorhamnetin (ISO), quercetin-3-O-glucuronide (3G), quercetin-3-O-sulfate (3S), as well as with 3S and quercetin-4-O-sulfate (4S) mixture (3S+4S). Triglyceride (TG) content in both cell types, as well as free fatty acid (FFA) and glycerol in the incubation medium of mature adipocytes were measured spectrophotometrically. Gene expression was assessed by RT-PCR. In mature adipocytes, Q decreased TG at 1 and 10 µM, 3S metabolite at 1 and 10 µM, and 3S+4S mixture at 10 µM. 3S treatment modified the glucose uptake, and TG assembling, but not lipolysis or apoptosis. During differentiation, only 10 µM of ISO reduced TG content, as did Q at physiological doses. In conclusion, 3S metabolite but not ISO, 3G, 4S and TAM metabolites can contribute to the in vivo delipidating effect of Q.

Anti-Obesity Effects of Microalgae.

In recent years, microalgae have attracted great interest for their potential applications in nutraceutical and pharmaceutical industry as an interesting source of bioactive medicinal products and food ingredients with anti-oxidant, anti-inflammatory, anti-cancer, and anti-microbial properties. One potential application for bioactive microalgae compounds is obesity treatment. This review gathers together in vitro and in vivo studies which address the anti-obesity effects of microalgae extracts. The scientific literature supplies evidence supporting an anti-obesity effect of several microalgae: Euglena gracilis, Phaeodactylum tricornutum, Spirulina maxima, Spirulina platensis, or Nitzschia laevis. Regarding the mechanisms of action, microalgae can inhibit pre-adipocyte differentiation and reduce de novo lipogenesis and triglyceride (TG) assembly, thus limiting TG accumulation. Increased lipolysis and fatty acid oxidation can also be observed. Finally, microalgae can induce increased energy expenditure via thermogenesis activation in brown adipose tissue, and browning in white adipose tissue. Along with the reduction in body fat accumulation, other hallmarks of individuals with obesity, such as enhanced plasma lipid levels, insulin resistance, diabetes, or systemic low-grade inflammation are also improved by microalgae treatment. Not only the anti-obesity effect of microalgae but also the improvement of several comorbidities, previously observed in preclinical studies, has been confirmed in clinical trials.

Involvement of 5'-Activated Protein Kinase (AMPK) in the Effects of Resveratrol on Liver Steatosis.

This review focuses on the role of 5'-activated protein kinase (AMPK) in the effects of resveratrol (RSV) and some RSV derivatives on hepatic steatosis. In vitro studies, performed in different hepatic cell models, have demonstrated that RSV is effective in preventing liver TG accumulation by activating AMPK, due to its phosphorylation. These preventive effects have been confirmed in studies conducted in animal models, such as mice and rats, by administering the phenolic compound at the same time as the diet which induces TG accumulation in liver. The literature also includes studies focused on other type of models, such as animals showing alcohol-induced steatosis or even steatosis induced by administering chemical products. In addition to the preventive effects of RSV on hepatic steatosis, other studies have demonstrated that it can alleviate previously developed liver steatosis, thus its role as a therapeutic tool has been proposed. The implication of AMPK in the delipidating effects of RSV in in vivo models has also been demonstrated.

Anti-Obesity Effect of Different Opuntia stricta var. dillenii's Prickly Pear Tissues and Industrial By-Product Extracts in 3T3-L1 Mature Adipocytes.

Opuntia stricta var. dillenii fruit is a source of phytochemicals, such as betalains and phenolic compounds, which may play essential roles in health promotion. The aim of this research was to study the triglyceride-lowering effect of green extracts, obtained from Opuntia stricta var. dillenii fruit (whole fruit, pulp, peel, and industrial by-products (bagasse)) in 3T3-L1 mature adipocytes. The cells were treated on day 12, for 24 h, after the induction of differentiation with the extracts, at doses of 10, 25, 50, or 100 µg/mL. The expression of genes (PCR-RT) and proteins (Western blot) involved in fatty acid synthesis, fatty acid uptake, triglyceride assembly, and triglyceride mobilisation was determined. The fruit pulp extraction yielded the highest levels of betalains, whereas the peel displayed the greatest concentration of phenolic compounds. The extracts from whole fruit, peel and pulp were effective in reducing triglyceride accumulation at doses of 50 µg/mL or higher. Bagasse did not show this effect. The main mechanisms of action underpinning this outcome encompass a reduction in fatty acids synthesis (de novo lipogenesis), thus limiting their availability for triglyceride formation, alongside an increase in triglyceride mobilisation. However, their reliance is contingent upon the specific Opuntia extract.

Glucuronide metabolites of trans-ε-viniferin decrease triglycerides accumulation in an in vitro model of hepatic steatosis.

Trans-ε-viniferin, a resveratrol dimer found mainly in grapevine wood, has shown protective capacities against hepatic steatosis in vivo. Nevertheless, this compound is very poorly bioavailable. Thus, the aim of the present study is to determine the potential anti-steatotic properties of 1 and 10 µM of trans-ε-viniferin and its four glucuronide metabolites in AML-12 cells treated with palmitic acid as an in vitro model of hepatic steatosis. The effect of the molecules in cell viability and triglyceride accumulation, and the underlying mechanisms of action by Real-Time PCR and Western Blot were analysed, as well as the quantification of trans-ε-viniferin and the identified bioactive metabolite inside cells and their incubation media. Interestingly, we were able to determine the triglyceride-lowering property of one of the glucuronides (trans-ε-viniferin-2-glucuronide), which acts on de novo lipogenesis, fatty acid uptake and triglyceride assembly. The glucuronides of trans-ε-viniferin would therefore be partly responsible for the in vivo observed anti-steatotic properties of the parent compound.

Polyphenols and metabolism: from present knowledge to future challenges.

A diet rich in polyphenols and other types of phytonutrients can reduce the occurrence of chronic diseases. However, a well-established cause-and-effect association has not been clearly demonstrated and several other issues will need to be fully understood before general recommendations will be carried out In the present review, some of the future challenges that the research on phenolic compounds will have to face in the next years are discussed: toxicological aspects of polyphenols and safety risk assessment; synergistic effects between different polyphenols; metabotype-based nutritional advice based on a differential gut microbial metabolism of polyphenols (precision nutrition); combination of polyphenols with other bioactive compounds; innovative formulations to improve the bioavailability of phenolic compounds; and polyphenols in sports nutrition and recovery.Other aspects related to polyphenol research that will have a boost in the next years are: polyphenol and gut microbiota crosstalk, including prebiotic effects and biotransformation of phenolic compounds into bioactive metabolites by gut microorganisms; molecular docking, molecular dynamics simulation, and quantum and molecular mechanics studies on the protein-polyphenol complexes; and polyphenol-based coating films, nanoparticles, and hydrogels to facilitate the delivery of drugs, nucleic acids and proteins.In summary, this article provides some constructive inspirations for advancing in the research of the applications, risk assessment and metabolic effects of dietary polyphenols in humans.

Beneficial Effects of ε-Viniferin on Obesity and Related Health Alterations.

Viniferin is a phenolic compound belonging to the group of stilbenoids. In particular, ε-viniferin is a dimer of resveratrol, found in many plant genders, among which grapes (Vitis vinifera) are a primary source. Due to the fact that ε-viniferin is mainly present in the woody parts of plants, their use as a source of this bioactive compound is a very interesting issue in a circular economy. Both, in vitro studies carried out in pre-adipocytes and mature adipocytes and in vivo studies addressed in mice show that ε-viniferin is able to reduce fat accumulation. Moreover, it prevents the development of some obesity co-morbidities, such as type 2 diabetes, dyslipidemias, hypertension and fatty liver. ε-viniferin can be absorbed orally, but it shows a very low bioavailability. In this scenario, further research on animal models is needed to confirm the effects reported in a great number of studies; to determine which metabolites are involved, including the main one responsible for the biological effects observed and the mechanisms that justify these effects. In a further phase, human studies should be addressed in order to use ε-viniferin as a new tool for obesity management, as a nutraceutical or to be included in functional foods.

Variability in the Beneficial Effects of Phenolic Compounds: A Review.

When analysing the beneficial effects of phenolic compounds, several factors that exert a clear influence should be taken into account. The content of phenolic compounds in foods is highly variable, directly affecting individual dietary intake. Once ingested, these compounds have a greater or lesser bioaccessibility, defined as the amount available for absorption in the intestine after digestion, and a certain bioavailability, defined as the proportion of the molecule that is available after digestion, absorption and metabolism. Among the external factors that modify the content of phenolic compounds in food are the variety, the cultivation technique and the climate. Regarding functional foods, it is important to take into account the role of the selected food matrix, such as dairy matrices, liquid or solid matrices. It is also essential to consider the interactions between phenolic compounds as well as the interplay that occurs between these and several other components of the diet (macro- and micronutrients) at absorption, metabolism and mechanism of action levels. Furthermore, there is a great inter-individual variability in terms of phase II metabolism of these compounds, composition of the microbiota, and metabolic state or metabotype to which the subject belongs. All these factors introduce variability in the responses observed after ingestion of foods or nutraceuticals containing phenolic compounds.

Scientific Evidence Supporting the Beneficial Effects of Isoflavones on Human Health.

Isoflavones are phenolic compounds with a chemical structure similar to that of estradiol. They are present in several vegetables, mainly in legumes such as soy, white and red clover, alfalfa and beans. The most significant food source of isoflavones in humans is soy-derived products. Isoflavones could be used as an alternative therapy for pathologies dependent on hormonal disorders such as breast and prostate cancer, cardiovascular diseases, as well as to minimize menopausal symptoms. According to the results gathered in the present review, it can be stated that there is scientific evidence showing the beneficial effect of isoflavones on bone health and thus in the prevention and treatment of osteoporosis on postmenopausal women, although the results do not seem entirely conclusive as there are discrepancies among the studies, probably related to their experimental designs. For this reason, the results should be interpreted with caution, and more randomized clinical trials are required. By contrast, it seems that soy isoflavones do not lead to a meaningful protective effect on cardiovascular risk. Regarding cancer, scientific evidence suggests that isoflavones could be useful in reducing the risk of suffering some types of cancer, such as breast and endometrial cancer, but further studies are needed to confirm these results. Finally, isoflavones could be useful in reducing hot flushes associated with menopause. However, a limitation in this field is that there is still a great heterogeneity among studies. Lastly, with regard to isoflavone consumption safety, it seems that they are safe and that the most common adverse effect is mild and occurs at the gastrointestinal level.

Anti-Obesity Effects of Macroalgae.

Macroalgae have attracted great interest for their potential applications in nutraceutical and pharmaceutical industries as source of bioactive medicinal products and food ingredients. This review gathers data from in vitro and in vivo studies addressing the anti-obesity effects of macroalgae. Great consensus exists in all reported in vitro studies concerning the reduction induced by seaweed extracts in the expression of transcriptional factors controlling adipogenesis. In animals, macroalgae reduced body fat accumulation and prevented other obesity features, such as dyslipidemia, insulin resistance and fatty liver. These effects are not due to food intake reduction, since few studies have reported such event. Indeed, the effects on metabolic pathways in target tissues/organs seem to play a more relevant role. Macroalgae can reduce de novo lipogenesis, limiting fatty acid availability for triglyceride synthesis in white adipose tissue. This effect has been observed in both cell cultures and adipose tissue from animals treated with macroalgae extracts. In addition, increased fatty acid oxidation and thermogenic capacity, as well as a shift towards healthier gut microbiota composition may contribute to the body fat-lowering effect of macroalgae. Studies in humans are needed to determine whether macroalgae can represent a feasible tool to prevent and/or manage overweight and obesity.

Lipid metabolism in adipose tissue and liver from diet-induced obese rats: a comparison between Wistar and Sprague-Dawley strains.

Some researchers have proposed important variations in adipose tissue among different strains of rats and mice in response to a high-caloric (hc) diet, but data concerning the mechanisms underlying these differences are scarce. The aim of the present research was to characterize different aspects of triacylglycerol (TG) metabolism and clock genes between Sprague-Dawley and Wistar rats. For this purpose, 16 male Sprague-Dawley and 16 male Wistar rats were divided into four experimental groups (n = 8) and fed either a normal-caloric (nc) diet or a hc diet for 6 weeks. After sacrifice, liver and epididymal, perirenal, mesenteric, and subcutaneous adipose tissue depots were dissected, weighed and immediately frozen. Liver TG content was quantified, RNA extracted for gene expression analysis and fatty acid synthase enzyme activity measured. Two-way ANOVA and Student's t test were used to perform the statistical analyses. Under hc feeding conditions, Wistar rats were more prone to fat accumulation in adipose tissue, especially in the epididymal fat depot, due to their increased lipogenesis and fatty acid uptake. By contrast, both strains of rats showed similarly fatty livers after hc feeding. Peripheral clock machinery seems to be a potential explanatory mechanism for Wistar and Sprague-Dawley strain differences. In conclusion, Wistar strain seems to be the best choice as animal model in dietary-induced obesity studies.

Potential miRNA involvement in the anti-adipogenic effect of resveratrol and its metabolites.

OBJECTIVE: Scientific research is constantly striving to find molecules which are effective against excessive body fat and its associated complications. Taking into account the beneficial effects that resveratrol exerts on other pathologies through miRNA, the aim of the present work was to analyze the possible involvement of miRNAs in the regulation of adipogenic transcription factors peroxisome proliferator-activated receptor γ (pparγ), CCAAT enhancer-binding proteins α and ß (cebpß and cebpα) induced by resveratrol and its metabolites. METHODS: 3T3-L1 maturing pre-adipocytes were treated during differentiation with 25 µM of trans-resveratrol (RSV), trans-resveratrol-3-O-sulfate (3S), trans-resveratrol-3'-O-glucuronide (3G) and trans-resveratrol-4'-O-glucuronide (4G). After computational prediction and bibliographic search of miRNAs targeting pparγ, cebpß and cebpα, the expression of microRNA-130b-3p (miR-130b-3p), microRNA-155-5p (miR-155-5p), microRNA-27b-3p (miR-27b-3p), microRNA-31-5p (miR-31-5p), microRNA-326-3p (miR-326-3p), microRNA-27a-3p (miR-27a-3p), microRNA-144-3p (miR-144-3p), microRNA-205-5p (miR-205-5p) and microRNA-224-3p (miR-224-3p) was analyzed. Moreover, other adipogenic mediators such as sterol regulatory element binding transcription factor 1 (srebf1), krüppel-like factor 5 (klf5), liver x receptor α (lxrα) and cAMP responding element binding protein 1 (creb1), were measured by Real Time RT-PCR. As a confirmatory assay, cells treated with RSV were transfected with anti-miR-155 in order to measure cebpß gene and protein expressions. RESULTS: Of the miRNAs analyzed only miR-155 was modified after resveratrol and glucuronide metabolite treatment. In transfected cells with anti-miR-155, RSV did not reduce cebpß gene and protein expression. 3S decreased gene expression of creb1, klf5, srebf1 and lxrα. CONCLUSIONS: While RSV and glucuronide metabolites exert their inhibitory effect on adipogenesis through miR-155 up-regulation, the anti-adipogenic effect of 3S is not mediated via miRNAs.

Are miRNA-103, miRNA-107 and miRNA-122 Involved in the Prevention of Liver Steatosis Induced by Resveratrol?

The aim of the present study was to determine whether the reduction in liver fat previously observed in our laboratory in a cohort of rats which had been fed an obesogenic diet was mediated by changes in the expression of microRNA (miRNA)-103-3p, miRNA-107-3p and miRNA-122-5p, which represent 70% of total miRNAs in the liver, as well as in their target genes. The expression of the three analysed miRNAs was reduced in rats treated with resveratrol. A reduction in sterol-regulatory element binding protein 1 (SREBP1) and an increase in carnitine palmitoyltransferase 1a (CPT1a) were observed in resveratrol-treated rats. No changes were found in fatty acid synthase (FAS). In cultured hepatocytes, SREBP1 protein was increased after the transfection of each miRNA. FAS protein expression was decreased after the transfection of miRNA-122-5p, and CPT1a protein was down-regulated by the over-expression of miRNA-107-3p. This study provides new evidences which show that srebf1 is a target gene for miRNA-103-3p and miRNA-107-3p, fasn a target gene for miRNA-122-5p and cpt1a a target gene for miRNA-107-3p. Moreover, the reduction in liver steatosis induced by resveratrol in rats fed an obesegenic diet is mediated, at least in part, by the increase in CPT1a protein expression and activity, via a decrease in miRNA-107-3p expression.

Screening of potential anti-adipogenic effects of phenolic compounds showing different chemical structure in 3T3-L1 preadipocytes.

This study was designed to analyze the anti-adipogenic effect of fifteen phenolic compounds from various chemical groups in 3T3-L1 pre-adipocytes. Cells were treated with 25 µM, 10 µM or 1 µM of apigenin, luteolin, catechin, epicatechin, epigallocatechin, genistein, daizein, naringenin, hesperidin, quercetin, kaempferol, resveratrol, vanillic acid, piceatannol and pterostilbene for 8 days. At 25 µM lipid accumulation was reduced by all the compounds, with the exception of catechin, epicatechin and epigallocatechin. At a dose of 10 µM apigenin, luteolin, naringenin, hesperidin, quercetin and kaempferol induced significant reductions, and at 1 µM only naringenin, hesperidin and quercetin were effective. The expression of c/ebpα was not. C/ebpß was significantly reduced by genistein and kaempferol, pparγ by genistein and pterostilbene, srebp1c by luteolin, genistein, hesperidin, kaempferol, pterostilbene and vanillic acid, and lpl by kaempferol. In conclusion, the most effective phenolic compounds are naringenin, hesperidin and quercetin. Differences were found in terms of effects on the expression of genes involved in adipogenesis among the analyzed compounds.

Involvement of miR-539-5p in the inhibition of de novo lipogenesis induced by resveratrol in white adipose tissue.

The epigenetic mechanisms of action of resveratrol as an anti-obesity molecule have not been fully addressed so far. The aim of the present study was to assess changes produced by resveratrol in the microRNA (miRNA) profile in white adipose tissue (WAT) and to relate these changes to those induced in the expression of genes involved in triacylglycerol metabolism. Male Wistar rats were fed (6 weeks) an obesogenic diet: a control group and a group treated with resveratrol (30 mg kg(-1) d(-1)). A miRNA microarray was carried out in perirenal adipose tissue. The overexpression of miR-539-5p and miR-1224-5p was performed in 3T3-L1 cells. Protein expression was analysed by western-blot and gene expression by qRT-PCR. Associations between variables were assessed by Pearson's correlations. The microarray showed that 3 miRNAs were decreased and 13 were increased after resveratrol treatment. Among those miRNAs increased, miR-129, miR-328-5p and miR-539-5p showed predicted target genes relevant for triacylglycerol metabolism in WAT (pparγ: peroxisome proliferator-activated receptor gamma, hsl: hormone sensitive lipase and sp1: SP1 transcription factor) in the miRWalk database. Moreover, the literature shows that miR-1224, another miRNA up-regulated by resveratrol, can also regulate sp1. Among the three targets, only SP1 showed a reduction in protein expression. Correlation and overexpression studies revealed that the decrease in SP1 protein expression was only associated with the increase of miR-539-5p. In addition, significant reductions in SREBP1 protein expression and fasn gene expression were found in resveratrol-treated rats. In conclusion, the up-regulation of miR-539-5p is involved in the inhibition of de novo lipogenesis induced by resveratrol in WAT.

Doses of Quercetin in the Range of Serum Concentrations Exert Delipidating Effects in 3T3-L1 Preadipocytes by Acting on Different Stages of Adipogenesis, but Not in Mature Adipocytes.

SCOPE: To determine whether doses of quercetin in the range of serum concentrations exert any effect on triacylglycerol accumulation in maturing preadipocytes and mature adipocytes. The influence on the expression of adipogenic markers as well as on gene expression and activity of enzymes involved in triacylglycerol metabolism were assessed. METHODS AND RESULTS: 3T3-L1 preadipocytes were treated during differentiation and mature adipocytes for 24 hours with low doses (0.1-10 µM) of quercetin. Triacylglycerol content in both cell types and free fatty acid and glycerol in the incubation medium of mature adipocytes were measured spectrophotometrically. Gene and protein expression were assessed by RT-PCR and Western blot. LPL and FAS activities were quantified. During differentiation quercetin reduced triacylglycerol content at doses from 0.5 to 10 µM. 1 µM of quercetin reduced C/EBPß gene expression, SREBP1 mature protein levels, and PPARγ gene expression. 10 µM of quercetin reduced LPL gene expression and PPARγ and SREBP1c expression. In mature adipocytes, only 10 µM of quercetin reduced triacylglycerol content. Lipogenic FAS expression and activity were reduced at this dose. CONCLUSION: Quercetin, in the range of serum concentrations, is able to inhibit adipogenesis, but higher doses, at least 10 µM, are needed to reduce fat accumulation in mature adipocytes.

Resveratrol metabolites modify adipokine expression and secretion in 3T3-L1 pre-adipocytes and mature adipocytes.

OBJECTIVE: Due to the low bioavailability of resveratrol, determining whether its metabolites exert any beneficial effect is an interesting issue. METHODS: 3T3-L1 maturing pre-adipocytes were treated during differentiation with 25 µM of resveratrol or with its metabolites and 3T3-L1 mature adipocytes were treated for 24 hours with 10 µM resveratrol or its metabolites. The gene expression of adiponectin, leptin, visfatin and apelin was assessed by Real Time RT-PCR and their concentration in the incubation medium was quantified by ELISA. RESULTS: Resveratrol reduced mRNA levels of leptin and increased those of adiponectin. It induced the same changes in leptin secretion. Trans-resveratrol-3-O-glucuronide and trans-resveratrol-4'-O-glucuronide increased apelin and visfatin mRNA levels. Trans-resveratrol-3-O-sulfate reduced leptin mRNA levels and increased those of apelin and visfatin. CONCLUSIONS: The present study shows for the first time that resveratrol metabolites have a regulatory effect on adipokine expression and secretion. Since resveratrol has been reported to reduce body-fat accumulation and to improve insulin sensitivity, and considering that these effects are mediated in part by changes in the analyzed adipokines, it may be proposed that resveratrol metabolites play a part in these beneficial effects of resveratrol.