Search

The present review is aimed at analysing the current evidence concerning the potential modulation of obesity and/or diet in adipose tissue ACE2. Additionally, the potential implications of these effects on COVID-19 are also addressed. The results published show that diet and obesity are two factors that effectively influence the expression of Ace2 gene in adipose tissue. However, the shifts in this gene do not always occur in the same direction, nor with the same intensity. Additionally, there is no consensus regarding the implications of increased adipose tissue ACE2 expression in health. Thus, while in some studies a protective role is attributed to ACE2 overexpression, other studies suggest otherwise. Similarly, there is much debate regarding the role played by ACE2 in COVID-19 in terms of degree of infection and disease outcomes. The greater risk of infection that may hypothetically derive from enhanced ACE2 expression is not clear since the functionality of the enzyme seems to be as important as the abundance. Thus, the greater abundance of ACE2 in adipose tissue of obese subjects may be counterbalanced by its lower activation. In addition, a protective role of ACE2 overexpression has also been suggested, associated with the increase in anti-inflammatory factors that it may produce., This research was funded by the University of the Basque Country under Grant GIU18-173 and CIBEROBN under Grant CB12/03/30007

Nephroblastoma overexpressed protein, also called NOV/CCN3, is an adipokine which is present in various tissues and recently linked to obesity. The objective of the study was to determine the effect of resveratrol and pterostilbene on NOV/CCN3 in adipose tissue from rats fed an obesogenic diet. Thirty-six male Wistar rats were split into four groups (n = 9): fed a standard diet (CC), high-fat high-sucrose (HFS) diet supplemented with resveratrol (RSV; 30 mg/kg/day) or with pterostilbene (PT; 30 mg/kg/day), or without phenolic supplementation (HFS). Rats were sacrificed after 6 weeks of treatment, and adipose tissue (white and brown) from different anatomical locations were dissected. Then, Nov/ccn3 gene and protein expression and the adipogenic genes, Ucp-1 and Pgc-1a, expressions were studied. Increased weight of white adipose tissues was found in rats fed the HFS diet. Whereas resveratrol-treated rats showed reduced internal and total adipose tissue weights, pterostilbene-treated rats showed reduced subcutaneous, internal and total adipose depots. Nov/ccn3 gene expression decreased in epididymal and interscapular brown depot in rats fed HFS diet when compared with the control group. Regarding the phenolic compounds, resveratrol prompted a Nov/ccn3 gene expression increase in epididymal fat tissue, whereas pterostilbene reduced its protein expression compared with the obese group. However, these phenolic compounds did not affect NOV/CCN3 expression in brown depot. NOV/CCN3 seems to be involved in weight changes in epididymal adipose tissue under obesogenic feeding, but not in subcutaneous, acting as a protective mechanism counteracting the fattening effect of the diet. To our knowledge, this is the first study analyzing whether NOV/CCN3 is involved in the anti-obesity effect of resveratrol and pterostilbene. Our results suggest that this is not the case.

Resveratrol and its 2-methoxy derivative pterostilbene are two phenolic compounds that occur in foodstuffs and feature hepato-protective effects. This study is devoted to analysing and comparing the metabolic effects of pterostilbene and resveratrol on gut microbiota composition in rats displaying NAFLD induced by a diet rich in saturated fat and fructose. The associations among changes induced by both phenolic compounds in liver status and those induced in gut microbiota composition were also analysed. For this purpose, fifty Wistar rats were distributed in five experimental groups: a group of animals fed a standard diet (CC group) and four additional groups fed a high-fat high-fructose diet alone (HFHF group) or supplemented with 15 or 30 mg/kg bw/d of pterostilbene (PT15 and PT30 groups, respectively) or 30 mg/kg bw/d of resveratrol (RSV30 group). The dramatic changes induced by high-fat high-fructose feeding in the gut microbiota were poorly ameliorated by pterostilbene or resveratrol. These results suggest that the specific changes in microbiota composition induced by pterostilbene (increased abundances of Akkermansia and Erysipelatoclostridium, and lowered abundance of Clostridum sensu stricto 1) may not entirely explain the putative preventive effects on steatohepatitis. This research was funded by Ministerio de Economía y Competitividad-Fondo Europeo de Desarrollo Regional (grant number AGL-2015-65719-R MINECO/FEDER, UE), Instituto de Salud Carlos III CIBERobn (grant number CB12/03/30007); University of the Basque Country (grant number GIU 18/173).

The use of phenolic compounds as a new therapeutic approach against NAFLD has emerged recently. In the present study, we aim to study the effect of pterostilbene in the prevention of liver steatosis developed as a consequence of high-fat (saturated) high-fructose feeding, by analysing the changes induced in metabolic pathways involved in triglyceride accumulation. Interestingly, a comparison with the anti-steatotic effect of its parent compound resveratrol will be made for the first time. Rats were distributed into 5 experimental groups and fed either a standard laboratory diet or a high-fat high-fructose diet supplemented with or without pterostilbene (15 or 30 mg per kg per d) or resveratrol (30 mg per kg per d) for 8 weeks. Serum triglyceride, cholesterol, NEFA and transaminase levels were quantified. Liver histological analysis was carried out by haematoxylin-eosin staining. Different pathways involved in liver triglyceride metabolism, including fatty acid synthesis, uptake and oxidation, triglyceride assembly and triglyceride release, were studied. Pterostilbene was shown to partially prevent high-fat high-fructose feeding induced liver steatosis in rats, demonstrating a dose-response pattern. In this dietary model, it acts mainly by reducing de novo lipogenesis and increasing triglyceride assembly and release. Improvement in mitochondrial functionality was also appreciated. At the same dose, the magnitude of pterostilbene and resveratrol induced effects, as well as the involved mechanisms of action, were similar.

The white adipose tissue (WAT), which is made up of adipocytes, is the main energy storage in the body. Depending on its distribution within the body, subcutaneous WAT (SWAT) and visceral WAT (VWAT) can be differentiated. With regard to adipocytes, those in the VWAT are metabolically more active than those from the SWAT, which tend to be bigger and have greater capacity to bind lipids. Obesity induces WAT expansion in two ways: increasing the amount of adipocytes, or increasing their size (hyperplasia and hypertrophy, respectively).These changes can affect the adequate functioning of this tissue. In this context, the WAT expansion driven by hypertrophy tend to be associated with obesity and related metabolic alterations. In order to highlight the importance of adipocyte hyperplasia and hypertrophy in the development of obesity related comorbidities, the terms "metabolically healthy obese" and "false slim" have been proposed. The first one refers to those subjects who don’t present metabolic alterations other than obesity itself. By contrast, the latter tend to have higher pro-inflammatory cytokine blood levels even though their body weight is normal. Altogether, it is clear the necessity of more research devoted to characterizing both, the expansion of adipose tissue in obese subjects and methods to identify "metabolically healthy obese" and "false slim" subjects.; Gantz-ehun zuria (GEZ) gorputzeko energia-biltegia da eta adipozito izena duten zelulez osaturik dago. Giza gorputzean duen kokalekuaren arabera, larruazalpeko GEZ (LGEZ) eta erraietako GEZ (EGEZ) bereizten dira. Adipozitoei dagokienez, EGEZko adipozitoak LGEZkoak baino aktiboagoak dira metabolikoki; azken horiek, berriz, tamaina handiagoa eta lipidoak hartzeko gaitasun handiagoa dute. Obesitateak GEZren hazkunde edo hedapena eragiten du, bi modutan: adipozitoen kopurua edo tamaina handituz (hiperplasia eta hipertrofia, hurrenez hurren). GEZn gertatzen diren aldaketa horiek, ehun honen funtzionamendu egokian eragin dezakete. Horrela, hipertrofia bidez gertatzen den GEZren hedapena obesitatearekin eta hari lotutako gaixotasun metabolikoekin erlazio- natzen da. Adipozitoen hipertrofiak eta hiperplasiak obesitatearekin lotutako komorbilitateetan duten garrantziaz jabetzeko, "metabolikoki osasuntsuak diren obesoak" eta "argal faltsuak" terminoak aipatu behar dira. Lehenengoen kasuan, obesitateaz gain ez da gainerako asaldura metabolikorik izango. Bigarrengoen kasuan, berriz, pisu egokia izan arren zitokina hantura-eragileen maila handiagoak izaten dituzte odolean. Etorkizunari begira, argi geratzen da pertsona obesoen gantz-gordailuen hedapena ezaugarritu eta "metabolikoki osasuntsuak diren obesoak" zein "argal faltsuak" identifikatzea ahalbidetuko duten ikerketa gehiagoren beharra.

Cancer is one of the most important public health problems of the last years, due to the fact that tumour incidence has increased dramatically over the last decade. Among other factors, the dietary pattern notably influences the development of cancer, as well as obesity and its comorbidities do. They increase the risk of developing several types of cancer: thyroid, esophagus, liver, gallbladder, colon, kidney and multiple myeloma cancer in men and women, breast and endometrium cancer in women and prostate cancer in men. However, the mechanism by which obesity can induce cancer has not been widely investigated. The known mechanisms that contribute to the association between cancer and obesity are related to hormonal changes, such as insulin and insulin-like growth hormone-1 (IGF-1), or sex steroids. Not only hormones can affect cancer development, but also adipokines (leptin and adiponectin) and inflammation. In the same way, patients with obesity and cancer have a higher risk of suffering metastasis, consequently having a lower survival rate. As pre-clinical research has shown, obesity can induce metastasis in melanoma and lung cancer models. Since it has been reported a relationship between obesity and a high mortality rate in oncological patients, it is essential to use drugs to treat obesity and metabolic syndrome in cancer patients, such as metformin, thiazolidinediones and statins. Finally, it is noteworthy to mention that further research is needed to better understand the mechanisms involved in this process, and even to find biomarkers that may be useful for an early cancer diagnosis.; Minbizia egungo osasun-arazo publiko garrantzitsuenetarikoa da; izan ere, tumoreen intzidentzia izugarri handitu da azken hamarkadetan. Beste faktore askoren artean, elikadura-patroiak nabarmen eragiten du minbiziaren garapenean; hala nola, obesitateak eta haren komorbilitateek. Hainbat minbizi mota garatzeko arriskua areagotzen dute, besteak beste gizon eta emakumezkoetan tiroide, hestegorri, gibel, behazun-besikula, kolon, giltzurrun eta mieloma anitzeko minbiziak, bular eta endometrioko minbiziak emakumezkoen kasuan eta prostatakoa gizonezkoenean. Azken urteetan nahiko ikertu da obesitatea-minbizia harremanean, baina oraindik ez dira ondorio garbiak lortu erlazio hori ezartzen duten mekanismo-multzoei dagokienez. Minbiziaren eta obesitatearen arteko asoziazioari laguntzen dioten mekanismoak aldaketa hormonalekin erlazionaturikoak izaten dira, besteak beste intsulina, intsulinaren antzekoa den 1 hazkuntza hormona (IGF-1) edo sexu esteroideak. Hormonak ez ezik, adipokinek (leptina eta adiponektina) eta hanturak ere parte hartzen dute minbiziaren garapenean.Era berean, obesitatea eta minbizia pairatzen duten pazienteek metastasi-arrisku handiagoa dute, eta ondorioz, biziraupen-ratio baxuagoa. Ikerketa pre-klinikoetan ikusi ahal izan denez, obesitateak metastasia bultzatzen du melanoma eta birika-minbizi ereduetan. Obesitateak paziente onkologikoen hilkortasun-tasa altuarekin duen lotura ikusita, ezinbestekotzat jotzen da minbizia duten pazienteetan, elikadura-patroi osasuntsuarekin eta jarduera fisikoarekin batera, obesitatea eta sindrome metabolikoa tratatzeko farmakoen erabilera; besteak beste, metformina, tiazolidinedionak eta estatinak erabili ohi dira. Amaitzeko, aipatzekoa da ikerlan gehiagoren beharra dagoela parte hartzen duten mekanismoak ondo ulertu ahal izateko, eta are gehiago, etorkizunean minbiziaren diagnostiko goiztiarrerako baliagarriak izan litezkeen bio-markatzaileak aurkitzeko.

The anti-obesity effects of resveratrol shown in rodents are not transposed into an efficient therapy of human obesity. Consequently, the search for molecules mimicking or surpassing resveratrol actions is ongoing. The natural phenolic compound pterostilbene exhibits beneficial health effects and has the capacity to limit fat mass in animal models. In this study, we tested whether pterostilbene modulates triacylglycerol accumulation/breakdown. Prolonged exposure to pterostilbene or resveratrol inhibited adipocyte differentiation in 3T3-F442A preadipocytes. Acute effects on lipolysis, antilipolysis and lipogenesis were determined for pterostilbene in mouse adipocytes, and compared with resveratrol. Pterostilbene was also tested on glycerol release and glucose uptake in subcutaneous human adipocytes. Dose–response analyses did not reveal a clear lipolytic effect in both species. The antilipolytic effect of insulin was improved by pterostilbene at 1–10 μM in mouse fat cells only, while at 1 mM, the phenolic compound was antilipolytic in human fat cells in a manner not additive to insulin. Pterostilbene dose-dependently inhibited glucose incorporation into lipids similarly to resveratrol and caffeine. However, only the former did not inhibit insulin-stimulated glucose uptake. Indeed, pterostilbene abolished the insulin lipogenic effect without inhibiting its antilipolytic action and rapid activation of glucose uptake. Pterostilbene therefore exhibits a unique panel of direct interactions with adipocytes that relies on its reported anti-obesity and antidiabetic properties. Copyright © 2017 John Wiley & Sons, Ltd.

Obesity and related comorbidities are a major health concern. The drugs used to treat these conditions are largely inadequate or dangerous, and a well-researched approach based on nutraceuticals would be highly useful. Pterostilbene (Pt), i.e., 3,5-dimethylresveratrol, has been reported to be effective in animal models of obesity, acting on different metabolic pathways. We investigate here its ability to induce browning of white adipose tissue. Pt (5 &micro, M) was first tested on 3T3-L1 mature adipocytes, and then it was administered (352 &micro, mol/kg/day) to mice fed an obesogenic high-fat diet (HFD) for 30 weeks, starting at weaning. In the cultured adipocytes, the treatment elicited a significant increase of the levels of Uncoupling Protein 1 (UCP1) protein&mdash, a key component of thermogenic, energy-dissipating beige/brown adipocytes. In vivo administration antagonized weight increase, more so in males than in females. Analysis of inguinal White Adipose Tissue (WAT) revealed a trend towards browning, with significantly increased transcription of several marker genes (Cidea, Ebf2, Pgc1&alpha, PPAR&gamma, Sirt1, and Tbx1) and an increase in UCP1 protein levels, which, however, did not achieve significance. Given the lack of known side effects of Pt, this study strengthens the candidacy of this natural phenol as an anti-obesity nutraceutical.

Pterostilbene, a phenolic compound derived from resveratrol, possesses greater bioavailability than its parent compound due to the presence of two methoxyl groups. In this review, the beneficial effects of pterostilbene on diabetes, liver steatosis and dyslipidemia are summarized. Pterostilbene is a useful bioactive compound in preventing type 1 diabetes, insulin resistance and type 2 diabetes in animal models. Concerning type 1 diabetes, the main mechanisms described to justify the positive effects of this phenolic compound are increased liver glycogen content and hepatic glucokinase and phosphofructokinase activities, the recovery of pancreatic islet architecture, cytoprotection and a decrease in serum and pancreatic pro-inflammatory cytokines. As for type 2 diabetes, increased liver glucokinase and glucose-6-phosphatase and decreased fructose-1,6-biphosphatase activities are reported. When insulin resistance is induced by diets, a greater activation of insulin signaling cascade has been reported, increased cardiotrophin-1 levels and liver glucokinase and glucose- 6-phosphatase activities, and a decreased fructose-1,6-biphosphatase activity. Data concerning pterostilbene and liver steatosis are scarce so far, but the reduction in oxidative stress induced by pterostilbene may be involved since oxidative stress is related to the progression of steatosis to steatohepatitis. Finally, pterostilbene effectively reduces total cholesterol, LDL-cholesterol and serum triglyceride levels, while increases HDL-cholesterol in animal models of dyslipidemia.

Novel mechanisms and health benefits have been recently suggested for the antidepressant drug phenelzine (PHE), known as a nonselective monoamine oxidase inhibitor. They include an antilipogenic action that could have an impact on excessive fat accumulation and obesity-related metabolic alterations. We evaluated the metabolic effects of an oral PHE treatment on mice fed a high-fat diet (HFD). Eleven-week-old male C57BL/6 mice were fed a HFD and either a 0.028% PHE solution (HFD + PHE) or water to drink for 11 weeks. PHE attenuated the increase in body weight and adiposity without affecting food consumption. Energy efficiency was lower in HFD + PHE mice. Lipid content was reduced in subcutaneous fat pads, liver, and skeletal muscle. In white adipose tissue (WAT), PHE reduced sterol regulatory element-binding protein-1c and phosphoenolpyruvate carboxykinase mRNA levels, inhibited amine-induced lipogenesis, and did not increase lipolysis. Moreover, HFD + PHE mice presented diminished levels of hydrogen peroxide release in subcutaneous WAT and reduced expression of leukocyte transmigration markers and proinflammatory cytokines in visceral WAT and liver. PHE reduced the circulating levels of glycerol, triacylglycerols, high-density lipoprotein cholesterol, and insulin. Insulin resistance was reduced, without affecting glucose levels and glucose tolerance. In contrast, PHE increased rectal temperature and slightly increased energy expenditure. The mitigation of HFD-induced metabolic disturbances points toward a promising role for PHE in obesity treatment and encourages further research on its mechanisms of action. SIGNIFICANCE STATEMENT Phenelzine reduces body fat, markers of oxidative stress, inflammation, and insulin resistance in high-fat diet mice. Semicarbazide-sensitive amine oxidase, monoamine oxidase, phosphoenolpyruvate carboxykinase, and sterol regulatory element-binding protein-1c are involved in the metabolic effects of phenelzine. Phenelzine could be potentially used for the treatment of obesity-related complications.

Aquaglyceroporins (AQPs) are transmembrane channels that mediate glycerol release and glycerol uptake. They are involved in fat metabolism, with implications in obesity. The aim was to determine whether the administration of resveratrol and pterostilbene during the six weeks of the experimental period would modify AQPs expression in white and brown adipose tissues from Wistar rats fed an obesogenic diet, and to establish a potential relationship with the delipidating properties of these compounds. Consequently, thirty-six rats were divided into four groups: (a) group fed a standard diet, and three more groups fed a high-fat high-sucrose diet: (b) high-fat high-sucrose group: (c) pterostilbene-treated group (30 mg/kg/d): (d) resveratrol-treated group (30 mg/kg/d). Epididymal, subcutaneous white adipose tissues and interscapular brown adipose tissue were dissected. AQPs gene expression (RT-PCR) and protein expression (western-blot) were measured. In white adipose tissue, pterostilbene reduced subcutaneous adipose tissue weight and prevented the decrease in AQP9 induced by obesogenic feeding, and thus glycerol uptake for triglyceride accumulation. Resveratrol reduced epididymal adipose tissue weight and avoided the decrease in AQPs related to glycerol release induced by high-fat high-sucrose feeding, suggesting the involvement of lipolysis in its body-fat lowering effect. Regarding brown adipose tissue, AQP7 seemed not to be involved in the previously reported thermogenic activity of both phenolic compounds.

Phenelzine has been suggested to have an antiobesity effect by inhibiting de novo lipogenesis, which led us to investigate the metabolic effects of oral chronic phenelzine treatment in high-sucrose-drinking mice. Sucrose-drinking mice presented higher body weight gain and adiposity versus controls. Phenelzine addition did not decrease such parameters, even though fat pad lipid content and weights were not different from controls. In visceral adipocytes, phenelzine did not impair insulin-stimulated de novo lipogenesis and had no effect on lipolysis. However, phenelzine reduced the mRNA levels of glucose transporters 1 and 4 and phosphoenolpyruvate carboxykinase in inguinal white adipose tissue (iWAT), and altered circulating levels of free fatty acids (FFA) and glycerol. Interestingly, glycemia was restored in phenelzine-treated mice, which also had higher insulinaemia. Phenelzine-treated mice presented higher rectal temperature, which was associated to reduced mRNA levels of uncoupling protein 1 in brown adipose tissue. Furthermore, unlike sucrose-drinking mice, hepatic malondialdehyde levels were not altered. In conclusion, although de novo lipogenesis was not inhibited by phenelzine, the data suggest that the ability to re-esterify FFA is impaired in iWAT. Moreover, the effects on glucose homeostasis and oxidative stress suggest that phenelzine could alleviate obesity-related alterations and deserves further investigation in obesity models., This study was partly supported by the DIOMED project (INTERREG IVB SUDOE 1/P1/E178).

This study aims to determine whether pterostilbene improves glycaemic control in rats showing insulin resistance induced by an obesogenic diet. Rats were divided into 3 groups: the control group and two groups treated with either 15 mg kg(-1) d(-1) (PT15) or 30 mg kg(-1) d(-1) of pterostilbene (PT30). HOMA-IR was decreased in both pterostilbene-treated groups, but this reduction was greater in the PT15 group (-45% and -22% respectively vs. the control group). The improvement of glycaemic control was not due to a delipidating effect of pterostilbene on skeletal muscle. In contrast, GLUT4 protein expression was increased (+58% and +52% vs. the control group), suggesting an improved glucose uptake. The phosphorylated-Akt/total Akt ratio was significantly enhanced in the PT30 group (+25%), and therefore a more efficient translocation of GLUT4 is likely. Additionally, in this group the amount of cardiotrophin-1 was significantly increased (+65%). These data suggest that the effect of pterostilbene on Akt is mediated by this cytokine. In the liver, glucokinase activity was significantly increased only in the PT15 group (+34%), and no changes were observed in glucose-6-phosphatase activity. The beneficial effect of pterostilbene on glycaemic control was more evident with the lower dose, probably because in the PT15 group both the muscle and the liver were contributing to this effect, but in the PT30 group only the skeletal muscle was responsible. In conclusion, pterostilbene improves glycaemic control in rats showing insulin resistance induced by an obesogenic diet. An increase in hepatic glucokinase activity, as well as in skeletal muscle glucose uptake, seems to be involved in the anti-diabetic effect of this phenolic compound.

Adipose tissue releases bioactive mediators called adipokines. This review focuses on the effects of omentin, vaspin, cardiotrophin-1, Tumor necrosis factor-like Weak Inducer of Apoptosis (TWEAK) and nephroblastoma overexpressed (NOV/CCN3) on obesity and diabetes. Omentin is produced by the stromal-vascular fraction of visceral adipose tissue. Obesity reduces omentin serum concentrations and adipose tissue secretion in adults and adolescents. This adipokine regulates insulin sensitivity, but its clinical relevance has to be confirmed. Vaspin is produced by visceral and subcutaneous adipose tissues. Vaspin levels are higher in obese subjects, as well as in subjects showing insulin resistance or type 2 diabetes. Cardiotrophin-1 is an adipokine with a similar structure as cytokines from interleukin-6 family. There is some controversy regarding the regulation of cardiotrophin-1 levels in obese -subjects, but gene expression levels of cardiotrophin-1 are down-regulated in white adipose tissue from diet-induced obese mice. It also shows anti-obesity and hypoglycemic properties. TWEAK is a potential regulator of the low-grade chronic inflammation characteristic of obesity. TWEAK levels seem not to be directly related to adiposity, and metabolic factors play a critical role in its regulation. Finally, a strong correlation has been found between plasma NOV/CCN3 concentration and fat mass. This adipokine improves insulin actions.

The current study aimed to demonstrate the effects of pterostilbene in rats fed an obesogenic diet. For this purpose, pterostilbene was administered at doses of 15 mg/kg body weight/day (PT15 group) or 30 mg/kg body weight/day (PT30 group) for 6 weeks. Pterostilbene reduced adipose tissue mass -15.1% (PT15) and -22.9% (PT30). In this tissue, it decreased malic enzyme (-39.4 and -49.5% for PT15 and PT30 groups, respectively) and fatty acid synthase (-45 and -53.4% for PT15 and PT30) activities. Acetyl-CoA carboxylase activity was reduced and AMPK activity was increased only in the PT30 group. In the liver, pterostilbene (PT30) reduced malic enzyme (-29.5%) and glucose-6-P dehydrogenase (-43.2%) activities and increased carnitine palmitoyltransferase-1a (37.5%) and acyl-coenzyme A oxidase (42.5%) activities. This increased oxidative capacity was not associated with increased mitochondriogenesis. Among biochemical serum parameters, only insulin was modified by pterostilbene (-31.6%) in the PT15 group. The amounts of pterostilbene in serum and tissues from rats in the PT30 group were in not all cases 2-fold greater than those found in the PT15 group. In conclusion, pterostilbene shows antiobesity properties due, at least in part, to reduced lipogenesis in adipose tissue and increased fatty acid oxidation in liver.

Objective The aim of this study was to examine whether resveratrol might represent a promising therapeutic tool with which to combat adipose tissue chronic inflammation in a model of genetic obesity and to link its anti-inflammatory activity with its effect on body fat reduction. Methods Twenty 6-wk-old male Zucker (fa/fa) rats were randomly distributed into two experimental groups. Resveratrol (RSV) was given orally (15 mg/kg body weight/d in RSV group) by means of an orogastric catheter for 6 wk. Enzyme activities were measured spectrophotometrically or fluorimetrically. Gene and protein expressions were analyzed by reverse transcriptase polymerase chain reaction and Western blot respectively. Cytokine concentrations and the activity of nuclear factor κ-light-chain-enhancer of activated β cells (NF-κB) were measured by using commercial kits. Results RSV reduced the weight of internal adipose tissues. In epididymal depot glucose-6P-dehydrogenase, acetyl-CoA carboxylase activities, as well as lipoprotein lipase expression and activity were reduced by RSV. The expression of hormone-sensitive lipase was increased, and that of the cluster of differentiation 36 was reduced. Serum concentrations of tumor necrosis factor-α, monocyte chemoattractant protein 1, and C-reactive protein were lower in the RSV-treated group than in the control group. Protein expression of interleukin-6 and the activity of NF-κB, were decreased by RSV. Conclusion The present results provide evidence that fatty acid uptake and lipolysis are metabolic pathways involved in the response of adipose tissue to RSV. This polyphenol modulates plasma cytokine levels partially by reducing macrophage infiltration in adipose tissue and inhibiting NF-κB activity.

Resveratrol is a naturally occurring polyphenol found in many dietary sources and red wine. Recognized as a cancer chemoprevention agent, an anti-inflammatory factor and an antioxidant molecule, resveratrol has been proposed as a potential anti-obesity compound and to be beneficial in diabetes. Most of the studies demonstrating the anti-adipogenic action of resveratrol were performed as long-term treatments on cultured preadipocytes. The aim of this study was to analyse the acute effects of resveratrol on glucose uptake and lipolysis in human mature adipocytes. Samples of subcutaneous abdominal adipose tissue were obtained from overweight humans and immediately digested by liberase. Fat cells were incubated (from 45 min to 4 h) with resveratrol 1 μM-1 mM. Then, glycerol release or hexose uptake was determined. Regarding lipolysis, the significant effects of resveratrol were found at 100 μM, consisting in a facilitation of isoprenaline stimulation and an impairment of insulin antilipolytic action. At 1 and 10 μM, resveratrol only tended to limit glucose uptake. Resveratrol 100 μM did not change basal glucose uptake but impaired its activation by insulin or by benzylamine. This inhibition was not found with other antioxidants. Such impairment of glucose uptake activation in fat cells may led to a reduced availability of glycerol phosphate and then to a decreased triacylglycerol assembly. Therefore, resveratrol increased triacylglycerol breakdown triggered by β-adrenergic activation and impaired lipogenesis. Consequently, our data indicate that resveratrol can be considered as limiting fat accumulation in human fat cells and further support its use for the mitigation of obesity.

Serotonin (5-HT) is a brain neurotransmitter instrumental for the antidepressant action of selective inhibitors of serotonin reuptake (SSRIs) while it also plays important roles in peripheral organs. Recently, the 5-HT oxidation products, 5-hydroxyindoleacetate and 5-methoxy-indoleacetate, have been shown to bind to peroxisome proliferator-activated receptor γ (PPARγ) and to enhance lipid accumulation in preadipocytes. Since we already reported that adipocytes exhibit elevated monoamine oxidase (MAO) and primary amine oxidase activities, we verified how adipocytes readily oxidize 5-HT, with the objective to determine whether such oxidation promotes PPARγ activation and lipid storage. To this aim, serotonin was tested on cultured 3T3 F442A preadipocytes and on human adipocytes. Results showed that 5-HT was oxidized by MAO in both models. Daily treatment of 3T3 F442A preadipocytes for 8 days with 100-500 μM 5-HT promoted triglyceride accumulation and emergence of adipogenesis markers. At 250 μM, 5-HT alone reproduced half of 50 nM insulin-induced adipogenesis, and exhibited an additive differentiating effect when combined with insulin. Moreover, the 5-HT-induced expression of PPARγ-responsive genes (PEPCK, aP2/FABP4) was blocked by GW 9662, a PPARγ-inhibitor, or by pargyline, a MAO-inhibitor. In human fat cells, 6-h exposure to 100 μM 5-HT increased PEPCK expression as did the PPARγ-agonist rosiglitazone. Since hydrogen peroxide, another amine oxidation product, did not reproduce such enhancement, we propose that serotonin can promote PPARγ activation in fat cells, via the indoleacetate produced during MAO-dependent oxidation. Such pathway could be involved in the adverse effects of several antidepressant SSRIs on body weight gain.

Resumen La diabetes mellitus tipo 2 (DM2) es una enfermedad muy frecuente a escala mundial y representa una gran causa de morbimortalidad. Su prevalencia ha aumentado enormemente en las ultimas decadas y si no se toman medidas la magnitud del problema crecera, con consecuencias para el paciente, para el sistema de salud y para los factores socioeconomicos. Esta demostrado que los cambios en el estilo de vida pueden prevenir el desarrollo de DM2 siempre y cuando se optimice la prescripcion de actividad fisica y aspectos nutricionales para este tipo de pacientes. Asi, esta revision trata del principal transportador de glucosa en el musculo esqueletico, el GLUT4, y pretende conseguir un mejor entendimiento de su implicacion a nivel molecular y su rol frente a distintos estimulos de nutricion y actividad fisica. Finalmente, se proponen aplicaciones practicas para la prescripcion de actividad fisica en la DM2.

Non-alcoholic fatty liver disease (NAFLD) is one of the most common manifestations of chronic liver disease worldwide. The aim of the present study was to assess the effect of resveratrol on liver fat accumulation, as well as on the activity of those enzymes involved in lipogenesis and fatty acid oxidation infa/faZucker rats. A total of thirty rats were assigned to three experimental groups and orally treated with resveratrol for 6 weeks, or without resveratrol (C: control group; RSV15 group: 15 mg/kg body weight per d; RSV45 group: 45 mg/kg body weight per d). Liver histological analysis was performed by microscopy. Levels of hepatic carnitine palmitoyltransferase-Ia (CPT-Ia), acyl-coenzyme A oxidase (ACO), fatty acid synthase, glucose-6-phosphate dehydrogenase and malic enzyme were assessed by spectrophotometry, and acetyl-CoA carboxylase was assessed by radiometry. Commercial kits were used to determine serum TAG, NEFA, total HDL and non-HDL-cholesterol, glycerol, ketonic bodies, glucose, insulin, adiponectin, aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP), hepatic TAG, thiobarbituric acid reactive substrates, GSH (GSSG) and superoxide dismutase. Resveratrol reduced liver weight and TAG content. It did not modify the activity of lipogenic enzymes but it did increase CPT-Ia and ACO activities. NEFA and ALP were reduced in both resveratrol-treated groups. AST/GOT was reduced only by the lowest dose. ALT/GPT, TAG and adiponectin remained unchanged. Resveratrol reduced liver oxidative stress. This study demonstrates that resveratrol can protect the liver from NAFLD by reducing fatty acid availability. Moreover, resveratrol also protects liver from oxidative stress.

During the last years, the list of resveratrol effects has grown in parallel with the number of other members of the polyphenol family described to modulate glucose or lipid handling. In the same time, more than ten human studies on the influence of resveratrol supplementation on two related metabolic diseases, obesity and diabetes, have indicated that impressive beneficial effects co-exist with lack of demonstration of clinical relevance, irrespective of the daily dose ingested (0.075 to 1.5 g per capita) or the number of studied patients. Such contrasting observations have been proposed to depend on the degree of insulin resistance of the patients incorporated in the study. To date, no definitive conclusion can be drawn on the antidiabetic or antiobesity benefits of resveratrol. On the opposite, studies on animal models of diabesity consistently indicated that resveratrol impairs diverse insulin actions in adipocytes, blunting glucose transport, lipogenesis and adipogenesis. Since resveratrol also favours lipolysis and limits the production of proinflammatory adipokines, its administration in rodents results in limitation of fat deposition, activation of hexose uptake into muscle, improvement of insulin sensitivity, and facilitation of glucose disposal. Facing to a somewhat disappointing extrapolation to man of these promising antidiabetic and antiobesity properties, attention must be paid to re-examine resveratrol targets, especially those attainable after polyphenol ingestion and to re-define the responses to low doses. In this context, human adipocytes are proposed as a convenient model for the screening of "novel" polyphenols that can reproduce, out class, or reinforce resveratrol metabolic actions, Moreover, the use of combination of polyphenols is proposed to treat diabesity complications in view of recently reported synergisms. Lastly, multidisciplinar approaches are recommended for future investigations, considering the wide range of polyphenol actions that induce body fat reduction, liver disease mitigation, muscle function improvement, cardiovascular and renal protection.

Scientific research is constantly looking for new molecules to be used as functional ingredients to combat obesity. The aim of the present study was to analyse whether resveratrol and conjugated linoleic acid (CLA) together could reduce body fat more efficiently than their separate administration. Thirty-six male Wistar rats were randomly divided into four groups: controls rats (C), rats treated with resveratrol (RSV), rats treated with CLA (CLA) and rats treated with a combination of resveratrol and CLA (RSV+CLA). All rats were fed on an obesogenic diet. In RSV and RSV+CLA groups, the rats received 30 mg resveratrol/kg body weight/day. In CLA and RSV+CLA groups, an equimolecular mixture of trans-10,cis-12 and cis-9,trans-11 was added to the diet to reach 0.5% of the active isomer trans-10,cis-12. After 6 weeks of treatment, white adipose tissue from different anatomical locations was dissected and weighed. Serum triacylglycerols, total and HDL cholesterols, glucose, insulin, fructosamine and TNF-α were measured. A glucose tolerance test was also performed. Separately, resveratrol and CLA significantly reduced body fat but did not do so when combined: 20% in the RSV group and 18% in CLA group but 7% in the RSV+CLA group. Resveratrol reduced serum triacylglycerols. No differences were found among groups in serum cholesterol. Resveratrol, as well as the combination RSV+CLA, improved glycaemic control. These results demonstrate that the combination RSV+CLA reduces the effectiveness of each compound on body fat-lowering action, but it maintains the positive effect of resveratrol on glycaemic control. Consequently, this combination has no usefulness in obesity prevention.