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The main function of brown adipose tissue (BAT) is thermogenesis, a process mediated by uncoupling protein 1 (UCP1), which is located in the inner mitochondrial membrane and acts uncoupling oxidative phosphorylation from ATP production, thereby dissipating energy as heat. White adipose tissue can also express UCP1 positive cells due to a process known as browning. This phenomenon could also increase the thermogenic effect in the classical brown adipose depots. BAT thermogenesis depends, among other factors on both, nutritional conditions and food availability. Indeed, some studies have found that BAT recruitment and function are enhanced by some food components. The present study focuses on the effects of resveratrol and pterostilbene, two phenolic compounds belonging to the stilbene group, on BAT thermogenic activation and white adipose tissue browning process. The reported studies, carried out in cell cultures and animal models, show that both resveratrol and pterostilbene induce thermogenic capacity in interscapular BAT by increasing mitochondriogenesis, as well as enhancing fatty acid oxidation and glucose disposal. In addition, resveratrol seems to promote browning by activating peroxisome proliferator-activated receptor (PPAR), while the lack of changes in mitochondrial biogenesis suggests that probably the browning process occurs by direct resveratrol-mediated upregulation of ucp1 mRNA expression.

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

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.

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. This study has been supported by grants from the Government of the Basque Country (ELKARTEK) under grant KK-2019/00031, Instituto de Salud Carlos III (CIBERobn) under Grant CB12/03/30007 and University of the Basque Country under Grant GIU18-173. M.G.-A. is a fellow from the University of the Basque Country.

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/ebpβ 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.

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.

Several studies have observed that gut microbiota can play a critical role in nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) development. The gut microbiota is influenced by different environmental factors, which include diet. The aim of the present review is to summarize the information provided in the literature concerning the impact of changes in gut microbiota on the effects which dietary fat has on liver steatosis in rodent models. Most studies in which high-fat feeding has induced steatosis have reported reduced microbiota diversity, regardless of the percentage of energy provided by fat. At the phylum level, an increase in Firmicutes and a reduction in Bacteroidetes is commonly found, although widely diverging results have been described at class, order, family, and genus levels, likely due to differences in experimental design. Unfortunately, this fact makes it difficult to reach clear conclusions concerning the specific microbiota patterns associated with this feeding pattern. With regard to the relationship between high-fat feeding-induced changes in liver and microbiota composition, although several mechanisms such as alteration of gut integrity and increased permeability, inflammation, and metabolite production have been proposed, more scientific evidence is needed to address this issue and thus further studies are needed. This research was funded by MINECO (AGL-2015-65719-R-MINECO/FEDER, UE) and Instituto de Salud Carlos III (CIBERobn, CB12/03/30007)

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.

The present review aims to gather scientific evidence regarding the beneficial effects of microalgae and macroalgae extracts on non-alcoholic fatty liver disease (NAFLD). The described data show that both microalgae and macroalgae improved this alteration. The majority of the reported studies analysed the preventive effects because algae were administered to animals concurrent with the diet that induced NAFLD. The positive effects were demonstrated using a wide range of doses, from 7.5 to 300 mg/kg body weight/day or from 1 to 10% in the diet, and experimental periods ranged from 3 to 16 weeks. Two important limitations on the scientific knowledge available to date are that very few studies have researched the mechanisms of action underlying the preventive effects of microalgae on NAFLD and that, for the majority of the algae studied, a single paper has been reported. For these reasons, it is not possible to establish the best conditions in order to know the beneficial effects that these algae could bring. In this scenario, further studies are needed. Moreover, the beneficial effects of algae observed in rodent need to be confirmed in humans before we can start considering these products as new tools in the fight against fatty liver disease. This study was funded by University of the Basque Country (grant: GIU18-173) and Carlos III Research Institute (CIBERobn) (grant CB12/03/30007).

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.

Science constantly seeks to identify new molecules that could be used as dietary functional ingredients in the fight against obesity and its co-morbidities. Among them, polyphenols represent a group of molecules of increasing interest. One of the most widely studied polyphenols is resveratrol (trans-3,4′,5-trihydroxystilbene), which has been proposed as an “energy restriction mimetic” because it can exert energy restriction-like effects. The aim of this review is to analyze the effects of resveratrol on obesity under different feeding conditions, such as overfeeding, normal feeding, and energy restriction, in animals and humans. The vast majority of the studies reported have addressed the administration of resveratrol to animals alongside an obesogenic diet. Under these experimental conditions usually a decreased body weight amount was found. To date, studies that focus on the effects of resveratrol under normal feeding or energy restriction conditions in animals and humans are scarcer. In these studies no changes in body fat were reported. After analyzing the results obtained under overfeeding, normal feeding, and energy restriction conditions, it can be stated that resveratrol is useful in reducing body fat accumulation, and thus preventing obesity. Nevertheless, for ethical reasons, these results have been obtained in animals. By contrast, there are no evidences showing the usefulness of this phenolic compound in reducing previously accumulated body fat. Consequently, as of yet, there is not scientific support for proposing resveratrol as a new anti-obesity treatment tool. This work has been supported by MINECO (AGL-2015-65719-R-MINECO/FEDER, UE), Fondo Europeo de Desarrollo Regional (FEDER) University of the Basque Country (ELDUNANOTEK UFI11/32), Instituto de Salud Carlos III (CIBEROBN) and Basque Government (IT-572-13). Inaki Milton is a recipient of a doctoral fellowship from the Basque Government.

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.

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.

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.

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.

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.

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).

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.