Effects of resveratrol and quercetin metabolites in adipogenesis and triglyceride metabolism of 3T3-L1 adipocytes and comparison to those of the parent compounds

305 p.El Resveratrol y la Quercetina son dos ingredientes funcionales a los que se les ha atribuido efecto reductor de grasa en diversos experimentos in vivo e in vitro. Sin embargo, su rápido metabolismo hace que solo una pequeña cantidad de estos compuestos lleguen al plasma y a los tejidos. Por esta razón, determinar si los metabolitos que derivan de estos compuestos fenólicos poseen o no actividad reductora de grasa es de gran interés. La presente tesis muestra por un lado, los resultados obtenidos tras el tratamiento con los principales metabolitos del resveratrol en pre-adipocitos en maduración y en adipocitos maduros 3T3-L1 y el análisis de sus posibles mecanismos de acción. Por otro lado, se analiza el potencial efecto de los metabolitos de la quercetina en el mismo tipo de células y las vías por las que ejercen esa función. Los resultados obtenidos demuestran que todos los metabolitos analizados del resveratrol contribuyen, en la misma medida que el polifenol, a la inhibición de la adipogenesis. En adipocitos maduros, aunque resultan activos, el resveratrol es mucho más eficaz. En el caso de la quercetina, solo se le puede atribuir este efecto al metabolito sulfatado y en adipocitos maduros únicamente. Ninguno de los metabolitos de la quercetina resulta eficaz en la inhibición de la adipogenesis. Por lo tanto, se puede concluir que el metabolismo de estos dos compuestos puede suponer una limitación en el caso de adipocitos maduros tratados con resveratrol y pre-adipocitos en maduración tratados con quercetina

Effects of resveratrol and quercetin metabolites in adipogenesis and triglyceride metabolism of 3T3-L1 adipocytes and comparison to those of the parent compounds

305 p.El Resveratrol y la Quercetina son dos ingredientes funcionales a los que se les ha atribuido efecto reductor de grasa en diversos experimentos in vivo e in vitro. Sin embargo, su rápido metabolismo hace que solo una pequeña cantidad de estos compuestos lleguen al plasma y a los tejidos. Por esta razón, determinar si los metabolitos que derivan de estos compuestos fenólicos poseen o no actividad reductora de grasa es de gran interés. La presente tesis muestra por un lado, los resultados obtenidos tras el tratamiento con los principales metabolitos del resveratrol en pre-adipocitos en maduración y en adipocitos maduros 3T3-L1 y el análisis de sus posibles mecanismos de acción. Por otro lado, se analiza el potencial efecto de los metabolitos de la quercetina en el mismo tipo de células y las vías por las que ejercen esa función. Los resultados obtenidos demuestran que todos los metabolitos analizados del resveratrol contribuyen, en la misma medida que el polifenol, a la inhibición de la adipogenesis. En adipocitos maduros, aunque resultan activos, el resveratrol es mucho más eficaz. En el caso de la quercetina, solo se le puede atribuir este efecto al metabolito sulfatado y en adipocitos maduros únicamente. Ninguno de los metabolitos de la quercetina resulta eficaz en la inhibición de la adipogenesis. Por lo tanto, se puede concluir que el metabolismo de estos dos compuestos puede suponer una limitación en el caso de adipocitos maduros tratados con resveratrol y pre-adipocitos en maduración tratados con quercetina

Zerk eragiten du obesitatea duen pertsona bat metabolikoki osasuntsua izatea edo ez izatea?

Obesitatea osasun-arazo garrantzitsua bihurtu da xxi. mendean, mundu osoan milioika pertsonei eragiten diena. Obesitatearekin batera hainbat komorbilitate agertzen direla onartuta dago, eta horiek bizi-itxaropena murriztearekin lotzen dira. Hala ere, obesitatea pairatzen duten pertsona guztiengan ez da egoera hori antzeman; izan ere, ikusi izan da hainbatek obesitatearekin lotutako asaldura kardiometabolikoen aurrean babesa erakusten dutela. Obesitatea pairatzen duten baina komorbilitaterik ez duten horiek metabolikoki osasuntsuak diren obesoak (MOO) dira. Gaur egun, MOO kontzeptuaren definizioa aldatu egiten da iturri bibliografikoen arabera; hortaz, ez da oso zehatza. Gainera, MOO identifikatzeko irizpide unibertsalik ez dagoenez, prebalentzia-datuak nabarmen aldatzen dira ikerketen artean. MOO eta metabolikoki osasuntsuak ez diren obesoen (MOEO) artean hainbat ezberdintasun fisiologiko, funtzional eta patologiko identifikatu dira: MOOek, adibidez, intsulinarekiko sentikortasunari eusten diote, eta ez dute ez hipertentsiorik ez dislipemiarik pairatzen. Gainera, MOOak 2 motako diabetesaren, gaixotasun kardiobaskularren eta beste heriotza-kausen aurrean babestuta daudela ikusi izan da. Ezberdintasun horien erantzuleetako batzuk MOOen eta MOEOen artean ezberdina den erraietako gantzaren metaketa eta gantz-ehunaren disfuntzioa direla proposatu da. Ondorioz, gorputz-masaren indizea komorbilitateen eraginez agertuko diren konplikazioen larritasunarekin zuzenki erlazionatuta egon arren, gantz-metaketaren kokalekuak eta gantz-ehunaren disfuntzioak erlazio zuzenagoa dute obesitatearekin batera etorri ohi diren komorbilitateen garapenarekin.; Obesity has become a major health problem in the 21st century, affecting millions of people around the world. It is assumed that obesity is accompanied by different comorbidities that are related to a reduction in life expectancy. However, this situation has not been seen in all people with obesity, since it has been observed that some obese people show protection against cardiometabolic disorders related to obesity, a condition known as metabolically healthy obesity (MHO). At present, the definition of MHO varies according to the bibliographic source used, so it is not very precise. Furthermore, in the absence of universal criteria for identification of MHO, prevalence data vary between investigations. Some physiological, functional and pathological differences have been identified between MHO and metabolically unhealthy obesity (MUO): individuals with MHU, for example, retain insulin sensitivity and do not suffer from hypertension or dyslipidemia compared to MUO. In addition, people with MHO are protected against type 2 diabetes, cardiovascular disease and other causes of death. Some responsible for these differences are the accumulation of visceral fat and the dysfunction of the adipose tissue. Consequently, despite the fact that the body mass index is directly related to the severity of the complications derived from obesity-related comorbidities, it can be stated that fat location and adipose tissue dysfunction are even more directly related

Involvement of 5′AMP-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.This study was supported by grants from the Instituto de Salud Carlos III (CIBERObn), Government of the Basque Country (IT-572-13)

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.This study was supported by grants from the Ministerio de Economia y Competitividad (AGL-2015-65719-FEDER-UE), Instituto de Salud Carlos III (CIBERobn), Government of the Basque Country (IT-572-13) and University of the Basque Country (UPV/EHU) (ELDUNANOTEK UFI11/32). A. Gracia is a PhD fellowship from the Ministerio de Economia y Competitividad

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.This research was funded by CIBEROBN under Grant CB12/03/30007 and the Government of the Basque Country (IT1482-22)

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

henolic 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. β-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 β-oxidation. Q increased AMPK, insulin receptor substrate 1 (IRS-1), and AS160 phosphorylation in basal conditions and glycogen synthase kinase 3 (GSK3β) in insulin-stimulated conditions. RSV tended to increase the phosphorylation rates of AMPK and GSK3β. 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.This research has been supported by Instituto de Salud Carlos III (CIBERObn) under Grant CB12/03/30007 (01/2013) and by the University of the Basque Country under Grant GIU18-173 (07/2018)

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.This study was supported by Instituto de Salud Carlos III (CIBERobn) under Grant CB12/03/30007, Basque Government under Grant PA20/04 and the University of the Basque Country under Grant GIU18-17

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 M 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 M, 3S metabolite at 1 and 10 M, and 3S+4S mixture at 10 M. 3S treatment modified the glucose uptake, and TG assembling, but not lipolysis or apoptosis. During differentiation, only 10 M 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.This research has been supported by Instituto de Salud Carlos III (CIBERobn), Basque Government (IT-572-13) and MINECO (AGL2015-64522-C2-2-R). Itziar Eseberri is a recipient of a doctoral fellowship from the University of the Basque Country. Andrea Mosqueda-Solís is a recipient of a doctoral fellowship from the CONACYT (Mexico)

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.This study was supported by Instituto de Salud Carlos III (CIBERobn) under Grant CB12/03/30007