stilbenes and Obesity

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 (

Topics: Animals; Diabetes Mellitus, Type 2; Female; Humans; Male; Mice; Obesity; Resveratrol; Stilbenes; Vitis

Diabetes mellitus is a significant health problem that is caused by chronic hyperglycaemia as a result of inadequate insulin production or ineffective insulin action in the body. In recent years, many new pharmacological and non-pharmacological therapies have been developed for improving pancreatic insulin secretion and insulin resistance. Resveratrol is a natural and biologically active stilbenoid polyphenol present in various plant species and has the potential to benefit diabetes. The anti-diabetic actions of resveratrol have also been extensively studied in diabetic human and animal models. Moreover, resveratrol might affect insulin sensitivity by regulating visceral fat derivated adipokine levels. The use of resveratrol in combination with anti-diabetic therapies or alone may have significant potential for the management of diabetes mellitus. This review provides an overview of the anti-diabetic action of resveratrol as well as the possible mechanisms that have an effect on insulin secretion and insulin resistance in diabetics.

Topics: Animals; Diabetes Mellitus; Humans; Hypoglycemic Agents; Insulin; Insulin Resistance; Obesity; Resveratrol; Stilbenes

Metabolic diseases (MDs), a series of chronic disorders, severely decreases the quality of life for patients but also cause a heavy economic burden. Emerging evidence suggests that Polydatin (PD), an important glucoside of resveratrol, is widely distributed in many plants and has shown good therapeutic potential in metabolic diseases.. To review the PD discovered before 2021 and their potential to treat metabolic diseases. The activities against diabetes, Obesity, atherosclerosis, NAFLD, NASH, hyperlipidemia, and gout with special emphasis on pharmacology, pharmacokinetics, mechanisms of action, possible roles in current medicine, and future perspectives are discussed.. A comprehensive search of published literature was conducted to locate original publications pertaining to polydatin and MDs through the end of 2021 using MEDLINE, Elsevier, Springer, PubMed, Scholar, and CNKI databases. The main inquiry used was for the presence of the following keywords in various combinations in the abstracts: 'Polydatin', 'Metabolic diseases', 'Pharmacology', 'Toxicology', 'Pharmacokinetics', 'Diabetes', 'Obesity', 'Atherosclerosis', 'Non-alcoholic fatty liver disease', 'Non-alcoholic steatohepatitis', 'Hyperlipidemia', and 'Gout'.. The search yielded 987 articles, of which 33 articles were included in this review. Studies have revealed that PD can promote insulin secretion, alleviate insulin resistance, regulate glucose and lipid metabolism, reduce liver lipid deposition, inhibit inflammation, oxidative stress, and decrease uric acid deposition in preclinical experiments. The underlying mechanisms of PD in treatment MDs may be attributed to the regulation of multiple signaling pathways, including. NF-κB, AGEs/RAGE, MAPK/ERK, AMPK/LDLR, IRS1/PI3K/AKT, LKB1/AMPK, PPARβ-NO, SIRT1-PGC-1α-SOD2, PKC, etc., The pharmacokinetic profiles of PD provide valuable information on therapeutic efficacy in treating metabolic diseases.. This review summarizes the available reports and evidence which support the use of PD as a potential candidate in the treatment of MDs and provides an overview of the modulatory effects of PD in metabolic diseases and cell signaling pathways, which may have important implications in its future clinical use.

Topics: AMP-Activated Protein Kinases; Atherosclerosis; Diabetes Mellitus; Glucosides; Gout; Humans; Non-alcoholic Fatty Liver Disease; Obesity; Phosphatidylinositol 3-Kinases; Quality of Life; Stilbenes

Pterostilbene, 3',5'-dimethoxy-4-hydroxystilbene, is a resveratrol analogue and has been reported to have similar and often potent health-promoting properties. Pterostilbene has been shown to reduce weight gain, liver fat, plasma cholesterol, adiposity, inflammatory biomarkers, blood glucose, and other physiological characteristics of metabolic diseases in animal models. Studies on pterostilbene suggest that it may improve risk factors associated with diabetes, cardiovascular disease, fatty liver diseases, Alzheimer's disease, and other neurodegenerative diseases. Many of the extensive studies on the potential health benefits of pterostilbene were conducted by Dr. Agnes Rimando, a scientist with the United States Department of Agriculture, in collaboration with many U.S. and other international research groups. This review highlights the pterostilbene research of Dr. Rimando.

Topics: Alzheimer Disease; Animals; Antioxidants; Cardiovascular Diseases; Humans; Obesity; Stilbenes

Obesity is a current global epidemic that has led to a marked increase in metabolic diseases. However, its treatment remains a challenge. Obesity is a multifactorial disease, which involves the dysfunction of neuropeptides, hormones, and inflammatory adipokines from the brain, gut, and adipose tissue. An understanding of the mechanisms and signal interactions in the crosstalk between organs and tissue in the coordination of whole-body energy metabolism would be helpful to provide therapeutic and putative approaches to the treatment and prevention of obesity and related complications. Resveratrol and pterostilbene are well-known stilbenes that provide various potential benefits to human health. In particular, their potential anti-obesity effects have been proven in numerous cell culture and animal studies. Both compounds act to regulate energy intake, adipocyte life cycle and function, white adipose tissue (WAT) inflammation, energy expenditure, and gut microbiota by targeting multiple molecules and signaling pathways as an intervention for obesity. Although the efficacy of both compounds in humans requires further investigation with respect to their oral bioavailability, promising scientific findings have highlighted their potential as candidates for the treatment of obesity and the improvement of obesity-related metabolic diseases. © 2018 BioFactors, 44(1):50-60, 2018.

Topics: Adipocytes; Adipokines; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Anti-Obesity Agents; Diet, High-Fat; Energy Metabolism; Gastrointestinal Microbiome; Gene Expression; Humans; Obesity; Resveratrol; Signal Transduction; Stilbenes; Thermogenesis

Inflammation is the principal response invoked by the body to address injuries. Despite inflammation constituting a crucial component of tissue repair, it is well known that unchecked or chronic inflammation becomes deleterious, leading to progressive tissue damage. Studies over the past years focused on foods rich in polyphenols with anti-inflammatory and immunomodulatory properties, since inflammation was recognized to play a central role in several diseases. In this review, we discuss the beneficial effects of resveratrol, the most widely investigated polyphenol, on cancer and neurodegenerative, respiratory, metabolic, and cardiovascular diseases. We highlight how resveratrol, despite its unfavorable pharmacokinetics, can modulate the inflammatory pathways underlying those diseases, and we identify future opportunities for the evaluation of its clinical feasibility.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cardiovascular Diseases; Clinical Trials as Topic; Humans; Inflammation; Mice; Neoplasms; Obesity; Rats; Respiratory Tract Diseases; Resveratrol; Stilbenes

The prevalence of obesity has been increasing in recent decades and is reaching epidemic proportions. The current options for overweight and obesity management are energy restriction and physical activity. However, compliance with these treatments is frequently poor and less successful than expected. Therefore, the scientific community is interested in active biomolecules, which may be useful in body weight management. Among them, resveratrol (3,5,4'-trihydroxy-trans-stilbene) has generated great interest as an antiobesity agent. The focus of this report is the mechanisms of action of resveratrol on several tissues (i.e., white and brown adipose tissues, liver, and skeletal muscle). Resveratrol blunts fat accumulation through decreasing adipogenesis and/or de novo lipogenesis in white adipose tissue. The effects on lipolysis are controversial. Regarding brown adipose tissue, resveratrol increases the capacity for adaptive thermogenesis. As far as liver and skeletal muscle is concerned, resveratrol increases lipid oxidation in both tissues. Therefore, in rodents, there is a general consensus concerning the effect of resveratrol on reducing body fat accumulation. By contrast, in humans, the studies are scarce, and no clear antiobesity action has been revealed so far.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Animals; Anti-Obesity Agents; Humans; Liver; Muscle, Skeletal; Obesity; Resveratrol; Stilbenes

Resveratrol could be beneficial to health and provides protection against a wide array of pathologies and age-associated problems, as evident from preclinical studies. However, a comparison of animal and human studies reveals that this dietary polyphenol cannot protect against metabolic diseases and their associated complications. The clinical outcomes are affected by many factors such as sample size. This article not only presents a comprehensive review of the current advances concerning the dose, the extent of absorption, interaction and toxicity of resveratrol in human studies, but also describes its therapeutic effects against several chronic diseases such as diabetes mellitus, obesity, cardiovascular diseases, cancer and aging and the related diseases.

Topics: Aging; Cardiovascular Diseases; Chronic Disease; Diabetes Mellitus; Dose-Response Relationship, Drug; Humans; Neoplasms; Obesity; Polyphenols; Resveratrol; Stilbenes

The incidence of overweight and obesity has reached epidemic proportions, making the control of body weight and its complications a primary health problem. Diet has long played a first-line role in preventing and managing obesity. However, beyond the obvious strategy of restricting caloric intake, growing evidence supports the specific antiobesity effects of some food-derived components, particularly (poly)phenolic compounds. The relatively new rediscovery of active brown adipose tissue in adult humans has generated interest in this tissue as a novel and viable target for stimulating energy expenditure and controlling body weight by promoting energy dissipation. This review critically discusses the evidence supporting the concept that the antiobesity effects ascribed to (poly)phenols might be dependent on their capacity to promote energy dissipation by activating brown adipose tissue. Although discrepancies exist in the literature, most in vivo studies with rodents strongly support the role of some (poly)phenol classes, particularly flavan-3-ols and resveratrol, in promoting energy expenditure. Some human data currently are available and most are consistent with studies in rodents. Further investigation of effects in humans is warranted.

Topics: Adipose Tissue, Brown; Adrenergic Agonists; Animals; Anti-Obesity Agents; Body Weight; Diet; Disease Models, Animal; Energy Metabolism; Flavonoids; Humans; Obesity; Polyphenols; Resveratrol; Stilbenes; Tea; Thermogenesis; Uncoupling Protein 1

Over the past two decades, obesity has been one of the major public health concerns in most countries. In the search for new molecules that could be used for the treatment of obesity, good perspectives have been opened up for polyphenols, a class of natural bioactive phytochemicals. Experimental and limited clinical trial evidence supports that some polyphenols such as quercetin, curcumin, and resveratrol have potential benefit functions on obesity treatment. This brief review focuses on the main functions of the above-named polyphenols on adipose tissue. These polyphenols may play beneficial effects on adipose tissue under obese condition by alleviating intracellular oxidative stress, reducing chronic low-grade inflammation, inhibiting adipogenesis and lipogenesis, and suppressing the differentiation of preadipocytes to mature adipocytes.

Topics: Animals; Antioxidants; Curcumin; Disease Models, Animal; Humans; Mice; Obesity; Quercetin; Rats; Resveratrol; Stilbenes

Encouraging scientific research into the health effects of dietary bioactive resveratrol has been confounded by its rapid first-pass metabolism, which leads to low in vivo bioavailability. Preliminary studies have shown that resveratrol can modulate gut microbiota composition, undergo biotransformation to active metabolites via the intestinal microbiota, or affect gut barrier function. In rodents, resveratrol can modify the relative Bacteroidetes:Firmicutes ratio and reverse the gut microbial dysbiosis caused by a high-fat diet. By upregulating the expression of genes involved in maintaining tight junctions between intestinal cells, resveratrol contributes to gut barrier integrity. The composition of the gut microbiome and rapid metabolism of resveratrol determines the production of resveratrol metabolites, which are found at greater concentrations in humans after ingestion than their parent molecule and can have similar biological effects. Resveratrol may affect cardiovascular risk factors such as elevated blood cholesterol or trimethylamine

Topics: Animals; Anti-Obesity Agents; Cardiovascular Diseases; Diet, High-Fat; Energy Metabolism; Gastrointestinal Microbiome; Humans; Intestinal Mucosa; Obesity; Resveratrol; Stilbenes

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 (

Topics: Adipose Tissue; Animals; Body Weight; Clinical Trials as Topic; Diet; Drug Evaluation, Preclinical; Energy Metabolism; Humans; Obesity; Resveratrol; Stilbenes

Adipogenesis is the process by which precursor stem cells differentiate into lipid laden adipocytes. Adipogenesis is regulated by a complex and highly orchestrated gene expression program. In mammalian cells, the peroxisome proliferator-activated receptor γ (PPARγ), and the CCAAT/enhancer binding proteins (C/EBPs) such as C/EBPα, β and δ are considered the key early regulators of adipogenesis, while fatty acid binding protein 4 (FABP4), adiponectin, and fatty acid synthase (FAS) are responsible for the formation of mature adipocytes. Excess accumulation of lipids in the adipose tissue leads to obesity, which is associated with cardiovascular diseases, type II diabetes and other pathologies. Thus, investigating adipose tissue development and the underlying molecular mechanisms is vital to develop therapeutic agents capable of curbing the increasing incidence of obesity and related pathologies. In this review, we address the process of adipogenic differentiation, key transcription factors and proteins involved, adipogenic regulators and potential anti-adipogenic bioactive molecules.

Topics: Adipocytes; Adipogenesis; Adiponectin; Adipose Tissue; Animals; CCAAT-Enhancer-Binding Protein-delta; CCAAT-Enhancer-Binding Proteins; Fatty Acid Synthase, Type I; Fatty Acid-Binding Proteins; Gene Expression Regulation; Genistein; Humans; Hydroxycholesterols; Mice; Obesity; PPAR gamma; Protein Isoforms; Resveratrol; Signal Transduction; Stilbenes

Leptin is mainly secreted by white adipose tissue and regulates energy homeostasis by inhibiting food intake and stimulating energy expenditure through its action in neuronal circuits in the brain, particularly in the hypothalamus. However, hyperleptinemia coexists with the loss of responsiveness to leptin in common obese conditions. This phenomenon has been defined as leptin resistance and the restoration of leptin sensitivity is considered to be a useful strategy to treat obesity. This review summarizes the existing literature on potentially valuable nutrients and food components to reverse leptin resistance. Notably, several food compounds, such as teasaponins, resveratrol, celastrol, caffeine, and taurine among others, are able to restore the leptin signaling in neurons by overexpressing anorexigenic peptides (proopiomelanocortin) and/or repressing orexigenic peptides (neuropeptide Y/agouti-related peptide), thus decreasing food intake. Additionally, some nutrients, such as vitamins A and D, can improve leptin transport through the blood-brain barrier. Therefore, food components can improve leptin resistance by acting at different levels of the leptin pathway; moreover, some compounds are able to target more than one feature of leptin resistance. However, systematic studies are necessary to define the actual effectiveness of each compound.

Topics: Agouti-Related Protein; Animals; Blood-Brain Barrier; Caffeine; Eating; Food; Hypothalamus; Leptin; Low Density Lipoprotein Receptor-Related Protein-2; Neurons; Neuropeptide Y; Obesity; Pentacyclic Triterpenes; Pro-Opiomelanocortin; Protein Tyrosine Phosphatase, Non-Receptor Type 1; Receptors, Leptin; Resveratrol; Saponins; Stilbenes; Taurine; Triterpenes

Obesity and metabolic syndrome are significant global health issues, with current public health messages predominately focused on altering dietary and physical activity behaviors. Resveratrol is a polyphenol (stilbenoid) commonly found in grapes, and human trials to date have shown conflicting and limited beneficial effects with respect to health. The aim of this study was to determine the effect of resveratrol supplementation on reducing body weight and modifying associated inflammatory markers.. A systematic review was undertaken following the PRISMA guidelines and using five indexed databases (OVID MEDLINE, Cochrane Library, Web of Science, SCOPUS, and CINAHL). A search strategy was formulated to select randomized, double-blind, placebo-controlled human trials investigating the effects of resveratrol supplementation on obesity or overweight, including body weight, metabolic and inflammatory markers.. Five thousand five hundred sixty-nine studies published from 1990 to November 2015 were identified, with only nine papers meeting the inclusion criteria. The studies involved 208 participants (aged 49.2 ± 8.3 years) and utilized a substantial range of resveratrol doses (75-3000 mg/day). Study durations were a minimum of 2 weeks (14-90 days). Seven studies indicated no significant change in body mass index or body weight (P > 0.05), and three studies showed no improvements in fat mass, fat volume, or abdominal fat distribution (P > 0.05). Four studies included measurements of inflammatory markers, with three of these finding resveratrol supplementation to have a significant positive effect (P > 0.05).. Based on the included studies, there is currently insufficient evidence to support the recommendation of resveratrol supplements in management of obesity. However, there were significant but not entirely consistent anti-inflammatory effects after resveratrol supplementation in overweight and obese individuals.

Topics: Anti-Inflammatory Agents; Dietary Supplements; Humans; Obesity; Overweight; Randomized Controlled Trials as Topic; Resveratrol; Stilbenes; Weight Loss

Potential effects of resveratrol consumption on cardiovascular disease risk factors and body weight in overweight/obese adults have not been fully elucidated. Our present analysis was to evaluate the effects of resveratrol consumption on risk markers related to cardiovascular health in overweight/obese Individuals.. Multiple literature databases were systematically searched, and 21 studies were included. Effect sizes were expressed as weighted mean difference (WMD) and 95% confidence interval (CI), and heterogeneity was assessed with the I2 test. Publication bias and subgroup analyses were also performed.. There were variations in reporting quality of included studies. Resveratrol intervention significantly lowered total cholesterol (WMD, -0.19 mmol/L; 95% CI, -0.32 to -0.06; P = 0.004), systolic blood pressure (WMD, -2.26 mmHg; 95% CI, -4.82 to -0.49; P = 0.02), and fasting glucose (WMD, -0.22 mmol/L; 95% CI, -0.42 to -0.03; P = 0.03). Heterogeneity was noted for these outcomes (35.6%, 38.7% and 71.4%, respectively). Our subgroup analysis showed significant reductions in total cholesterol, systolic blood pressure, diastolic blood pressure, glucose, and insulin in subjects ingesting higher dose of resveratrol (≥300 mg/day).. Our finding provides evidence that daily resveratrol consumption might be a candidate as an adjunct to pharmacological management to better prevent and control cardiovascular disease in overweight/obese individuals.

Topics: Biomarkers; Blood Pressure; Body Mass Index; Cardiovascular Diseases; Cholesterol; Humans; Insulin Resistance; Meta-Analysis as Topic; Obesity; Overweight; Randomized Controlled Trials as Topic; Reproducibility of Results; Resveratrol; Risk Factors; Stilbenes

The prevalence of obesity has increased rapidly during recent years and has reached epidemic proportions. As a result, the scientific community is interested in active biomolecules which are naturally present in plants and foodstuffs and may be useful in body weight management. In recent years, polyphenols have made up one of the most frequently studied groups among these molecules. Numerous studies have been carried out on animals to analyse the potential anti-obesity effects of resveratrol, a non-flavonoid polyphenol, and a general consensus concerning the body-fat-lowering effect of this compound exists. By contrast, studies in humans have been few so far. Moreover, in these studies, the effectiveness of resveratrol is low. The aims of the present review are to summarize the results reported so far on this topic and to justify the differences observed between animals and humans. It seems that the reduced response to resveratrol in humans cannot be attributed to the use of lower doses in humans because the doses that induce body-fat-lowering effects in rodents are in the same range as those used in human studies. With regard to the experimental period length, treatments were longer in animal studies than in human studies. This can be one of the reasons contributing to the reduced responses observed in humans. Moreover, animals used in the reported studies are young while volunteers participating in human studies are adults, suggesting that resveratrol may be more efficient in young individuals. In addition to differences in the experimental designs, metabolic differences between animals and human cannot be discarded.

Topics: Animals; Anti-Obesity Agents; Disease Models, Animal; Drug Evaluation, Preclinical; Humans; Obesity; Resveratrol; Stilbenes

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.

Topics: Adipocytes; Animals; Diabetes Mellitus; Glucose; Humans; Hypoglycemic Agents; Insulin Resistance; Obesity; Polyphenols; Resveratrol; Stilbenes

There is an increasing need for novel preventive and therapeutic strategies to combat obesity and related metabolic disorders. In this respect, the natural polyphenol resveratrol has attracted significant interest. Animal studies indicate that resveratrol mimics the effects of calorie restriction via activation of sirtuin 1 (SIRT1). SIRT1 is an important player in the regulation of cellular energy homeostasis and mitochondrial biogenesis. Rodent studies have shown beneficial effects of resveratrol supplementation on mitochondrial function, glucose metabolism, body composition and liver fat accumulation. However, confirmation of these beneficial effects in humans by placebo-controlled clinical trials remains relatively limited. This review will give an overview of pre-clinical and clinical studies examining the effects of resveratrol on obesity-induced negative health outcomes. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes.

Topics: Adipose Tissue, Brown; AMP-Activated Protein Kinases; Animals; Humans; Mitochondria; Obesity; Resveratrol; Sirtuins; Stilbenes

Resveratrol, a polyphenol found in a number of plant-based foods such as red wine, has received a great deal of attention for its diverse array of healthful effects. Beneficial effects of resveratrol are diverse; they include improvement of mitochondrial function, protection against obesity and obesity-related diseases such as type-2 diabetes, suppression of inflammation and cancer cell growth and protection against cardiovascular dysfunction, just to name a few. Investigations into the metabolic effects of resveratrol are furthest along and now include a number of clinical trials, which have yielded mixed results. There are a number of controversies surrounding resveratrol that have not been resolved. Here, we will review these controversies with particular emphasis on its mechanism of metabolic action and how lessons from resveratrol may help develop therapies that harness the effects of resveratrol but without the undesirable properties of resveratrol.

Topics: AMP-Activated Protein Kinases; Animals; Antioxidants; Cyclic Nucleotide Phosphodiesterases, Type 4; Diabetes Mellitus, Type 2; Humans; Longevity; Neuroprotective Agents; Obesity; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes

Throughout the Western world obesity prevalence is steadily increasing, and associated metabolic co-morbidities are projected to rise during the years to come. As weight loss and weight maintenance remains a major problem, new strategies to protect against obesity-related morbidity are needed. There is a clear association between obesity, low-grade inflammation and obesity-associated diseases, thus, the development of new anti-inflammatory substances is urgently needed as these may ultimately pave the way for novel treatments of obesity and lifestyle-related diseases. A candidate molecule is the polyphenolic compound resveratrol, and in the present review, we provide an overview of the field, and discuss the future scientific perspectives. This article is part of a Special Issue entitled: Resveratrol: Challenges in translating pre-clinical findings to improved patient outcomes.

Topics: Adipose Tissue; Animals; Anti-Inflammatory Agents, Non-Steroidal; Clinical Trials as Topic; Humans; Inflammation; Obesity; Resveratrol; Stilbenes; Translational Research, Biomedical

Civilization development is associated with immense progress in science and significant improvement of human living conditions but simultaneously it contributes to many health problems including metabolic syndrome. Metabolic syndrome is a set of mutually associated factors including insulin resistance, hyperinsulinemia, obesity, lipids disorders and hypertension, which is the main cause of development of coronary heart disease and type 2 diabetes. The first line of defense against metabolic syndrome is a change of life style including body mass reduction, application of a low-calorie diet and performance of physical activity. In spite of the simplicity of therapy, long-term success of the above treatment among patients is observed seldom because it is very difficult to obey rigorous rules. Nowadays, it is considered that diet supplements including antioxidants, polyunsaturated fatty acids and mineral elements are helpful in metabolic syndrome treatment due to their antioxidant and anti-inflammatory properties. It is considered that a health balanced diet enriched with various diet supplements may be the best strategy in metabolic syndrome treatment.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Calcium; Caloric Restriction; Diabetes Mellitus, Type 2; Dietary Supplements; Fatty Acids, Omega-3; Garlic; Humans; Magnesium; Metabolic Syndrome; Obesity; Panax; Photinia; Phytotherapy; Plant Preparations; Resveratrol; Risk Reduction Behavior; Selenium; Stilbenes; Tea; Zinc

Numerous studies have highlighted the key roles of oxidative stress and inflammation in aging-related diseases such as obesity, type 2 diabetes, age-related macular degeneration (AMD), and Alzheimer's disease (AD). In aging cells, the natural antioxidant capacity decreases and the overall efficiency of reparative systems against cell damage becomes impaired. There is convincing data that stilbene compounds, a diverse group of natural defence phenolics, abundant in grapes, berries, and conifer bark waste, may confer a protective effect against aging-related diseases. This review highlights recent data helping to clarify the molecular mechanisms involved in the stilbene-mediated protection against oxidative stress. The impact of stilbenes on the nuclear factor-erythroid-2-related factor-2 (Nrf2) mediated cellular defence against oxidative stress as well as the potential roles of SQSTM1/p62 protein in Nrf2/Keap1 signaling and autophagy will be summarized. The therapeutic potential of stilbene compounds against the most common aging-related diseases is discussed.

Topics: Adaptor Proteins, Signal Transducing; Diabetes Mellitus, Type 2; Humans; Neurodegenerative Diseases; NF-E2-Related Factor 2; Obesity; Oxidative Stress; Polyphenols; Reactive Oxygen Species; Signal Transduction; Stilbenes

Obesity as part of metabolic syndrome is a major lifestyle disorder throughout the world. Current drug treatments for obesity produce small and usually unsustainable decreases in body weight with the risk of major adverse effects. Surgery has been the only treatment producing successful long-term weight loss. As a different but complementary approach, lifestyle modification including the use of functional foods could produce a reliable decrease in obesity with decreased comorbidities. Functional foods may include fruits such as berries, vegetables, fibre-enriched grains and beverages such as tea and coffee. Although health improvements continue to be reported for these functional foods in rodent studies, further evidence showing the translation of these results into humans is required. Thus, the concept that these fruits and vegetables will act as functional foods in humans to reduce obesity and thereby improve health remains intuitive and possible rather than proven.

Topics: Animals; Anthocyanins; Antioxidants; Caffeine; Dietary Fiber; Disease Models, Animal; Ellagic Acid; Fatty Acids; Feeding Behavior; Fruit; Functional Food; Humans; Metabolic Syndrome; Nutritional Physiological Phenomena; Obesity; Olive Oil; Prebiotics; Probiotics; Quercetin; Rats; Rutin; Stilbenes; Thermogenesis; Vegetables; Vitamins

Resveratrol is a polyphenol that can be found in various plants, including grapes. Wines therefore also contain this compound. The famous phenomenon, named "French paradox" is considered to be an effect of resveratrol: the regular, modest consumption of red wine causes low incidence of cardiovascular diseases. Resveratrol is also reported to have anti-carcinogenic, anti-inflammatory, neuroprotective, and several further beneficial effects. As yet, resveratrol is not a registered drug in Hungary; nevertheless it is a common food supplement. Paradoxically, this is the very danger of its use: it can have harmful side-effects with several drugs. The bioavailability of resveratrol is, however, not favorable, due to its poor water-solubility and extensive metabolism. Our current knowledge is still far from being sufficient to understand its mode of action at a molecular level. Only a few of the most important physicochemical properties has been determined so far. The two major directions of pharmaceutical research of resveratrol are the elaboration of formulation systems that can improve the water solubility; the other is the development of analogous agents of enhanced effects.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Anticarcinogenic Agents; Antineoplastic Agents, Phytogenic; Antioxidants; Blood Glucose; Cardiovascular System; Chemistry, Pharmaceutical; Dietary Supplements; Humans; Hungary; Obesity; Resveratrol; Solubility; Stilbenes

Nonalcoholic fatty liver disease (NAFLD) refers to a wide spectrum of liver disease that is not from excess alcohol consumption, but is often associated with obesity, type 2 diabetes, and metabolic syndrome. NAFLD pathogenesis is complicated and involves oxidative stress, lipotoxicity, mitochondrial damage, insulin resistance, inflammation, and excessive dietary fat intake, which increase hepatic lipid influx and de novo lipogenesis and impair insulin signaling, thus promoting hepatic triglyceride accumulation and ultimately NAFLD. Overproduction of proinflammatory adipokines from adipose tissue also affects hepatic metabolic function. Current NAFLD therapies are limited; thus, much attention has been focused on identification of potential dietary substances from fruits, vegetables, and edible plants to provide a new strategy for NAFLD treatment. Dietary natural compounds, such as carotenoids, omega-3-PUFAs, flavonoids, isothiocyanates, terpenoids, curcumin, and resveratrol, act through a variety of mechanisms to prevent and improve NAFLD. Here, we summarize and briefly discuss the currently known targets and signaling pathways as well as the role of dietary natural compounds that interfere with NAFLD pathogenesis.

Topics: Adipokines; Animals; Carotenoids; Curcumin; Fatty Acids, Omega-3; Fatty Liver; Flavonols; Humans; Insulin Resistance; Non-alcoholic Fatty Liver Disease; Obesity; Oxidative Stress; Polyphenols; Resveratrol; Stilbenes

The prevalence of obesity has steadily increased over the past three decades both in the United States and worldwide. Recent studies have shown the role of dietary polyphenols in the prevention of obesity and obesity-related chronic diseases. Here, we evaluated the impact of commonly consumed polyphenols, including green tea catechins, especially epigallocatechin gallates, resveratrol and curcumin, on obesity and obesity-related inflammation. Cellular studies demonstrated that these dietary polyphenols reduce viability of adipocytes and proliferation of preadipocytes, suppress adipocyte differentiation and triglyceride accumulation, stimulate lipolysis and fatty acid β-oxidation, and reduce inflammation. Concomitantly, the polyphenols modulate signaling pathways including the adenosine-monophosphate-activated protein kinase, peroxisome proliferator activated receptor γ, CCAAT/enhancer binding protein α, peroxisome proliferator activator receptor gamma activator 1-alpha, sirtuin 1, sterol regulatory element binding protein-1c, uncoupling proteins 1 and 2, and nuclear factor-κB that regulate adipogenesis, antioxidant and anti-inflammatory responses. Animal studies strongly suggest that commonly consumed polyphenols described in this review have a pronounced effect on obesity as shown by lower body weight, fat mass and triglycerides through enhancing energy expenditure and fat utilization, and modulating glucose hemostasis. Limited human studies have been conducted in this area and are inconsistent about the antiobesity impact of dietary polyphenols probably due to the various study designs and lengths, variation among subjects (age, gender, ethnicity), chemical forms of the dietary polyphenols used and confounding factors such as other weight-reducing agents. Future randomized controlled trials are warranted to reconcile the discrepancies between preclinical efficacies and inconclusive clinic outcomes of these polyphenols.

Topics: Adipocytes; Animals; Catechin; Cell Differentiation; Curcumin; Diet; Humans; Obesity; Plant Extracts; Polyphenols; Randomized Controlled Trials as Topic; Resveratrol; Stilbenes; Tea

Adiponectin is produced predominantly by adipocytes and plays an important role in metabolic and cardiovascular homeostasis through its insulin-sensitizing actions and anti-inflammatory and anti-atherogenic properties. Recently, it has been observed that lower levels of adiponectin can substantially increase the risk of developing type 2 diabetes, metabolic syndrome, atherosclerosis, and cardiovascular disease in patients who are obese. Circulating adiponectin levels are inversely related to the inflammatory process, oxidative stress, and metabolic dysregulation. Intensive lifestyle modifications and pharmacologic agents, including peroxisome proliferator-activated receptor-γ or α agonists, some statins, renin-angiotensin-aldosterone system blockers, some calcium channel blockers, mineralocorticoid receptor blockers, new β-blockers, and several natural compounds can increase adiponectin levels and suppress or prevent disease initiation or progression, respectively, in cardiovascular and metabolic disorders. Therefore, it is important for investigators to have a thorough understanding of the interventions that can modulate adiponectin. Such knowledge may lead to new therapeutic approaches for diseases such as type 2 diabetes, metabolic syndrome, cardiovascular disease, and obesity. This review focuses on recent updates regarding therapeutic interventions that might modulate adiponectin.

Topics: Adiponectin; Antihypertensive Agents; Atherosclerosis; Bariatric Surgery; Cardiovascular Diseases; Clinical Trials as Topic; Combined Modality Therapy; Diabetes Mellitus, Type 2; Diet, Reducing; Exercise; Humans; Hypoglycemic Agents; Insulin Resistance; Life Style; Metabolic Syndrome; Metabolism, Inborn Errors; Obesity; Peroxisome Proliferator-Activated Receptors; Receptors, Adiponectin; Resveratrol; Stilbenes

Resveratrol is a non-flavonoid polyphenol which belongs to the stilbenes group and is produced naturally in several plants in response to injury or fungal attack. Resveratrol has been recently reported as preventing obesity. The present review aims to compile the evidence concerning the potential mechanisms of action which underlie the anti-obesity effects of resveratrol, obtained either in cultured cells lines and animal models. Published studies demonstrate that resveratrol has an anti-adipogenic effect. A good consensus concerning the involvement of a down-regulation of C/EBPα and PPARγ in this effect has been reached. Also, in vitro studies have demonstrated that resveratrol can increase apoptosis in mature adipocytes. Furthermore, different metabolic pathways involved in triacylglycerol metabolism in white adipose tissue have been shown to be targets for resveratrol. Both the inhibition of de novo lipogenesis and adipose tissue fatty acid uptake mediated by lipoprotein lipase play a role in explaining the reduction in body fat which resveratrol induces. As far as lipolysis is concerned, although this compound per se seems to be unable to induce lipolysis, it increases lipid mobilization stimulated by β-adrenergic agents. The increase in brown adipose tissue thermogenesis, and consequently the associated energy dissipation, can contribute to explaining the body-fat lowering effect of resveratrol. In addition to its effects on adipose tissue, resveratrol can also acts on other organs and tissues. Thus, it increases mitochondriogenesis and consequently fatty acid oxidation in skeletal muscle and liver. This effect can also contribute to the body-fat lowering effect of this molecule.

Topics: Adipocytes; Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; CCAAT-Enhancer-Binding Proteins; Down-Regulation; Fatty Acids; Humans; Lipogenesis; Liver; Muscle, Skeletal; Obesity; PPAR gamma; Resveratrol; Stilbenes

In the search for novel preventive and therapeutic modalities in the management of metabolic diseases and obesity, resveratrol has attracted great attention over the past decades. Preclinical trials suggest that resveratrol mimics the metabolic effects of calorie restriction (CR) via activation of silent mating type information regulation 2 homolog 1 (SIRT1). In experimental animals, this potential translates into prevention or improvement of glucose metabolism, anti-inflammation, cancer, and nonalcoholic fatty liver disease. Moreover, and in accordance with CR, supplementation with resveratrol promotes longevity in several primitive species and protects against diet-induced metabolic abnormalities in rodents. Despite the substantial preclinical evidence, human clinical data are very scarce, and even though the compound is widely distributed as an over-the-counter human nutritional supplement, its therapeutic rationale has not been well characterized. In this review, we provide a brief overview of the field and discuss the future scientific directions of resveratrol research.

Topics: Animals; Caloric Restriction; Clinical Trials as Topic; Dietary Supplements; Energy Metabolism; Humans; Metabolic Diseases; Obesity; Resveratrol; Sirtuin 1; Stilbenes

The number of people suffering from metabolic disorders is dramatically increasing worldwide. The need for new therapeutic strategies to combat this growing epidemic of metabolic diseases is therefore also increasing. In 2003, resveratrol was discovered to be a small molecule activator of sirtuin 1 (SIRT1), an important molecular target regulating cellular energy metabolism and mitochondrial homeostasis. Rodent studies have clearly demonstrated the potential of resveratrol to improve various metabolic health parameters. To date, however, only limited clinical data are available that have systematically examined the health benefits of resveratrol in metabolically challenged humans. This short review will give an overview of the currently available clinical studies examining the effects of resveratrol on obesity and type 2 diabetes from a human perspective.

Topics: Animals; Clinical Trials as Topic; Diabetes Mellitus, Type 2; Energy Metabolism; Humans; Insurance Benefits; Obesity; Resveratrol; Stilbenes

Adipose tissue is an active endocrine organ that responds to changes in energy balance and influences whole-body physiology. Adipose tissue dysfunction with obesity is associated with metabolic disease, neurodegeneration, inflammation, and cancer, whereas calorie restriction (CR) decreases both adiposity and disease risk. Although resveratrol does not affect obesity, it mimics long-term CR by increasing both life span in model organisms and health span in rodents. Because resveratrol's benefits in experimental animals are reminiscent of improved adipose tissue function under CR, this review synthesizes existing data to assess if resveratrol's effects may be mediated by mimicking CR in adipose tissue. In metabolically unhealthy humans, resveratrol consumption recapitulates the health benefits of CR, whereas short-term resveratrol in otherwise healthy humans mimics CR at the transcriptional, but not physiological, level. This latter observation (neutral effect of short-term resveratrol) may be protective against future disease risk; however, long-term studies in healthy humans will be needed to support this hypothesis.

Topics: Adipose Tissue; Adiposity; Animals; Biomimetic Materials; Caloric Restriction; Humans; Obesity; Resveratrol; Stilbenes

Higher levels of body fat are associated with increased risk for development of numerous adverse health conditions. Phytochemicals are potential agents to inhibit differentiation of preadipocytes, stimulate lipolysis, and induce apoptosis of existing adipocytes, thereby reducing adipose tissue mass. Resveratrol decreased adipogenesis and viability in maturing preadipocytes; these effects were mediated not only through down-regulating adipocyte specific transcription factors and enzymes but also by genes that modulate mitochondrial function. Additionally, resveratrol increased lipolysis and reduced lipogenesis in mature adipocytes. In addition, combining resveratrol with other natural products produced synergistic activities from actions on multiple molecular targets in the adipocyte life cycle. Treatment of mice with resveratrol alone was shown to improve resistance to weight gain caused by a high-fat diet. Moreover, dietary supplementation of aged ovariectomized rats with a combination of resveratrol and vitamin D, quercetin, and genistein not only decreased weight gain but also inhibited bone loss. Combining several phytochemicals, including resveratrol, or using them as templates for synthesizing new drugs, provides a large potential for using phytochemicals to target adipocyte adipogenesis, apoptosis, and lipolysis.

Topics: Adipogenesis; Adipose Tissue; Animals; Humans; Lipolysis; Obesity; Resveratrol; Signal Transduction; Stilbenes

Resveratrol, a phytoalexin, has gained much attention recently due to its effects on sirtuins. While the anti-cancer properties of resveratrol have been extensively investigated, the anti-adipogenic and osteogenic effects of resveratrol are also gaining considerable interest. The finding that resveratrol supplementation mimics caloric restriction prompted researchers to study the effects of resveratrol on lipid metabolism. Mesenchymal stem cells are the precursors for both adipocytes and osteoblasts. In the aging population, differentiation to adipocytes dominates over the differentiation to osteoblasts in bone marrow, contributing to the increased tendency for fractures to occur in the elderly. Thus, an inverse relationship exists between adipocytes and osteoblasts in the bone marrow. Resveratrol acts on several molecular targets in adipocytes and osteoblasts leading to a decrease in adipocyte number and size and an increase in osteogenesis. Furthermore, resveratrol in combination with genistein and quercetin synergistically decreased adipogenesis in murine and human adipocytes. A recent in vivo study showed that phytochemicals including resveratrol in combination with vitamin D prevented weight gain and bone loss in a postmenopausal rat model. Therefore, combinations of resveratrol with other phytochemicals may lead to potential novel potent therapies for both obesity and osteoporosis.

Topics: Adipocytes; Animals; Caloric Restriction; Drug Synergism; Humans; Lipolysis; Obesity; Osteoblasts; Osteoporosis; Resveratrol; Stilbenes

In the past decade, the small polyphenol resveratrol has received widespread attention as either a potential therapy or as a preventive agent for numerous diseases. Studies using purified enzymes, cultured cells, and laboratory animals have suggested that resveratrol has anti-aging, anti-carcinogenic, anti-inflammatory, and anti-oxidant properties that might be relevant to chronic diseases and/or longevity in humans. Although the supporting research in laboratory models is quite substantial, only recently data has emerged to describe the effects of resveratrol supplementation on physiological responses in humans. The limited number of human clinical trials that are available has largely described various aspects of resveratrol's safety and bioavailability, reaching a consensus that it is generally well-tolerated, but have poor bioavailability. Very few published human studies have explored the ability of resveratrol to achieve the physiological benefits that have been observed in laboratory models, although many clinical trials have recently been initiated. This review aims to examine the current state of knowledge on the effects of resveratrol on humans and to utilize this information to develop further guidelines for the implementation of human clinical trials.

Topics: Animals; Biological Availability; Cardiovascular Diseases; Clinical Trials as Topic; Diabetes Mellitus; Dietary Supplements; Humans; Liver; Obesity; Oxidative Stress; Resveratrol; Stilbenes; Wine

Members of the sirtuin family of NAD(+)-dependent protein deacetylases are important regulators of longevity in yeast, worms, and flies. Mammals have seven sirtuins (SIRT1-7), each characterized by differences in subcellular localization, substrate preference, and biological function. While it is unclear whether sirtuins regulate aging in mammals, it is clear that sirtuins influence diverse aspects of their metabolism. Indeed, SIRT1 promotes oxidation of fatty acids in liver and skeletal muscle, cholesterol metabolism in liver, and lipid mobilization in white adipose tissue. Moreover, small-molecule activators of SIRT1 have recently been shown to protect mice from the negative effects of a high-fat diet. These findings suggest that sirtuins might provide important new targets for the treatment of obesity and related diseases. In this review, we discuss the major findings linking sirtuins with the regulation of lipid metabolism.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Animals; Caloric Restriction; Dietary Fats; Enzyme Activation; Humans; Insulin; Insulin Secretion; Lipid Metabolism; Liver; Mice; Models, Biological; Muscle, Skeletal; Obesity; Resveratrol; Sirtuins; Stilbenes

Dietary restriction (DR) delays or prevents age-related diseases and extends lifespan in species ranging from yeast to primates. Although the applicability of this regimen to humans remains uncertain, a proportional response would add more healthy years to the average life than even a cure for cancer or heart disease. Because it is unlikely that many would be willing or able to maintain a DR lifestyle, there has been intense interest in mimicking its beneficial effects on health, and potentially longevity, with drugs. To date, such efforts have been hindered primarily by our lack of mechanistic understanding of how DR works. Sirtuins, NAD(+)-dependent deacetylases and ADP-ribosyltransferases that influence lifespan in lower organisms, have been proposed to be key mediators of DR, and based on this model, the sirtuin activator resveratrol has been proposed as a candidate DR mimetic. Indeed, resveratrol extends lifespan in yeast, worms, flies, and a short-lived species of fish. In rodents, resveratrol improves health, and prevents the early mortality associated with obesity, but its precise mechanism of action remains a subject of debate, and extension of normal lifespan has not been observed. This review summarizes recent work on resveratrol, sirtuins, and their potential to mimic beneficial effects of DR.

Topics: ADP Ribose Transferases; Animals; Diet; Diet, Reducing; Energy Metabolism; Humans; Longevity; Obesity; Primates; Resveratrol; Saccharomyces cerevisiae; Sirtuins; Stilbenes

To review the pathophysiology, pharmacology, and current or future therapies under study for use in treating diabetes mellitus, inflammation associated with diabetes mellitus, and/or obesity related to diabetes mellitus, through 1 of 4 investigational pathways: adiponectin, ghrelin, resveratrol, or leptin.. A literature search using MEDLINE (1966-December 12, 2009), PubMed (1950-December 12, 2009), Science Direct (1994-December 12, 2009), and International Pharmaceutical Abstracts (1970-December 12, 2009) was performed using the terms adiponectin, ghrelin, resveratrol, leptin, inflammation, obesity, and diabetes mellitus. English-language, original research, and review articles were examined, and citations from these articles were assessed as well.. Clinical studies and in vitro studies were included in addition to any Phase 1, 2, or 3 clinical trials.. Mechanistic pathways regarding adiponectin, ghrelin, resveratrol, and leptin are of interest as future treatment options for diabetes mellitus. Each of these pathways has produced significant in vitro and in vivo clinical data warranting further research as a possible treatment pathway for diabetes-related inflammation and/or obesity reduction. While research is still underway to determine the exact effects these pathways have on metabolic function, current data suggest that each of these compounds may be of interest for future therapies.. While several pathways under investigation may offer additional benefits in the treatment of diabetes mellitus and associated impairments, further investigation is necessary for both investigational and approved therapies to ensure that the impact in new pathways does not increase risks to patient safety and outcomes.

Topics: Adiponectin; Animals; Anti-Inflammatory Agents; Anti-Obesity Agents; Antioxidants; Diabetes Mellitus; Ghrelin; Humans; Hypoglycemic Agents; Inflammation; Leptin; Obesity; Resveratrol; Stilbenes

Resveratrol belongs to the large group of biologically active substances found in plants. This compound is classified as phytoestrogen because of its ability to interact with estrogen receptor. Numerous beneficial effects of resveratrol described in the literature involve cardioprotective, anti-cancer, anti-inflammatory and antioxidant action. Recently, this broad spectrum of effects is enlarged by new data demonstrating a great potency of this compound in relation to obesity and diabetes. It is well established that resveratrol exerts beneficial effects in rodents fed a high-calorie diet. In some studies, resveratrol was reported to reduce body weight and adiposity in obese animals. The action of this compound involves favourable changes in gene expressions and in enzyme activities. The accumulating evidence also indicates the benefits of resveratrol in diabetes and diabetic complications. It is known that resveratrol affects insulin secretion and blood insulin concentration. In animals with hyperinsulinemia, resveratrol was found to reduce blood insulin. Moreover, numerous data indicate that in diabetic rats, resveratrol is able to reduce hyperglycemia. The mechanism of resveratrol's action is complex and is demonstrated to involve both insulin-dependent and insulin-independent effects. These data point to the potential possibility of use of resveratrol in preventing and/or treating both obesity and diabetes.

Topics: Animals; Diabetes Mellitus; Humans; Obesity; Resveratrol; Stilbenes

The silent information regulator (SIR) genes (sirtuins) comprise a highly conserved family of proteins, with one or more sirtuins present in virtually all species from bacteria to mammals. In mammals seven sirtuin genes - SIRT1 to SIRT7 - have been identified. Emerging from research on the sirtuins is a growing appreciation that the sirtuins are a very complicated biological response system that influences many other regulator molecules and pathways in complex manners. Responses of this system to environmental factors, as well as its role in health and disease, are currently incompletely characterized and at most partially understood. This article reviews the mammalian sirtuin system, discusses the dietary, lifestyle, and environmental factors that influence sirtuin activity, and summarizes research on the importance of vitamin B3 in supporting sirtuin enzyme activity, as well as the role specifically of the amide form of this vitamin - nicotinamide - to inhibit sirtuin enzyme activity. Polyphenols, especially resveratrol, influence sirtuins. Existing evidence on these nutritional compounds, as they relate to the sirtuin system, is reviewed. In Part 2 of this review, clinical situations where sirtuins might play a significant role, including longevity, obesity, fatty liver disease, cardiovascular health, neurological disease, and cancer, are discussed.

Topics: Aging; Biological Availability; Cardiovascular Diseases; Enzyme Activators; Humans; Learning; Longevity; Memory; Neoplasms; Nervous System Diseases; Obesity; Phenols; Resveratrol; Sirtuins; Stilbenes

The silent information regulator (SIR) genes (sirtuins) comprise a highly conserved family of proteins, with one or more sirtuins present in virtually all species from bacteria to mammals. In mammals seven sirtuin genes - SIRT1 to SIRT7 - have been identified. Emerging from research on the sirtuins is a growing appreciation that they are a very complicated biological response system that influences many other regulator molecules and pathways in complex manners. Part 1 of this article provided an overview of the mammalian sirtuin system, discussed the dietary, lifestyle, and environmental factors that influence sirtuin activity, and summarized research on the importance of vitamin B3 in supporting sirtuin enzyme activity, as well as the role specifically of the amide form of this vitamin - nicotinamide - to inhibit sirtuin enzyme activity. In Part 2 of this review, clinical situations where sirtuins might play a significant role, including longevity, obesity, fatty liver disease, cardiovascular health, neurological disease, and cancer are discussed. Research on the ability of nutritional substances, especially resveratrol, to influence sirtuin expression and function, and hence alter the courses of some clinical situations, is also reviewed.

Topics: Aging; Biological Availability; Cardiovascular Diseases; Enzyme Activators; Humans; Longevity; Neoplasms; Nervous System Diseases; Obesity; Phenols; Resveratrol; Sirtuins; Stilbenes

The prevalence of overweight and obesity and their associated metabolic disorders are considered a major threat to the public's health. While several diet and exercise programs are available for weight loss and prevention of weight regain, progress is often slow and disappointing. Recently, natural bioactive phytochemicals present in foods have been discovered for their potential health benefit effects on the prevention of chronic disorders such as cancer, cardiovascular disease, inflammatory and metabolic diseases including obesity. Polyphenols are a class of naturally-occurring phytochemicals, of which some such as catechins, anthocynines, resveratrol and curcumin have been shown to modulate physiological and molecular pathways that are involved in energy metabolism, adiposity, and obesity. The potential in vivo, beneficial effects of these polyphenols on adiposity and obesity as complementary agents in the up-regulation of energy expenditure have emerged by investigating these compounds in cell cultures, animal models of obesity and in some human clinical and epidemiological studies. In this brief review, the efficacy of the above-named polyphenols and their potential efficacy to modulate obesity and some associated disorders are discussed.

Topics: Adipogenesis; Animals; Anthocyanins; Catechin; Cells, Cultured; Curcumin; Diet; Energy Metabolism; Fruit; Humans; Obesity; Polyphenols; Resveratrol; Stilbenes; Tea

Sirtuin 1-7 (SIRT1-7) are deacetylases that are dependent on NAD(+) for their activity. SIRT1 down-regulates p53 activity, increasing lifespan, cell survival, and neuroprotection; it also deacetylates peroxisome proliferator-activated receptor-gamma and its coactivator 1alpha, promoting fat mobilization, increasing mitochondrial size and number, and positively regulating insulin secretion. Sirtuins link nutrient availability and energy metabolism. Calorie restriction, which increases lifespan and is beneficial in age-related disorders, activates sirtuin. Major efforts are thus focused to developing sirtuin activators.. After discussing the potential involvement of sirtuins in pathophysiological processes, this review looks at new, synthetic sirtuin activators.. To date, resveratrol is the most potent natural compound able to activate SIRT1, mimicking the positive effect of calorie restriction. Resveratrol might help in the treatment or prevention of obesity and in preventing the aging-related decline in heart function and neuronal loss. As resveratrol has low bioavailability and interacts with multiple molecular targets, the development of new molecules with better bioavailability and targeting sirtuin at lower concentrations is a promising field of the medicinal chemistry. New SIRT1 activators that are up to 1000 times more effective than resveratrol have recently been identified. These improve the response to insulin and increase the number and activity of mitochondria in obese mice. Human trials with a formulation of resveratrol with improved bioavailability and with a synthetic SIRT1 activator are in progress.

Topics: Animals; Biological Availability; Drug Delivery Systems; Drug Design; Enzyme Activators; Flavonoids; Humans; Obesity; Phenols; Polyphenols; Resveratrol; Sirtuin 1; Sirtuins; Stilbenes

Obesity is a multi-faceted disease, predisposing sufferers to numerous co-morbidities such as epithelial dysfunction and insulin resistance which ultimately result in CVD. Visceral adipose tissue in particular is associated with inflammation due to the release of pro-inflammatory cytokines by adipocytes. Inflammation seems to be rather central in causing damage to endothelial cells as well as exerting negative effects on glucose metabolism, ultimately leading to insulin resistance. Resveratrol is a naturally occurring phenolic substance which has been found to display anti-inflammatory, vasoprotective and insulin-sensitising effects, among others. The popularity of resveratrol use is escalating in the treatment of various ailments including obesity in adults. The use of the substance in childhood obesity is, however, a worrying factor, as no studies have as yet been performed on adolescent animals and there is evidence of kidney toxicity of resveratrol and its metabolites at intake levels below those currently approved as safe. Another cause for concern is the uncertainty surrounding long-term, low-dose administration of the substance in humans. The supplement should thus not be recommended for use in the prevention and treatment of obesity until conclusive research is established on the safety of long-term usage of resveratrol in both children and adults.

Topics: Adult; Animals; Antioxidants; Child; Drug Administration Schedule; Humans; Inflammation; Intra-Abdominal Fat; Kidney; Obesity; Phenols; Plant Extracts; Resveratrol; Stilbenes

Evidence from animal models and preliminary studies in humans indicates that calorie restriction (CR) delays cardiac aging and can prevent cardiovascular disease. These effects are mediated by a wide spectrum of biochemical and cellular adaptations, including redox homeostasis, mitochondrial function, inflammation, apoptosis, and autophagy. Despite the beneficial effects of CR, its large-scale implementation is challenged by applicability issues as well as health concerns. However, preclinical studies indicate that specific compounds, such as resveratrol, may mimic many of the effects of CR, thus potentially obviating the need for drastic food intake reductions. Results from ongoing clinical trials will reveal whether the intriguing alternative of CR mimetics represents a safe and effective strategy to promote cardiovascular health and delay cardiac aging in humans.

Topics: Aged; Animals; Antioxidants; Apoptosis; Autophagy; Caloric Restriction; Cardiovascular Diseases; Disease Models, Animal; Forecasting; Heart Diseases; Homeostasis; Humans; Inflammation; Inflammation Mediators; Mitochondria, Heart; Mitochondrial Diseases; Obesity; Oxidation-Reduction; Oxidative Stress; Resveratrol; Stilbenes

Resveratrol, a polyphenol found in several vegetal sources, has been shown to possess lifespan-promoting properties in yeast and metazoans, including small mammals. While in yeast and low metazoans resveratrol acts mainly by activating the histone deacetylase Sir2, in mammals it appears to target - besides the Sir2 homolog SIRT1 - several crucial pathways for the control of metabolism, including the AMPK and the insulin-IGF1 receptors axis. The action of resveratrol on these pathways has been linked to its capability to i) prolong lifespan following chronic administration to mice and ii) protect from the development of diet-induced obesity and obesity-dependent metabolic disorders. Here we summarise the current understanding on how resveratrol displays its remarkable properties by acting on the control of insulin secretion and by modulation of insulin action in pheripheral insulin-responsive tissues. Since resveratrol has the potential for pharmacological exploitation to prevent the establishment of insulin-resistance and thus postpone - or even prevent - the onset of type 2 diabetes, toxicologic and pharmacodynamics studies in humans have been initiated. These studies show that resveratrol is non-toxic and easily absorbed by humans. As a drawback, its bioavailability is very limited due to the fast metabolic alterations to which it is subjected in the plasma. Therefore, we also review here the efforts that have been made - in the drug discovery field - to identify new molecules endowed with resveratrol-like pharmacological properties but with better bioavailability, which could prove to possess therapeutic potential.

Topics: Aging; AMP-Activated Protein Kinases; Animals; Humans; Insulin; Insulin-Secreting Cells; Longevity; Mammals; Mice; Obesity; Resveratrol; Signal Transduction; Stilbenes

Sirtuins represent a novel family of enzymes that are collectively well situated to help regulate nutrient sensing and utilization, metabolic rate and ultimately metabolic disease. Activation of one of these enzymes, SIRT1, leads to enhanced activity of multiple proteins, including peroxisome-proliferator activated receptor coactivator-1alpha (PGC-1alpha), which helps to mediate some of the in vitro and in vivo effects of sirtuins. As such, enhanced SIRT1 activity decreases glucose levels, improves insulin sensitivity, increases mitochondrial number and function, decreases adiposity, improves exercise tolerance and potentially lowers body weight. SRT-501 is a proprietary formulation of resveratrol with improved bioavailability. As such, SRT-501 represents the first in a novel class of SIRT1 activators that has proven to be safe and well-tolerated in humans. Clinical trials in type 2 diabetic patients are currently underway.

Topics: Base Sequence; Diabetes Mellitus, Type 2; Energy Metabolism; Enzyme Activators; Enzyme Inhibitors; Humans; Metabolic Diseases; Molecular Sequence Data; Molecular Structure; Obesity; Resveratrol; Sirtuin 1; Sirtuins; Stilbenes

In most countries the prevalence of obesity now exceeds 15%, the figure used by the World Health Organization to define the critical threshold for intervention in nutritional epidemics. Here we describe Homo obesus (man the obese) as a recent phenotypic expression of Homo sapiens. Specifically, we classified Homo obesus as a species deficient of metabotrophic factors (metabotrophins), including endogenous proteins, which play essential role in the maintenance of glucose, lipid, energy and vascular homeostasis, and also improve metabolism-related processes such as inflammation and wound healing. Here we propose that pharmaceuticals, nutraceuticals and xenohormetics targeting transcriptional, secretory and/or signaling pathways of metabotrophins, particularly adiponectin, nerve growth factor, brain-derived neurotrophic factor, interleukin-10, and sirtuins, might be new tools for therapy of Homo obesus. Brief comment is also given to (i) exogenous metabotrophic agents represented by various classes of drugs, and (ii) adiponutrigenomics of lifespan.

Topics: Brain-Derived Neurotrophic Factor; Caloric Restriction; Energy Metabolism; Glucose; Humans; Lipid Metabolism; Nerve Growth Factor; Nutritional Physiological Phenomena; Obesity; Resveratrol; Stilbenes

Obstetrical complications affect more than a third of women globally, but are underrepresented in clinical research. Little is known about the comprehensive obstetrical clinical trial landscape, how it compares with other fields, or factors associated with the successful completion of obstetrical trials.. This study aimed to characterize obstetrical clinical trials registered on ClinicalTrials.gov with the primary objective of identifying features associated with early discontinuation and results reporting.. This is a cross-sectional study with descriptive, logistic regression and Cox regression analyses of clinical trials registered on ClinicalTrials.gov. Our primary exposure variables were trial focus (obstetrical or nonobstetrical) and trial funding (industry, United States government, or academic). We conducted additional exploratory analyses of other trial features including design, enrollment, and therapeutic focus. We examined the associations of exposure variables and other trial features with 2 primary outcomes: early discontinuation and results reporting.. Obstetrical trials represent only 1.9% of all clinical trials in ClinicalTrials.gov and have comparatively poor completion. All stakeholders should commit to increasing the number of obstetrical trials and improving their completion and dissemination to ensure clinical research reflects the obstetrical burden of disease and advances maternal health.

Topics: Adipose Tissue, White; Adult; Aged; Air Pollutants; Animals; Anti-Inflammatory Agents; Arginine; bcl-2-Associated X Protein; Biofuels; Biological Products; Blood Glucose; Breast Neoplasms; Caspases; CD36 Antigens; Cell Communication; Cell Proliferation; Cell Survival; Cooking; Cross-Sectional Studies; Databases, Factual; Diabetes Mellitus, Type 2; Diphtheria Toxin; Double-Blind Method; Exenatide; Extracellular Polymeric Substance Matrix; Feasibility Studies; Female; Filgrastim; Fruit; Galactose; Gene Deletion; Gene Knockdown Techniques; Glucagon; Glucagon-Like Peptide-1 Receptor; Glucagon-Secreting Cells; Glucose; Glycated Hemoglobin; Hematopoietic Stem Cell Mobilization; Household Articles; Humans; Hypoglycemic Agents; Insulin; Insulin Secretion; Islets of Langerhans; Lung; Lymphoma; Male; Metals, Heavy; Mice; Mice, Inbred C57BL; Mice, Knockout; Middle Aged; Nanoparticles; Neoplasms; Obesity; Obstetrics; Odds Ratio; Oxygen; Peripheral Blood Stem Cell Transplantation; Photochemotherapy; Plant Extracts; Polyethylene Glycols; Polyglutamic Acid; Porosity; Postprandial Period; Prospective Studies; Quality of Life; Receptors, Glucagon; Receptors, LDL; Receptors, Somatostatin; Registries; Rhodophyta; Rhodotorula; Risk Factors; Saccharomyces cerevisiae; Saccharomyces cerevisiae Proteins; Signal Transduction; Somatostatin; Stilbenes; Terminalia; Treatment Outcome; United States; Venoms

The obese insulin-resistant state is characterized by impairments in lipid metabolism. We previously showed that 3-d supplementation of combined epigallocatechin-3-gallate and resveratrol (EGCG+RES) increased energy expenditure and improved the capacity to switch from fat toward carbohydrate oxidation with a high-fat mixed meal (HFMM) test in men.. The present study aimed to investigate the longer-term effect of EGCG+RES supplementation on metabolic profile, mitochondrial capacity, fat oxidation, lipolysis, and tissue-specific insulin sensitivity.. In this randomized double-blind study, 38 overweight and obese subjects [18 men; aged 38 ± 2 y; body mass index (kg/m(2)): 29.7 ± 0.5] received either EGCG+RES (282 and 80 mg/d, respectively) or placebo for 12 wk. Before and after the intervention, oxidative capacity and gene expression were assessed in skeletal muscle. Fasting and postprandial (HFMM) lipid metabolism was assessed by using indirect calorimetry, blood sampling, and microdialysis. Tissue-specific insulin sensitivity was assessed by a hyperinsulinemic-euglycemic clamp with [6,6-(2)H2]-glucose infusion.. EGCG+RES supplementation did not affect the fasting plasma metabolic profile. Although whole-body fat mass was not affected, visceral adipose tissue mass tended to decrease after the intervention compared with placebo (P-time × treatment = 0.09). EGCG+RES supplementation significantly increased oxidative capacity in permeabilized muscle fibers (P-time × treatment < 0.05, P-EGCG+RES < 0.05). Moreover, EGCG+RES reduced fasting (P-time × treatment = 0.03) and postprandial respiratory quotient (P-time × treatment = 0.01) compared with placebo. Fasting and postprandial fat oxidation was not significantly affected by EGCG+RES (P-EGCG+RES = 0.46 and 0.38, respectively) but declined after placebo (P-placebo = 0.05 and 0.03, respectively). Energy expenditure was not altered (P-time × treatment = 0.96). Furthermore, EGCG+RES supplementation attenuated the increase in plasma triacylglycerol concentrations during the HFMM test that was observed after placebo (P-time × treatment = 0.04, P-placebo = 0.01). Finally, EGCG+RES had no effect on insulin-stimulated glucose disposal, suppression of endogenous glucose production, or lipolysis.. Twelve weeks of EGCG+RES supplementation increased mitochondrial capacity and stimulated fat oxidation compared with placebo, but this did not translate into increased tissue-specific insulin sensitivity in overweight and obese subjects. This trial was registered at clinicaltrials.gov as NCT02381145.

Topics: Adult; Blood Glucose; Catechin; Dietary Supplements; Double-Blind Method; Energy Metabolism; Fasting; Female; Humans; Insulin; Insulin Resistance; Intra-Abdominal Fat; Lipid Metabolism; Male; Mitochondria; Muscles; Obesity; Plant Extracts; Postprandial Period; Resveratrol; Stilbenes

Risk of insulin resistance, impaired glycemic control, and cardiovascular disease is excessive in overweight and obese populations. We hypothesized that increasing expression of glyoxalase 1 (Glo1)-an enzyme that catalyzes the metabolism of reactive metabolite and glycating agent methylglyoxal-may improve metabolic and vascular health. Dietary bioactive compounds were screened for Glo1 inducer activity in a functional reporter assay, hits were confirmed in cell culture, and an optimized Glo1 inducer formulation was evaluated in a randomized, placebo-controlled crossover clinical trial in 29 overweight and obese subjects. We found trans-resveratrol (tRES) and hesperetin (HESP), at concentrations achieved clinically, synergized to increase Glo1 expression. In highly overweight subjects (BMI >27.5 kg/m(2)), tRES-HESP coformulation increased expression and activity of Glo1 (27%, P < 0.05) and decreased plasma methylglyoxal (-37%, P < 0.05) and total body methylglyoxal-protein glycation (-14%, P < 0.01). It decreased fasting and postprandial plasma glucose (-5%, P < 0.01, and -8%, P < 0.03, respectively), increased oral glucose insulin sensitivity index (42 mL ⋅ min(-1) ⋅ m(-2), P < 0.02), and improved arterial dilatation Δbrachial artery flow-mediated dilatation/Δdilation response to glyceryl nitrate (95% CI 0.13-2.11). In all subjects, it decreased vascular inflammation marker soluble intercellular adhesion molecule-1 (-10%, P < 0.01). In previous clinical evaluations, tRES and HESP individually were ineffective. tRES-HESP coformulation could be a suitable treatment for improved metabolic and vascular health in overweight and obese populations.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Blood Glucose; Cell Line; Cross-Over Studies; Female; Glutathione; Glutathione Disulfide; Hep G2 Cells; Hesperidin; Humans; Lactoylglutathione Lyase; Male; Middle Aged; Models, Biological; Obesity; Overweight; Pyruvaldehyde; Resveratrol; Stilbenes; Young Adult

To evaluate the efficacy of an orlistat-resveratrol (O-R) combination in subjects with obesity over a 6-month period.. This study was a double-blind, parallel, randomized controlled clinical trial. Patients fulfilling the selection criteria (age from 20 to 60 years and body mass index (BMI) ≥30 and ≤39.9 kg/m(2) ) consumed an energy-reduced diet with 500 fewer calories than their usual diet for 2 weeks. Then the participants were randomly assigned to four groups, placebo, resveratrol, orlistat, or O-R, and they consumed the energy-reduced diet for 6 months. The study consisted of seven visits. During each visit, a 24-h recall was performed, along with measurements of anthropometric and serum biochemical parameters.. A total of 161 participants were selected. Of these, 84 participants completed the study. A significant weight loss of -6.82 kg (95% CI -8.37 to -5.26) was observed in the O-R group compared with -3.50 kg (-5.05 to -1.95, P = 0.021) in the placebo group. In contrast, the -6.02 kg (-7.68 to -4.36) orlistat and -4.68 kg (-6.64 to -2.71) resveratrol monotherapy losses did not significantly differ from the placebo. Significant decreases in BMI, waist circumference, fat mass, triglycerides, leptin, and leptin/adiponectin ratio were observed with the O-R combination.. The O-R combination was the most effective weight loss treatment.

Topics: Adult; Aged; Anthropometry; Anti-Obesity Agents; Body Mass Index; Caloric Restriction; Diet; Double-Blind Method; Drug Therapy, Combination; Energy Intake; Female; Humans; Lactones; Leptin; Male; Mexico; Middle Aged; Obesity; Orlistat; Placebos; Resveratrol; Stilbenes; Treatment Outcome; Triglycerides; Weight Loss

In vitro and animal studies have shown positive effects of resveratrol on lipid and lipoprotein metabolism, but human studies specifically designed to examine these effects are lacking.. The primary outcome parameter of this study in overweight and slightly obese subjects was the effect of resveratrol on apoA-I concentrations. Secondary outcome parameters were effects on other markers of lipid and lipoprotein metabolism, glucose metabolism, and markers for inflammation and endothelial function.. This randomized, placebo-controlled crossover study was conducted in 45 overweight and slightly obese men (n = 25) and women (n = 20) with a mean age of 61 ± 7 years. Subjects received in random order resveratrol (150 mg per day) or placebo capsules for 4 weeks, separated by a 4-week wash-out period. Fasting blood samples were collected at baseline and at the end of each intervention period.. Compliance was excellent as indicated by capsule count and changes in resveratrol and dihydroresveratrol concentrations. No difference between resveratrol and placebo was found in any of the fasting serum or plasma metabolic risk markers (mean ± SD for differences between day 28 values of resveratrol vs. placebo: apoA-I; 0.00 ± 0.12 g/L (P = 0.791), apoB100; -0.01 ± 0.11 g/L (P = 0.545), HDL cholesterol; 0.00 ± 0.09 mmol/L (P = 0.721), LDL cholesterol -0.03 ± 0.57 mmol/L (P = 0.718), triacylglycerol; 0.10 ± 0.54 mmol/L (P = 0.687), glucose; -0.08 ± 0.28 mmol/L (P = 0.064), insulin; -0.3 ± 2.5 mU/L (P = 0.516)). Also, no effects on plasma markers for inflammation and endothelial function were observed. No adverse events related to resveratrol intake were observed.. 150 mg of daily resveratrol intake for 4 weeks does not change metabolic risk markers related to cardiovascular health in overweight and slightly obese men and women. Effects on glucose metabolism warrant further study.. ClinicalTrials.gov NCT01364961.

Topics: Aged; Apolipoprotein A-I; Biomarkers; Cardiovascular Diseases; Cross-Over Studies; Female; Humans; Lipid Metabolism; Lipoproteins; Male; Middle Aged; Obesity; Overweight; Resveratrol; Stilbenes

Polyphenolic compounds, such as resveratrol, have recently received widespread interest because of their ability to mimic effects of calorie restriction. The objective of the present study was to gain more insight into the effects of 30 days resveratrol supplementation on adipose tissue morphology and underlying processes. Eleven healthy obese men were supplemented with placebo and resveratrol for 30 days (150 mg per day), separated by a 4-week washout period in a double-blind randomized crossover design. A postprandial abdominal subcutaneous adipose tissue biopsy was collected to assess adipose tissue morphology and gene expression using microarray analysis. Resveratrol significantly decreased adipocyte size, with a shift toward a reduction in the proportion of large and very-large adipocytes and an increase in small adipocytes. Microarray analysis revealed downregulation of Wnt and Notch signaling pathways and upregulation of pathways involved in cell cycle regulation after resveratrol supplementation, suggesting enhanced adipogenesis. Furthermore, lysosomal/phagosomal pathway and transcription factor EB were upregulated reflecting an alternative pathway of lipid breakdown by autophagy. Further research is necessary to investigate whether resveratrol improves adipose tissue function.

Topics: Adipocytes; Adipogenesis; Adipose Tissue; Adult; Aged; Cross-Over Studies; Double-Blind Method; Enzyme Inhibitors; Gene Expression Profiling; Humans; Male; Middle Aged; Obesity; Receptors, Notch; Resveratrol; Signal Transduction; Stilbenes; Treatment Outcome; Wnt Signaling Pathway

Metabolic syndrome (MetS) is associated with low-grade inflammation, which may harmfully affect bone. Resveratrol (RSV) possesses anti-inflammatory properties, and rodent studies suggest bone protective effects.. This study sought to evaluate effects of RSV treatment on bone in men with MetS.. The study was conducted at Aarhus University Hospital as a randomized, double-blinded, placebo-controlled trial assessing changes in bone turnover markers, bone mineral density (BMD), and geometry.. The study population comprised 74 middle-aged obese men with MetS recruited from the general community, of which 66 completed all visits. Mean age of participants was 49.3 ± 6.3 years and mean body mass index was 33.7 ± 3.6 kg/m(2).. Oral treatment with 1.000 mg RSV (RSV(high)), 150 mg RSV (RSV(low)), or placebo daily for 16 weeks.. Prespecified primary endpoint was change in bone alkaline phosphatase (BAP).. BAP increased dose dependently with RSV (R = 0.471, P < .001), resulting in a significantly greater increase in BAP in the RSV(high) group compared with placebo at all time-points (week 4, 16.4 ± 4.2%, P < .001; week 8, 16.5 ± 4.1%, P < .001; week 16, 15.2 ± 3.7%, P < .001). Lumbar spine trabecular volumetric bone mineral density (LS vBMD(trab)) also increased dose dependently with RSV (R = 0.268, P = .036), with a significant increase of 2.6 ± 1.3% in the RSV(high) group compared with placebo (P = .043). In addition, changes in BAP and LS vBMD(trab) were positively correlated (R = 0.281, P = .027). No consistent changes were detected in bone density at the hip.. Our data suggest that high-dose RSV supplementation positively affects bone, primarily by stimulating formation or mineralization. Future studies of longer duration comprising populations at risk of osteoporosis are needed to confirm these results.

Topics: Absorptiometry, Photon; Alkaline Phosphatase; Antioxidants; Bone and Bones; Bone Density; Double-Blind Method; Humans; Male; Metabolic Syndrome; Middle Aged; Obesity; Patient Compliance; Resveratrol; Stilbenes

Resveratrol, a natural polyphenolic compound produced by various plants (e.g. red grapes) and found in red wine, has glucose-lowering effects in humans and rodent models of obesity and/or diabetes. The mechanisms behind these effects have been suggested to include resveratrol-induced secretion of the gut incretin hormone glucagon-like peptide-1. We investigated postprandial incretin hormone and glucagon responses in obese human subjects before and after 30 days of resveratrol supplementation.. Postprandial plasma responses of the incretin hormones glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide and glucagon were evaluated in 10 obese men [subjects characteristics (mean ± standard error of the mean): age 52 ± 2 years; BMI 32 ± 1 kg/m(2), fasting plasma glucose 5.5 ± 0.1 mmol/l] who had been given a dietary supplement of resveratrol (Resvida(®) 150 mg/day) or placebo for 30 days in a randomized, double-blind, crossover design with a 4-week washout period. At the end of each intervention period a standardized meal test (without co-administration of resveratrol) was performed.. Resveratrol supplementation had no impact on fasting plasma concentrations or postprandial plasma responses (area under curve values) of glucose-dependent insulinotropic polypeptide (11.2 ± 2.1 vs. 11.8 ± 2.2 pmol/l, P = 0.87; 17.0 ± 2.2 vs. 14.8 ± 1.6 min × nmol/l, P = 0.20) or glucagon-like peptide-1 (15.4 ± 1.0 vs. 15.2 ± 0.9 pmol/l, P = 0.84; 5.6 ± 0.4 vs. 5.7 ± 0.3 min × nmol/l, P = 0.73). Resveratrol supplementation significantly suppressed postprandial glucagon responses (4.4 ± 0.4 vs. 3.9 ± 0.4 min × nmol/l, P = 0.01) without affecting fasting glucagon levels (15.2 ± 2.2 vs. 14.5 ± 1.5 pmol/l, P = 0.56).. Our data suggest that 30 days of resveratrol supplementation does not affect fasting or postprandial incretin hormone plasma levels in obese humans, but suppresses postprandial glucagon responses.

Topics: Antioxidants; Blood Glucose; Cross-Over Studies; Dietary Supplements; Double-Blind Method; Fasting; Gastric Inhibitory Polypeptide; Glucagon; Glucagon-Like Peptide 1; Humans; Incretins; Male; Middle Aged; Obesity; Postprandial Period; Resveratrol; Stilbenes; Time Factors; Treatment Outcome

We have previously demonstrated acute dose-dependent increases of flow-mediated dilatation (FMD) in the brachial artery after resveratrol consumption in mildly hypertensive, overweight/obese adults. Resveratrol supplementation has also been shown to increase cerebral blood flow acutely, without affecting cognition.. To evaluate the effects of chronic resveratrol supplementation on both FMD and cognitive performance.. Twenty-eight obese but otherwise healthy adults (BMI: 33.3 ± 0.6 kg/m) were randomized to take a single 75 mg capsule of trans-resveratrol (Resvida) or placebo daily for 6 weeks each in a double-blind crossover supplementation trial. Blood pressure, arterial compliance, FMD, and performance on the Stroop Color-Word Test were assessed at the end of each 6-week intervention period while fasted and at least 18 h after taking the last daily capsule. An additional capsule of the same supplement was then taken. FMD assessment was repeated 1 h later.. Chronic resveratrol supplementation for 6 weeks was well tolerated and resulted in a 23% increase in FMD compared with placebo (P=0.021, paired t-test). The extent of increase correlated negatively with baseline FMD (r=-0.47, P=0.01). A single dose of resveratrol (75 mg) following chronic resveratrol supplementation resulted in a 35% greater acute FMD response than the equivalent placebo supplementation. These FMD improvements remained significant after adjusting for baseline FMD. Blood pressure, arterial compliance, and all components of the Stroop Color-Word Test were unaffected by chronic resveratrol supplementation.. Daily resveratrol consumption was well tolerated and has the potential to maintain healthy circulatory function in obese adults.

Topics: Adult; Aged; Blood Flow Velocity; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Body Mass Index; Brachial Artery; Carotid Arteries; Cross-Over Studies; Dietary Supplements; Double-Blind Method; Endothelium, Vascular; Female; Humans; Male; Middle Aged; Obesity; Overweight; Postmenopause; Resveratrol; Stilbenes; Stroop Test; Surveys and Questionnaires; Vasodilation

Overproduction of hepatic apolipoprotein B (apoB)-100 containing very low-density lipoprotein particles and intestinal apoB-48 containing chylomicrons contributes to hypertriglyceridemia seen in conditions such as obesity and insulin resistance. Some, but not all, preclinical and clinical studies have demonstrated that the polyphenol resveratrol ameliorates insulin resistance and hypertriglyceridemia. Here, we assessed intestinal and hepatic lipoprotein turnover, in humans, after 2 weeks of treatment with resveratrol (1000 mg daily for week 1 followed by 2000 mg daily for week 2) or placebo.. Eight overweight or obese individuals with mild hypertriglyceridemia were studied on 2 occasions, 4 to 6 weeks apart, after treatment with resveratrol or placebo in a randomized, double-blinded, crossover study. Steady-state lipoprotein kinetics was assessed in a constant fed state with a primed, constant infusion of deuterated leucine. Resveratrol treatment did not significantly affect insulin sensitivity (homeostasis model of assessment of insulin resistance), fasting or fed plasma triglyceride concentration. Resveratrol reduced apoB-48 production rate by 22% (P=0.007) with no significant effect on fractional catabolic rate. Resveratrol reduced apoB-100 production rate by 27% (P=0.02) and fractional catabolic rate by 26% (P=0.04).. These results indicate that 2 weeks of high-dose resveratrol reduces intestinal and hepatic lipoprotein particle production. Long-term studies are needed to evaluate the potential clinical benefits of resveratrol in patients with hypertriglyceridemia, who have increased concentrations of triglyceride-rich lipoprotein apoB-100 and apoB-48.. www.clinicaltrials.gov. Unique identifier: NCT01451918.

Topics: Adult; Analysis of Variance; Apolipoprotein B-100; Apolipoprotein B-48; Biomarkers; Cross-Over Studies; Double-Blind Method; Drug Administration Schedule; Humans; Hypertriglyceridemia; Hypolipidemic Agents; Insulin Resistance; Intestinal Mucosa; Intestines; Lipoproteins; Liver; Male; Middle Aged; Obesity; Ontario; Overweight; Resveratrol; Stilbenes; Time Factors; Treatment Outcome; Triglycerides

Obesity, diabetes, hypertension, and hyperlipidemia constitute risk factors for morbidity and premature mortality. Based on animal and in vitro studies, resveratrol reverts these risk factors via stimulation of silent mating type information regulation 2 homolog 1 (SIRT1), but data in human subjects are scarce. The objective of this study was to examine the metabolic effects of high-dose resveratrol in obese human subjects. In a randomized, placebo-controlled, double-blinded, and parallel-group design, 24 obese but otherwise healthy men were randomly assigned to 4 weeks of resveratrol or placebo treatment. Extensive metabolic examinations including assessment of glucose turnover and insulin sensitivity (hyperinsulinemic euglycemic clamp) were performed before and after the treatment. Insulin sensitivity, the primary outcome measure, deteriorated insignificantly in both groups. Endogenous glucose production and the turnover and oxidation rates of glucose remained unchanged. Resveratrol supplementation also had no effect on blood pressure; resting energy expenditure; oxidation rates of lipid; ectopic or visceral fat content; or inflammatory and metabolic biomarkers. The lack of effect disagrees with persuasive data obtained from rodent models and raises doubt about the justification of resveratrol as a human nutritional supplement in metabolic disorders.

Topics: Adolescent; Adult; Aged; Antioxidants; Body Composition; Dietary Supplements; Dose-Response Relationship, Drug; Double-Blind Method; Energy Metabolism; Gene Expression Regulation; Humans; Insulin Resistance; Male; Middle Aged; Obesity; Pilot Projects; Resveratrol; Stilbenes; Young Adult

The preventive effect of resveratrol (RES) on the development of human diseases has been verified by numerous epidemiological studies. Resveratrol triphosphate (RTP) is a stable derivative of RES in which phosphate groups protect the phenolic groups.. This study compared the effect of RTP on biochemical and molecular markers of oxidative stress to equimolar doses (0.66 mmol) of RES and catechin-rich grape seed extract (CGSE) in a model of oxidative and metabolic stress associated with obesity in humans.. Thirty-two obese subjects (BMI between 30 and 40) were enrolled. They all received 1 capsule of placebo/day for 28 days before being randomly devised into three arms receiving 1 capsule/day of RES, CGSE, or RTP during the following consecutive 28 days. Blood samples were collected at baseline, after the end of placebo intake, and after the end of the investigational product intake. Biochemical parameters of oxidative stress and blood expression of 200 redox-related genes were determined at each time point.. RTP and CGSE showed better antioxidant activities compared to RES and induced important modulations of gene expression.. The results suggest that RTP and CGSE could contribute to a significant reduction of oxidative stress in obese subjects.

Topics: Adult; Antioxidants; Biomarkers; Catechin; Dietary Supplements; Female; Gene Expression; Grape Seed Extract; Humans; Male; Microarray Analysis; Middle Aged; Obesity; Organophosphates; Oxidative Stress; Resveratrol; Stilbenes

Flow-mediated dilatation of the brachial artery (FMD) is a biomarker of endothelial function and cardiovascular health. Impaired FMD is associated with several cardiovascular risk factors including hypertension and obesity. Various food ingredients such as polyphenols have been shown to improve FMD. We investigated whether consuming resveratrol, a polyphenol found in red wine, can enhance FMD acutely and whether there is a dose-response relationship for this effect.. 19 overweight/obese (BMI 25-35 kg m(-2)) men or post-menopausal women with untreated borderline hypertension (systolic BP: 130-160 mmHg or diastolic BP: 85-100 mmHg) consumed three doses of resveratrol (resVida™ 30, 90 and 270 mg) and a placebo at weekly intervals in a double-blind, randomized crossover comparison. One hour after consumption of the supplement, plasma resveratrol and FMD were measured. Data were analyzed by linear regression versus log(10) dose of resveratrol. 14 men and 5 women (age 55 ± 2 years, BMI 28.7 ± 0.5 kg m(-2), BP 141 ± 2/89 ± 1 mmHg) completed this study. There was a significant dose effect of resveratrol on plasma resveratrol concentration (P < 0.001) and on FMD (P < 0.01), which increased from 4.1 ± 0.8% (placebo) to 7.7 ± 1.5% after 270 mg resveratrol. FMD was also linearly related to log(10) plasma resveratrol concentration (P < 0.01).. Acute resveratrol consumption increased plasma resveratrol concentrations and FMD in a dose-related manner. This effect may contribute to the purported cardiovascular health benefits of grapes and red wine.

Topics: Brachial Artery; Cardiovascular Diseases; Cross-Over Studies; Dietary Supplements; Dose-Response Relationship, Drug; Double-Blind Method; Endothelium, Vascular; Female; Humans; Hypertension; Male; Middle Aged; Obesity; Overweight; Placebos; Resveratrol; Risk Factors; Stilbenes; Vasodilation

Resveratrol is a natural compound that affects energy metabolism and mitochondrial function and serves as a calorie restriction mimetic, at least in animal models of obesity. Here, we treated 11 healthy, obese men with placebo and 150 mg/day resveratrol (resVida) in a randomized double-blind crossover study for 30 days. Resveratrol significantly reduced sleeping and resting metabolic rate. In muscle, resveratrol activated AMPK, increased SIRT1 and PGC-1α protein levels, increased citrate synthase activity without change in mitochondrial content, and improved muscle mitochondrial respiration on a fatty acid-derived substrate. Furthermore, resveratrol elevated intramyocellular lipid levels and decreased intrahepatic lipid content, circulating glucose, triglycerides, alanine-aminotransferase, and inflammation markers. Systolic blood pressure dropped and HOMA index improved after resveratrol. In the postprandial state, adipose tissue lipolysis and plasma fatty acid and glycerol decreased. In conclusion, we demonstrate that 30 days of resveratrol supplementation induces metabolic changes in obese humans, mimicking the effects of calorie restriction.

Topics: Adipose Tissue; Alanine Transaminase; AMP-Activated Protein Kinase Kinases; Blood Glucose; Blood Pressure; Caloric Restriction; Citrate (si)-Synthase; Cross-Over Studies; Double-Blind Method; Energy Metabolism; Fatty Acids; Glycerol; Heat-Shock Proteins; Humans; Liver; Male; Middle Aged; Mitochondria, Muscle; Muscle, Skeletal; Netherlands; Obesity; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Protein Kinases; Resveratrol; Sirtuin 1; Stilbenes; Switzerland; Transcription Factors; Triglycerides

Peroxisome proliferator-activated receptors are promising therapeutic targets for metabolic diseases, including obesity, diabetes, and dyslipidemia. This study describes the design, synthesis and pharmacological evaluation of stilbene-based compounds as dual PPARα/γ partial agonists with potency in the nanomolar range. In vitro and in vivo assays revealed that the lead compound (E)-4-styrylphenoxy-propanamide (5b) removed

Topics: Adipogenesis; Animals; Cholesterol; Diabetes Mellitus; Diet, High-Fat; Dyslipidemias; Glucose; Lipoproteins, HDL; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; PPAR alpha; Stilbenes

The previous evidence shows that there is an association between total dietary polyphenols intake (DPI) and its subclasses and lower risk of metabolic Syndrome (MetS). This cross-sectional study aims to evaluate associations between DPI and cardiometabolic factors in Iranian women.. A total of 404 Iranian women were included in this study. Dietary intakes and polyphenols intakes were measured using a validated semi-quantitative food frequency questionnaire (FFQ) and the Phenol-Explorer database, respectively. Biochemical variables and blood pressure were evaluated using Pars Azmoon kits and mercury sphygmomanometer.. The mean intake of total polyphenol was 2533.96 ± 1223.67 g. While there were significant negative associations between stilbenes and lignans intake and body mass index (BMI) (P-value = 0.04; P-value = 0.02, respectively), beverages containing phenolic acids and hip circumference (HC) (P-value = 0.02), total polyphenols intake and weight to hip ratio (WHR) (P-value = 0.04). Also there was significant negative associations between stilbenes intake and cholesterol (CHOL) level (P-value = 0.03), other polyphenols intake and triglyceride (TG) ((P-value = 0.01), lignan intake and homeostasis model assessment insulin resistance (HOMA-IR) (P-value = 0.03).. These findings demonstrated that dietary polyphenols were associated with cardiometabolic factors in Iranian women. Prospective and interventional studies in both genders, different populations and ethnicities need to be conducted to further the knowledge about examine associations between consumption of polyphenols and metabolic component.

Topics: Cardiovascular Diseases; Cross-Sectional Studies; Diet; Eating; Female; Humans; Iran; Male; Obesity; Overweight; Polyphenols; Prospective Studies; Stilbenes

Diabetes incidence is rising globally at an accelerating rate causing issues at both the individual and societal levels. However, partly inspired by Ayurvedic medicine, a naturally occurring compound called pterostilbene has been demonstrated to protect against diabetes symptoms, though mainly in rats. The purpose of this study was to investigate the putative protective effect of pterostilbene on the two main aspects of diabetes, namely insulin resistance and decreased insulin secretion, in mice. To accomplish this, we employed diet-induced obese as well as streptozotocin-induced diabetic C57BL/6NTac mice for fasting glucose homeostasis assessment, tolerance tests and pancreas perfusions. In addition, we used the polygenic model of diabetes TALLYHO/JngJ to assess for prevention of β-cell burnout. We found that the diet-induced obese C57BL/6NTac mice were insulin resistant, but that pterostilbene had no impact on this or on overall glucose regulation. We further found that the reported protective effect of pterostilbene against streptozotocin-induced diabetes was absent in C57BL/6NTac mice, despite a promising pilot experiment. Lastly, we observed that pterostilbene does not prevent or delay onset of β-cell burnout in TALLYHO/JngJ mice. In conjunction with the literature, our findings suggest variations in the response to pterostilbene between species or between strains of species.

Topics: Animals; Blood Glucose; Diabetes Mellitus, Experimental; Disease Models, Animal; Glucose; Insulin; Insulin Secretion; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Rats; Stilbenes; Streptozocin

Dissipating energy by activating thermogenic adipose to combating obesity attracts many interests. Ski-interacting protein (Skip) has been known to play an important role in cell proliferation and differentiation, but whether it participates in energy metabolism is not known. Our previous study revealed that BTM-0512 could induce beige adipose formation, accompanying with up-regulation of Skip, but the role of Skip in metabolism was unknown. In this study, we mainly investigated whether Skip was involved in beige remodeling of subcutaneous white preadipocytes as well as in lipid metabolism of differentiated beige adipocytes. The results showed that in high fat diet-induced obesity mice, the protein levels of Skip in subcutaneous and visceral white adipose as well as in brown adipose were all down-regulated, especially in subcutaneous white adipose. Then we cultured subcutaneous adipose derived-stem cells (ADSCs) and found knock-down of Skip (siSkip) inhibited the expressions of thermogenic adipose specific genes including PRDM16 and UCP1 in both undifferentiated ADSCs and differentiated beige adipocytes, which could abolish the effects of BTM-0512 on beige remodeling. We further observed that siSkip affected multiple rate-limiting enzymes in lipid metabolism. The expressions of ACC, GPAT-1, HSL and ATGL were down-regulated, while CPT1α expression was up-regulated by siSkip. The expression of AMPK was also decreased by siSkip. In conclusion, our study demonstrated that Skip might play an important role in the beige remodeling of white adipocytes as well as lipid metabolism of beige adipose.

Topics: Adipose Tissue, Beige; Animals; Cell Differentiation; Diet; Down-Regulation; Lipid Metabolism; Male; Mice, Inbred C57BL; Obesity; Phosphoric Monoester Hydrolases; Sirtuin 1; Stem Cells; Stilbenes; Thermogenesis; Uncoupling Protein 1

Epidemiological surveys show that obesity and the western diet increase the risk of colitis. Studies have also confirmed that the high-fat-diet (HFD) promoted the deterioration of colitis-related indicators in mice. Compared with stilbenoids, the results showed that 3'-hydroxypterostilbene (HPSB) was found to be the most effective inhibitor for the antiadipogenesis and anti-inflammation. However, its role in ameliorating obesity-promoted colitis is still unknown. We intend to investigate the protective effect and related molecular mechanisms of HPSB on HFD promoted dextran sodium sulfate (DSS)-induced colitis in mice. The results indicate that colitis in the HFD+DSS group tends to be more apparent in the DSS-only group, while feeding 0.025% of HPSB at different stages can improve the colitis induced by HFD+DSS. HPSB significantly reduced the levels of interleukin-6 (IL-6) and monocyte chemoattractant protein-1 (MCP-1) induced by HFD+DSS in mice. Furthermore, the Western blotting revealed that the administration of HPSB significantly downregulated cyclooxygenase-2 (COX-2), plasmalemma vesicle-associated protein-1 (PV-1), and phospho-signal transducer and activator of transcription 3 (p-STAT3) expressions in HFD+DSS treated mice. Presented results reveal that HPSB is a novel functional agent capable of preventing HFD exacerbated colitis.

Topics: Animals; Anti-Inflammatory Agents; Chemokine CCL2; Colitis; Dextran Sulfate; Diet, High-Fat; Disease Models, Animal; Humans; Interleukin-6; Male; Mice; Mice, Inbred C57BL; Obesity; STAT3 Transcription Factor; Stilbenes

Polyphenol consumption is implicated in gut microbiome composition and improved metabolic outcomes, but it is unclear whether the effect is independent of dietary fiber.. We investigated the links between (poly)phenol intake, gut microbiome composition (16s RNA) and obesity independently of fiber intake in UK women (. (Poly)phenol intakes correlated with microbiome alpha diversity (Shannon Index) after adjusting for confounders and fiber intake. Moreover, flavonoid intake was significantly correlated with the abundance of. Our findings highlight the importance of (poly)phenol consumption for optimal human health.

Topics: Adolescent; Adult; Aged; Bacteria; Cohort Studies; Diet; Dietary Fiber; Female; Flavonoids; Gastrointestinal Microbiome; Humans; Male; Middle Aged; Obesity; Stilbenes; United Kingdom; Young Adult

Visceral obesity and fatty liver are prevalent in postmenopausal women. The stilbene-rich extract of Cajanus cajan (L.) Millsp. has been reported to prevent ovariectomy-induced and diet-induced weight gain in animal models, and stilbenoids from C. cajan are thought to have the potential to prevent postmenopausal obesity and fatty liver.. Cajanolactone A (CLA) is the main stilbenoid from C. cajan with osteoblastogenic promoting activity. This study investigated the potential of CLA to prevent postmenopausal obesity and fatty liver. Underlying mechanisms were also investigated.. Ovariectomized C57BL/6 mice fed a regular diet were used as mimics of postmenopausal women and given 10, 20, or 40 mg/kg/d of CLA, 0.1 mg/kg/d of estradiol valerate (EV, positive control), or vehicle (OVX) orally for 16 weeks. Mice of the same age subjected to a sham operation were used as control (Sham). Body weights were recorded every 2 weeks for 16 weeks. Body compositions were analyzed via micro-CT. Serum levels of lipids, adipocytokines and aminotransferases were measured using the relevant kits. mRNA levels of genes of interest were detected by RT-qPCR. Proteomic study of perigonadal white adipose tissue (pWAT) was performed using tandem-mass-tags-based proteomic technology combined with Parallel-Reaction-Monitoring (PRM) validation.. CLA showed potential equivalent to that of EV to prevent ovariectomy-induced overweight, obesity, dyslipidemia, liver steatosis and liver dysfunction, but did not prevent uterine atrophy. In the liver, CLA significantly inhibited ovariectomy-induced upregulation in expression of lipogenic genes SREBP-1c and ChREBP, and stimulated the mRNA expression of apolipoprotein B gene ApoB. In pWAT, CLA reversed, or partially reversed ovariectomy-induced downregulation in the expression of a number of metabolism- and mitochondrial-function-related proteins, including Ndufa3, Pcx, Pdhb, Acly, Acaca, Aldh2, Aacs and Echs1. In addition, ovariectomy-inhibited mRNA expression of Pdhb, Aacs, Acsm5, Echs1, and Aldh2 genes in pWAT was also reversed.. CLA was demonstrated to be a potential non-estrogen-like drug candidate for prevention of postmenopausal obesity and fatty liver. The underlying mechanism might involve the inhibition of lipogenesis and promotion of triglycerides output in the liver, and the promotion of metabolism and mitochondrial functions of visceral white adipose tissue.

Topics: Adipose Tissue, White; Animals; Anti-Obesity Agents; Apolipoprotein B-100; Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; Body Weight; Cajanus; Diet; Female; Gene Expression Regulation; Lipogenesis; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease; Obesity; Ovariectomy; Postmenopause; Stilbenes; Triglycerides

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 µM) was first tested on 3T3-L1 mature adipocytes, and then it was administered (352 µmol/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-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 (

Topics: 3T3-L1 Cells; Adipocytes, Brown; Adipose Tissue, Brown; Adipose Tissue, White; Animals; Apoptosis Regulatory Proteins; Basic Helix-Loop-Helix Transcription Factors; Body Weight; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; Female; Gene Expression Regulation; Male; Mice; Mice, Inbred C57BL; Obesity; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; PPAR gamma; Sirtuin 1; Stilbenes; T-Box Domain Proteins; Thermogenesis; Uncoupling Protein 1

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.

Topics: Adipose Tissue; Adiposity; Animals; Diet, Carbohydrate Loading; Diet, High-Fat; Immediate-Early Proteins; Male; Obesity; Rats; Rats, Wistar; Resveratrol; Stilbenes; Sucrose

We compared the effects of resveratrol and rosiglitazone, alone and in combination, on indices of fatty acid re-esterification in cultured adipose tissue from obese participants (n = 17) undergoing gastric bypass. Rosiglitazone induced PDK4 and PEPCK gene expression to a greater extent than resveratrol. Co-treatment with both compounds induced PDK4 and PEPCK expression in parallel with reductions in the fatty acid to glycerol ratio. Our findings suggest beneficial effects of resveratrol and rosiglitazone co-treatment.

Topics: Adipose Tissue; Adult; Female; Gene Expression Regulation; Humans; Male; Middle Aged; Obesity; Pregnancy; Resveratrol; Rosiglitazone; Stilbenes; Thiazolidinediones; Tissue Culture Techniques

Exercise and resveratrol supplementation exhibit anti-obesity functions in the long term but have not been fully investigated yet in terms of their early potential effectiveness. Mice fed with high-fat diet were categorized into control (Cont), exercise (Ex), resveratrol supplementation (Res), and exercise combined with resveratrol supplementation (Ex ＋ Res) groups. In the four-week period of weight loss, exercise combined with resveratrol supplementation exerted no additional effects on body weight loss but significantly improved whole-body glucose and lipid homeostasis. The combined treatment significantly decreased intrahepatic lipid content but did not affect intramyocellular lipid content. Moreover, the treatment significantly increased the contents of mtDNA and cytochrome c, the expression levels of peroxisome proliferator-activated receptor gamma coactivator-1 alpha and its downstream transcription factors, and the activities of ATPase and citrate synthase. However, exercise, resveratrol, and their combination did not promote myofiber specification toward slow-twitch type. The effects of exercise combined with resveratrol supplementation on weight loss could be partly due to enhanced mitochondrial biogenesis and not to fiber-type shift in skeletal muscle tissues. [BMB Reports 2018; 51(4): 200-205].

Topics: Animals; Diet, High-Fat; Glucose; Homeostasis; Lipids; Male; Mice; Mice, Inbred ICR; Mice, Obese; Muscle, Skeletal; Obesity; Physical Conditioning, Animal; Resveratrol; Stilbenes; Transcription Factors; Weight Loss

Reproductive dysfunction associated with obesity is increasing among women of reproductive age, including infertility and increasing risk of miscarriage. In females, reproductive disorders are linked to declining quality of oocytes. Using a model of diet-induced obesity, we have investigated the possible effects of obesity on oocyte quality, including metabolism, lipid accumulation, ROS levels, meiosis and changes in spindle structure in Metaphase II. Our study showed that obesity induced by a high fat diet can impair oocyte meiosis, destroy spindle assembly, and promote oxidative stress and abnormal mitochondrial distribution. With the addition of resveratrol, the negative impact of diet-induced obesity on the quality of oocytes was alleviated to some extent. In addition, we found that obesity causes mouse oocytes to soften, and resveratrol can restore the zona pellucida of oocytes to the same state as the control group. In conclusion, resveratrol can reverse the adverse effects of obesity on oocytes, which is beneficial for subsequent embryonic development.

Topics: Animals; Diet, High-Fat; Disease Models, Animal; Female; Humans; Meiosis; Mice; Mice, Inbred C57BL; Obesity; Oocytes; Oxidative Stress; Resveratrol; Stilbenes; Zona Pellucida

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.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Aquaglyceroporins; Diet, High-Fat; Gene Expression Regulation; Male; Obesity; Rats, Wistar; Resveratrol; Stilbenes; Triglycerides

The phytochemical oxyresveratrol has been shown to exert diverse biological activities including prevention of obesity. However, the exact reason underlying the anti-obese effects of oxyresveratrol is not fully understood. Here, we investigated the effects and mechanism of oxyresveratrol in adipocytes and high-fat diet (HFD)-fed obese mice. Oxyresveratrol suppressed lipid accumulation and expression of adipocyte markers during the adipocyte differentiation of 3T3-L1 and C3H10T1/2 cells. Administration of oxyresveratrol in HFD-fed obese mice prevented body-weight gains, lowered adipose tissue weights, improved lipid profiles, and increased glucose tolerance. The anti-obese effects were linked to increases in energy expenditure and higher rectal temperatures without affecting food intake, fecal lipid content, and physical activity. The increased energy expenditure by oxyresveratrol was concordant with the induction of thermogenic genes including Ucp1, and the reduction of white adipocyte selective genes in adipose tissue. Furthermore, Foxo3a was identified as an oxyresveratrol-induced gene and it mimicked the effects of oxyresveratrol for induction of thermogenic genes and suppression of white adipocyte selective genes, suggesting the role of Foxo3a in oxyresveratrol-mediated anti-obese effects. Taken together, these data show that oxyresveratrol increases energy expenditure through the induction of thermogenic genes in adipose tissue and further implicates oxyresveratrol as an ingredient and Foxo3a as a molecular target for the development of functional foods in obesity and metabolic diseases.

Topics: 3T3-L1 Cells; Adipocytes; Adipose Tissue; Animals; Cell Differentiation; Cell Line; Cell Survival; Diet, High-Fat; Energy Metabolism; Forkhead Box Protein O3; Gene Expression Regulation; Lipid Metabolism; Male; Metabolomics; Mice; Obesity; Plant Extracts; Stilbenes; Thermogenesis; Uncoupling Protein 1

Pterostilbene (trans-3,5-dimethoxy-4-hydroxystilbene) is a dimethylated analog of resveratrol and has been reported to exert various pharmacological effects. In this study, we evaluated the effect of pterostilbene on the pathogenesis of obesity and energy metabolism in obese rats. Pterostilbene significantly activates silent mating type information regulation 2 homolog-1 and peroxisome proliferator-activated receptor-alpha in vitro. At 4 weeks a 0.5% pterostilbene diet markedly suppressed the abdominal white adipose tissue (WAT) accumulation in obese rats. The oxygen consumption and energy expenditure were significantly higher in the pterostilbene group, and pterostilbene increased the fat metabolism rather than the carbohydrate metabolism in obese rats. The mRNA level of uncoupling protein, a thermogenic regulator, was increased and the mRNA levels of fatty acid synthase and leptin, which are involved in lipogenesis and fat storage, were markedly decreased in WAT after the pterostilbene feeding. These results suggest that pterostilbene prevents WAT accumulation through the enhancement of energy metabolism and partly the suppression of lipogenesis in obese OLETF rats.

Topics: Adipose Tissue; Animals; Dietary Supplements; Disease Models, Animal; Energy Metabolism; Gene Expression Regulation; Lipid Metabolism; Male; Obesity; PPAR alpha; Rats; Sirtuin 1; Stilbenes

Recent studies revealed that sirtuin 1 (SIRT1) is involved in the regulation of energy metabolism and its agonist resveratrol showed anti-obesity effect. This study aims to determine whether BTM-0512, a novel derivative of resveratrol, acts as an antagonist of obesity and to explore its possible mechanisms. High-fat diet (HFD)-induced obese mice were intragastrically administered with BTM-0512 (5, 10, and 20 mg/kg/day) or resveratrol (10 mg/kg/day). It was found that the body weight, Lee's index, ratio of visceral adipose tissue (VAT) to body weight, and blood glucose were significantly reduced in BTM-0512-treated mice when compared with those in mice treated with resveratrol. BTM-0512 up-regulated the expressions of SIRT1, full length PRDM16 (fPRDM16), total PRDM16 (tPRDM16, including fPPRDM16 and other PRDM16 isoforms), and uncoupling protein 1 (UCP1) in both brown and subcutaneous adipose tissues. Although BTM-0512 and resveratrol also up-regulated SIRT1 and tPRDM16 levels in VAT of HFD-induced obese mice, the expressions of fPRDM16, UCP1, and TMEM26 were down-regulated. In mouse primary subcutaneous preadipocytes cultured with or without adipogenic medium, BTM-0512 up-regulated fPRDM16, tPRDM16, and UCP1 expressions, which was reversed by SIRT1 antagonists. But in cultured brown and visceral adipocytes, the UCP1 protein level showed no significant change after treatment with 1 μM of BTM-0512. Moreover, transfection with human SIRT1 plasmid reduced lipid deposit, as well as the mRNA levels of fPRDM16, UCP1, and TMEM26, in cultured human visceral adipose-derived stem cells. In conclusion, BTM-0512 has stronger anti-obesity effect than resveratrol, which might be associated with activation of beige remodeling in subcutaneous adipose tissue.

Topics: Adipocytes; Adipose Tissue, Beige; Adipose Tissue, Brown; Animals; Blotting, Western; Body Weight; Cells, Cultured; Diet, High-Fat; DNA-Binding Proteins; Gene Expression; Humans; Male; Mice, Inbred C57BL; Molecular Structure; Obesity; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Sirtuin 1; Stilbenes; Subcutaneous Fat; Transcription Factors; Uncoupling Protein 1

Obesity and associated pathologies are a dramatically growing problem. New therapies to prevent and/or cure them are strongly needed. Adipose tissue is a logical target for pharmacological intervention, since it is now recognized to exert an important endocrine function, secreting a variety of adipokines affecting, for example, adiposity and insulin resistance. This proof of principle work focuses on the development of novel lipid-mimetic prodrugs reaching fat deposits by the same lymphatic absorption route followed by dietary triglycerides. Pterostilbene, a natural phenolic compound with potential anti-obesity effects, was used as model "cargo", attached via a carbamate group to an ω-aminodecanoate chain linked to either position 1 or position 2 of the glycerol moiety of synthetic triglycerides. The prodrugs underwent position-selective hydrolysis when challenged with pancreatic lipases in vitro. Pterostilbene-containing triglycerides as well as pterostilbene and its metabolites were present in the adipose tissue of mice fed an obesogenic diet containing one or the other of the derivatives. For the first time this approach is used to deliver an obesity antagonist to the adipose tissue. The results demonstrate the feasibility of delivering active compounds to adipose tissue by reversibly incorporating them into triglyceride-mimetic structures. Upon release in the target site these compounds are expected to exert their pharmacological activity precisely where needed.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Dose-Response Relationship, Drug; Lipids; Mice; Mice, Inbred C57BL; Molecular Structure; Obesity; Prodrugs; Stilbenes; Structure-Activity Relationship

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.

Topics: 3T3 Cells; Adipocytes; Adult; Animals; Biological Transport; Caffeine; Cell Differentiation; Female; Glucose; Glycerol; Humans; Insulin; Lipogenesis; Lipolysis; Mice; Middle Aged; Obesity; Resveratrol; Stilbenes

Evidence suggests that dietary pattern may affect polyphenol absorption and/or metabolism. Further, obesity is associated with lower circulating nutrients, though the reason is unclear. We investigated the pharmacokinetic (PK) response of polyphenols in obese/overweight versus lean individuals before and after repeated dosing of grape polyphenols.. A pilot study was conducted in which PK challenges were administered before and after 10 days of repeated dosing with polyphenols. Volunteers (6 lean, 6 overweight/obese) consumed resveratrol, grape seed extract, and grape juice (2125 mg total polyphenols) daily. On days 1 and 11, blood samples were collected for 6 h after the polyphenol dose and analyzed for deconjugated catechin, epicatechin, resveratrol, and quercetin. Area under the plasma polyphenol mass by time curves (AUCs) were greater for catechin, epicatechin, and quercetin on day 11 versus day 1 for low BMI individuals (p = 0.039) but not high BMI individuals. Further, AUCs were greater for epicatechin and resveratrol for low versus high BMI individuals (p = 0.041), with a similar trend for catechin (p = 0.065), on day 11 but not day 1.. These results suggest that that obesity and repeated exposure may modify polyphenol absorption and/or metabolism in humans.

Topics: Aged; Anti-Obesity Agents; Area Under Curve; Body Mass Index; Dietary Supplements; Female; Fruit; Fruit and Vegetable Juices; Humans; Kinetics; Male; Middle Aged; Obesity; Overweight; Pilot Projects; Plant Extracts; Polyphenols; Resveratrol; Seeds; Stilbenes; Vitis

Obesity is a major risk for hypertension. Endothelial dysfunction contributes to increased peripheral vascular resistance and subsequent hypertension. Autophagy regulates endothelial function, however, whether autophagy is related to hypertension in obesity remains largely unclear. We wished to ascertain: (i) the role of autophagy in obesity-induced hypertension and the underlying mechanisms; (ii) if tetrahydroxystilbene glycoside (TSG) influences endothelial dysfunction and obesity-associated hypertension.. (TSG-treated) male Zucker diabetic fatty (ZDF) rats and cultured human umbilical vein endothelial cells (HUVECs) were used. Blood pressure was measured non-invasively with a tail-cuff system. Westernblotting was performed to determine the expression of autophagy-associated proteins. Autophagy flux was assessed by transfection HUVECs with the Ad-mGFP-RFP-LC3.. Compared with their lean counterparts, obese ZDF rats exhibited hypertension and endothelial dysfunction, along with impaired Akt/mTOR signaling and upregulated expression of autophagy-associated proteins beclin1, microtubule-associated protein 1 light chain 3 II/I, autophagy protein (ATG)5 and ATG7. Two-week TSG administration restored blood pressure and endothelial function, reactivated Akt/mTOR pathway and decreased endothelial autophagy in ZDF rats. Rapamycin pretreatment blocked the hypotensive effect of TSG in ZDF rats. Suppression of Akt/mTOR expression with siRNA significantly blunted the anti-autophagic effect of TSG in HUVECs as evidenced by abnormal autophagic flux and increased expression of autophagy-associated proteins.. Endothelial dysfunction in ZDF rats is partially attributable to excessive autophagy. TSG improves endothelial function and exerts hypotensive effects via regulation of endothelial autophagy.

Topics: Animals; Apoptosis; Autophagy; Blood Pressure; Glycosides; Human Umbilical Vein Endothelial Cells; Humans; Hypertension; Male; Microtubule-Associated Proteins; Obesity; Proto-Oncogene Proteins c-akt; Rats; Rats, Zucker; RNA Interference; Signal Transduction; Sirolimus; Stilbenes; TOR Serine-Threonine Kinases; Up-Regulation; Vasodilation

Obesity is clearly associated with an increased risk of breast cancer in postmenopausal women. The purpose was to determine if obesity alters the adipocyte adipokine secretion profile, thereby altering the adipose-dependent paracrine/endocrine growth microenvironment surrounding breast cancer cells (MCF7). Additionally, we determined whether resveratrol (RSV) supplementation can counteract any obesity-dependent effects on breast cancer tumor growth microenvironment. Obese ZDF rats received standard chow diet or diet supplemented with 200 mg/kg body weight RSV. Chow-fed Zucker rats served as lean controls. After 6 weeks, conditioned media (CM) prepared from inguinal subcutaneous adipose tissue (scAT) was added to MCF7 cells for 24 hrs. Experiments were also conducted using purified isolated adipocytes to determine whether any endocrine effects could be attributed specifically to the adipocyte component of adipose tissue. scAT from ZDF rats promoted cell cycle entry in MCF7 cells which was counteracted by RSV supplementation. RSV-CM had a higher ratio of ADIPO:LEP compared to ZDF-CM. This altered composition of the CM led to increased levels of pAMPKT172, p27, p27T198 and AdipoR1 while decreasing pAktT308 in MCF7 cells grown in RSV-CM compared to ZDF-CM. RSV-CM increased number of cells in G0/G1 and decreased cells in S-phase compared to ZDF-CM. Co-culture experiments revealed that these obesity-dependent effects were driven by the adipocyte component of the adipose tissue. Obesity decreased the ratio of adiponectin:leptin secreted by adipocytes, altering the adipose-dependent growth microenvironment resulting in increased breast cancer cell proliferation. Supplementation with RSV reversed these adipose-dependent effects suggesting a potential for RSV as a nutritional supplementation to improve breast cancer treatment in obese patients.

Topics: Adipocytes; Adipokines; Adipose Tissue; Animals; Body Weight; Breast Neoplasms; Cell Cycle; Cell Proliferation; Coculture Techniques; Culture Media, Conditioned; Endocrine System; Female; Humans; Male; MCF-7 Cells; Obesity; Rats; Rats, Zucker; Resveratrol; Stilbenes; Time Factors

Resveratrol and quercetin, widely found in foods and vegetables, are plant polyphenols reported to have a wide range of biological activities. Despite their limited bioavailabilities, both resveratrol and quercetin are known to exhibit anti-inflammation and anti-obesity effects. We hypothesized that gut microbiota may be a potential target for resveratrol and quercetin to prevent the development of obesity. The aim of this research was to confirm whether a combination of quercetin and resveratrol (CQR) could restore the gut microbiota dysbiosis induced by a high-fat diet (HFD). In this study, Wistar rats were divided into three groups: a normal diet (ND) group, a HFD group and a CQR group. The CQR group was treated with a HFD and administered with a combination of quercetin [30 mg per kg body weight (BW) per day] and resveratrol [15 mg per kg body weight (BW) per day] by oral gavage. At the end of 10 weeks, CQR reduced the body weight gain and visceral (epididymal, perirenal) adipose tissue weight. Moreover, CQR also reduced serum lipids, attenuated serum inflammatory markers [interleukin (IL)-6, tumor necrosis factor (TNF)-α, monocyte chemotactic protein (MCP)-1] and reversed serum biochemical parameters (adiponectin, insulin, leptin, etc.). Importantly, our results demonstrated that CQR could modulate the gut microbiota composition. 16S rRNA gene sequencing revealed that CQR had an impact on gut microbiota, decreasing Firmicutes (P < 0.05) and the proportion of Firmicutes to Bacteroidetes (P = 0.052). CQR also significantly inhibited the relative abundance of Desulfovibrionaceae (P < 0.01), Acidaminococcaceae (P < 0.05), Coriobacteriaceae (P < 0.05), Bilophila (P < 0.05), Lachnospiraceae (P < 0.05) and its genus Lachnoclostridium (P < 0.001), which were reported to be potentially related to diet-induced obesity. Moreover, compared with the HFD group, the relative abundance of Bacteroidales_S24-7_group (P < 0.01), Christensenellaceae (P < 0.001), Akkermansia (P < 0.01), Ruminococcaceae (P < 0.01) and its genera Ruminococcaceae_UCG-014 (P < 0.01), and Ruminococcaceae_UCG-005 (P < 0.01), which were reported to have an effect of relieving HFD-induced obesity, was markedly increased in the CQR group. Overall, these results indicated that administration of CQR may have beneficial effects on ameliorating HFD-induced obesity and reducing HFD-induced gut microbiota dysbiosis.

Topics: Animals; Bacteria; Diet, High-Fat; Dysbiosis; Gastrointestinal Microbiome; Humans; Male; Obesity; Quercetin; Rats; Rats, Wistar; Resveratrol; Stilbenes

To investigate the effects of different intensity exercise combined with resveratrol on retinol binding protein 4(RBP4) mRNA and protein expression in visceral adipose tissue and plasma RBP4 concentration of aged obese rats.. Compared with normal (C) group, the expressions of RBP4 mRNA and protein and plasma concentration and plasma glucose of the model (CO) group were increased obviously (. Different intensities exercise combined with resveratrol could reduce the RBP4 mRNA and protein expression in visceral adipose tissue and plasma RBP4 concentrations of aged obese rats, but less affected by exercise intensity.

Topics: Aging; Animals; Insulin Resistance; Male; Obesity; Physical Conditioning, Animal; Random Allocation; Rats; Rats, Sprague-Dawley; Resveratrol; Retinol-Binding Proteins, Plasma; Stilbenes

Nutritional interventions based on the use of natural bioactive compounds might offer new possibilities for reshaping obesity-associated bacterial dysregulation or dysbiosis and improving health. We evaluated whether pterostilbene supplementation could induce changes in gut microbiota composition and whether these modifications were associated with improvements in metabolic variables.. Zucker (fa/fa) rats were given a standard diet supplemented (n = 10) or not (n = 9) with pterostilbene (15 mg/kg body weight/day) by oral gavage for 6 weeks. Faucal samples at the beginning and at the end of the intervention period were analyzed by Illumina Mi-Seq sequencing approach. Pterostilbene exerted protective antiobesity effects, improved metabolic function (insulin sensitivity), and induced structural changes in gut microbiota composition. A decrease in the levels of Firmicutes and an increase in Verrucomicrobia phyla were detected in the pterostilbene-treated group. Bacterial species belonging to genera Akkermansia and Odoribacter were also increased. A strong inverse correlation between Akkermansia muciniphila and body weight was evidenced. Odoribacter splanchnicus showed a negative correlation with adiposity.. Pterostilbene modifies intestinal bacteria composition toward a healthier microbial profile and suggests that the antiobesity effects induced in Zucker rats could be associated with an enrichment of the mucin-degrading bacterial members, namely Akkermansia and Odoribacter genus.

Topics: Animals; Anti-Obesity Agents; Body Weight; Dietary Supplements; Dysbiosis; Gastrointestinal Microbiome; Obesity; Rats, Zucker; Stilbenes

Enhancing the formation and function of brown adipose tissue (BAT) increases thermogenesis and hence reduces obesity. Thus, we investigate the effects of resveratrol (Resv) on brown adipocyte formation and function in mouse interscapular BAT (iBAT).. CD1 mice and stromal vascular cells (SVCs) isolated from iBAT were treated with Resv. Expression of brown adipogenic and thermogenic markers, and involvement of AMP-activated protein kinase (AMPK)α1 were assessed. In vivo, Resv-enhanced expression of brown adipogenic markers, PR domain-containing 16 (PRDM16) and thermogenic genes, uncoupling protein 1 (UCP1) and cytochrome C in iBAT, along with smaller lipid droplets, elevated AMPKα activity and increased oxygen consumption. Meanwhile, Resv promoted expression of PRDM16, UCP1, PGC1α, cytochrome C and pyruvate dehydrogenase (PDH) in differentiated iBAT SVCs, suggesting that Resv enhanced brown adipocyte formation and function in vitro. In addition, Resv stimulated AMPKα and oxygen consumption in differentiated iBAT SVCs. However, the promotional effects of Resv were diminished by AMPK inhibition or AMPKα1 knockout, implying the involvement of AMPKα1 in this process.. Resv enhanced brown adipocyte formation and thermogenic function in mouse iBAT by promoting the expression of brown adipogenic markers via activating AMPKα1, which contributed to the anti-obesity effects of Resv.

Topics: Adipocytes, Brown; Adipogenesis; Adipose Tissue, Brown; AMP-Activated Protein Kinases; Animals; Diet, High-Fat; Ion Channels; Mice; Mitochondrial Proteins; Obesity; Resveratrol; Stilbenes; Thermogenesis; Transcription Factors

Maternal high-fat diet impairs brown adipocyte function and correlates with obesity in offspring. Maternal resveratrol administration recovers metabolic activity of offspring brown adipose tissue. Maternal resveratrol promotes beige adipocyte development in offspring white adipose tissue. Maternal resveratrol intervention protects offspring against high-fat diet-induced obesity.. Promoting beige/brite adipogenesis and thermogenic activity is considered as a promising therapeutic approach to reduce obesity and metabolic syndrome. Maternal obesity impairs offspring brown adipocyte function and correlates with obesity in offspring. We previously found that dietary resveratrol (RES) induces beige adipocyte formation in adult mice. Here, we evaluated further the effect of resveratrol supplementation of pregnant mice on offspring thermogenesis and energy expenditure. Female C57BL/6 J mice were fed a control diet (CON) or a high-fat diet (HFD) with or without 0.2% (w/w) RES during pregnancy and lactation. Male offspring were weaned onto a HFD and maintained on this diet for 11 weeks. The offspring thermogenesis and related regulatory factors in adipose tissue were evaluated. At weaning, HFD offspring had lower thermogenesis in brown and white adipose tissues compared with CON offspring, which was recovered by maternal RES supplementation, along with the appearance of multilocular brown/beige adipocytes and elevated thermogenic gene expression. Adult offspring of RES-treated mothers showed increased energy expenditure and insulin sensitivity when on an obesogenic diet compared with HFD offspring. The elevated metabolic activity was correlated with enhanced brown adipose function and white adipose tissue browning in HFD+RES compared with HFD offspring. In conclusion, RES supplementation of HFD-fed dams during pregnancy and lactation promoted white adipose browning and thermogenesis in offspring at weaning accompanied by persistent beneficial effects in protecting against HFD-induced obesity and metabolic disorders.

Topics: Adipocytes, Beige; Adipocytes, Brown; Animals; Diet, High-Fat; Energy Metabolism; Female; Male; Mice; Obesity; Pregnancy; Resveratrol; Stilbenes; Thermogenesis

Oral administration of resveratrol is able to improve glucose homeostasis in obese individuals. Herein we show that resveratrol ingestion produces taxonomic and predicted functional changes in the gut microbiome of obese mice. In particular, changes in the gut microbiome were characterized by a decreased relative abundance of Turicibacteraceae, Moryella, Lachnospiraceae, and Akkermansia and an increased relative abundance of Bacteroides and Parabacteroides Moreover, fecal transplantation from healthy resveratrol-fed donor mice is sufficient to improve glucose homeostasis in obese mice, suggesting that the resveratrol-mediated changes in the gut microbiome may play an important role in the mechanism of action of resveratrol.

Topics: Animals; Bacteroides; Blood Glucose; Chromatography, Liquid; Fecal Microbiota Transplantation; Gastrointestinal Microbiome; Glucose; Glucose Tolerance Test; Homeostasis; Male; Mice; Mice, Obese; Obesity; Resveratrol; Stilbenes; Tandem Mass Spectrometry

Oxyresveratrol has been proven effective in inhibiting adipogenesis in a 3T3-L1 cell model. We investigated the preventive effect of oxyresveratrol supplementation on obesity development in high-fat diet-fed mice. Male C57bl/6 mice were randomly subjected to control (5% fat by weight, LF), high-fat (30% fat by weight, HF), and high-fat supplemented with 0.25% and 0.5% oxyresveratrol (OXY1 and OXY2, respectively) diet groups for eight weeks. Oxyresveratrol supplementation effectively alleviated obesity-associated symptoms such as insulin resistance, hyperglycemia, and hepatic steatosis in high-fat diet-fed mice. Compared to the high-fat diet group, oxyresveratrol supplementation suppressed expression of glucose-6-phosphatase, sterol regulatory element-binding proteins 1, fatty acid synthase and CCAAT/Enhancer-binding proteins α, and elevated AMP-activated protein kinase (α2-catalytic subunit) level in liver, upregulated insulin-dependent glucose transporter type 4 level in adipose tissue, and increased expression of insulin receptor substrate 1, insulin-dependent glucose transporter type 4, AMP-activated protein kinase α, peroxisome proliferator-activated receptor γ coactivator-1α, and sirtuin 1 in muscle to regulate lipid and glucose homeostasis in these tissues. This study demonstrated that oxyresveratrol supplementation effectively ameliorated obesity-associated symptoms in high-fat diet-fed mice, presumably attributed to mediating critical regulators involved in lipid and glucose homeostasis in liver, visceral fat, and muscle.

Topics: Adipogenesis; Animals; Diet, High-Fat; Dietary Supplements; Fatty Liver; Glucose; Homeostasis; Hyperglycemia; Insulin Resistance; Intra-Abdominal Fat; Lipid Metabolism; Liver; Male; Mice; Mice, Inbred C57BL; Muscles; Obesity; Plant Extracts; Stilbenes

Resveratrol (RSV) has been proposed as an energy restriction mimetic. This study aimed to compare the effects of RSV and energy restriction on insulin resistance induced by an obesogenic diet. Any additive effect of both treatments was also analyzed. Rats were fed a high-fat high-sucrose diet for 6 weeks. They were then distributed in four experimental groups which were either fed a standard control diet (C), or treated with RSV (30 mg/kg/d), or submitted to energy restriction (R, 15%), or treated with RSV and submitted to energy restriction (RR). A glucose tolerance test was performed, and serum glucose, insulin, fructosamine, adiponectin, and leptin concentrations determined. Muscle triacylglycerol content and protein expression of insulin receptor (IRβ), protein kinase B (Akt), Akt substrate of 160 kDa (AS160) and glucose transporter 4 (GLUT-4) were measured. In RSV rats, fructosamine concentrations were reduced, HOMA-IR remained unchanged, but glucose tolerance was improved, without changes in phosphorylation of IRβ, Akt, and AS160 or in GLUT-4 protein expression. Rats under energy restriction showed an improvement in all the markers related to glycemic control, as well as increased phosphorylation of AS160 and protein expression of GLUT-4. In rats from RR group the results were similar to R group, with the exception of IRβ and Akt phosphorylation, which were increased. In conclusion, mild energy restriction is more efficient than intake of RSV within a standard balanced diet, and acts by means of a different mechanism from that of RSV. No additive effects between RSV and energy restriction were observed. © 2017 BioFactors, 43(3):371-378, 2017.

Topics: Adiponectin; Animals; Antioxidants; Blood Glucose; Caloric Restriction; Diet, High-Fat; Fructosamine; Gene Expression; Glucose Tolerance Test; Glucose Transporter Type 4; Insulin; Insulin Resistance; Leptin; Male; Muscle, Skeletal; Obesity; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Receptor, Insulin; Resveratrol; Stilbenes; Sucrose; Triglycerides

Topics: Administration, Oral; Animals; Anti-Inflammatory Agents; Blotting, Western; Diet, High-Fat; Enzyme-Linked Immunosorbent Assay; Inflammation; Male; Mice; Mice, Inbred C57BL; Obesity; Osteoarthritis; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; Signal Transduction; Stilbenes

Resveratrol possesses several beneficial metabolic effects in rodents, while the effects of resveratrol in humans remain unclear. Therefore, we performed a non-targeted comprehensive metabolomic analysis on blood, urine, adipose tissue, and skeletal muscle tissue in middle-aged men with metabolic syndrome randomized to either resveratrol or placebo treatment for four months. Changes in steroid hormones across all four matrices were the most pronounced changes observed. Resveratrol treatment reduced sulfated androgen precursors in blood, adipose tissue, and muscle tissue, and increased these metabolites in urine. Furthermore, markers of muscle turnover were increased and lipid metabolism was affected, with increased intracellular glycerol and accumulation of long-chain saturated, monounsaturated, and polyunsaturated (n3 and n6) free fatty acids in resveratrol-treated men. Finally, urinary derivatives of aromatic amino acids, which mainly reflect the composition of the gut microbiota, were altered upon resveratrol treatment. In conclusion, the non-targeted metabolomics approach applied to four different matrices provided evidence of subtle but robust effects on several metabolic pathways following resveratrol treatment for four months in men with metabolic syndrome-effects that, for the most part, would not have been detected by routine analyses. The affected pathways should be the focus of future clinical trials on resveratrol's effects, and perhaps particularly the areas of steroid metabolism and the gut microbiome.

Topics: Adipose Tissue; Biomarkers; Blood Pressure; Gastrointestinal Microbiome; Humans; Insulin Resistance; Male; Metabolic Syndrome; Metabolomics; Middle Aged; Muscles; Obesity; Randomized Controlled Trials as Topic; Resveratrol; Stilbenes

In this study, hot-water extracts (HW) from roots of Vitis thunbergii var. taiwaniana (VTT-R) were shown to lower levels of lipid accumulation significantly (P < 0.01 or 0.001) compared to the control in 3T3-L1 adipocytes. The VTT-R-HW (40 mg/kg) interventions concurrent with a high-fat (HF) diet in C57BL/6 mice over a 5 eek period were shown to reduce body weights significantly (P < 0.05) compared to those of mice fed a HF diet under the same food-intake regimen. The (+)-ε-viniferin isolated from VTT-R-HW was shown to reduce the size of lipid deposits significantly compared to the control (P < 0.05 or 0.001) in 3T3-L1 adipocytes, and dose-dependent 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitions showed that the 50% inhibitory concentration was calculated to be 96 μM. The two-stage (+)-ε-viniferin interventions (10 mg/kg, day 1 to day 38; 25 mg/kg, day 39 to day 58) were shown to lower mice body weights significantly (P < 0.05 or 0.001), the weight ratio of mesenteric fat, blood glucose, total cholesterol, and low-density lipoprotein compared to that of the HF group under the same food-intake regimen but without concurrent VTT-R-HW interventions. It might be possible to use VTT-R-HW or (+)-ε-viniferin as an ingredient in the development of functional foods for weight management, and this will need to be investigated further.

Topics: Animals; Benzofurans; Blood Glucose; Cholesterol; Diet, High-Fat; Humans; Male; Mice; Mice, Inbred C57BL; Molecular Structure; Obesity; Plant Extracts; Plant Roots; Stilbenes; Vitis

Perinatal high-fat diet is associated with obesity and metabolic diseases in adult offspring. Resveratrol has been shown to exert antioxidant and anti-obesity actions. However, the effects of resveratrol on leptinemia and leptin signaling are still unknown as well as whether resveratrol treatment can improve metabolic outcomes programmed by maternal high-fat diet. We hypothesize that resveratrol treatment in male rats programmed by high-fat diet would decrease body weight and food intake, and leptinemia with changes in central leptin signaling.. Female Wistar rats were divided into two groups: control group (C), which received a standard diet containing 9 % of the calories as fat, and high-fat group (HF), which received a diet containing 28 % of the calories as fat. Dams were fed in C or HF diet during 8 weeks before mating and throughout gestation and lactation. C and HF male offspring received standard diet throughout life. From 150 until 180 days of age, offspring received resveratrol (30 mg/Kg body weight/day) or vehicle (carboxymethylcellulose).. HF offspring had increased body weight, hyperphagia and increased subcutaneous and visceral fat mass compared to controls, and resveratrol treatment decreased adiposity. HF offspring had increased leptinemia as well as increased SOCS3 in the arcuate nucleus of the hypothalamus, which suggest central leptin resistance. Resveratrol treatment rescued leptinemia and increased p-STAT3 content in the hypothalamus with no changes in SOCS3, suggesting improvement in leptin signaling.. Collectively, our data suggest that resveratrol could reverse hyperleptinemia and improve central leptin action in adult offspring from HF mothers attenuating obesity.

Topics: Adipose Tissue; Animals; Body Composition; Diet, High-Fat; Female; Hyperphagia; Hypothalamus; Janus Kinase 2; Leptin; Male; Maternal Nutritional Physiological Phenomena; Obesity; Pregnancy; Prenatal Exposure Delayed Effects; Rats; Rats, Wistar; Resveratrol; Signal Transduction; STAT3 Transcription Factor; Stilbenes; Suppressor of Cytokine Signaling 3 Protein; Weight Gain

Obesity-associated nephropathy is considered to be a leading cause of end-stage renal disease. Resveratrol supplementation represents a promising therapy to attenuate kidney injury, but the poor solubility and limited bioavailability of this polyphenol limits its use in dietary intervention. Piceatannol, a resveratrol analogue, has been suggested as a better option. In this study, we aimed to provide evidence of a preventive action of piceatannol in very early stages of obesity-associated nephropathy. Thirty obese Zucker rats were divided into three experimental groups: one control and two groups orally treated for 6 weeks with 15 and 45 mg piceatannol/kg body weight/day. Enzyme-linked immunosorbent assays (ELISA) were used to determine renal and urinary kidney injury molecule-1 (Kim-1), renal fibrosis markers (transforming growth factor β1 and fibronectin) and renal sirtuin-1 protein. Oxidative stress was assessed in the kidney by measuring lipid peroxidation and nitrosative stress (thiobarbituric acid reactive substrates and 3-nitrotyrosine levels, respectively) together with the activity of the antioxidant enzyme superoxide dismutase. Renal fatty acids profile analysis was performed by thin-layer and gas chromatography. Piceatannol-treated rats displayed lower levels of urinary and renal Kim-1. Renal fibrosis biomarkers and lipid peroxidation exhibited a tendency to decrease in the piceatannol-treated groups. Piceatannol treatment did not modify superoxide dismutase activity or sirtuin-1 protein levels, while it seemed to increase the levels of polyunsaturated and omega-6 polyunsaturated fatty acids in the kidneys. Our findings suggest a mild renoprotective effect of piceatannol in obese Zucker rats and the need of intervention at early stages of renal damage.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Biomarkers; Cell Adhesion Molecules; Dietary Supplements; Fibrosis; Kidney; Lipid Peroxidation; Male; Obesity; Organ Size; Oxidative Stress; Random Allocation; Rats, Zucker; Renal Insufficiency; Severity of Illness Index; Stilbenes; Thiobarbituric Acid Reactive Substances; Tyrosine

Studies on resveratrol in a wide range of concentrations on obese mice and adipose cells are necessary to comprehend its range of diverse and contradictory effects. In this study, we examined the anti-obesity effects of resveratrol on high-fat diet (HFD)-induced obese mice at dosages ranging from 1 to 30 mg/kg treatment for 10 wk. We also evaluated the effects of resveratrol on cytotoxicity, proliferation, adipogenic differentiation, and lipolysis of 3T3-L1 cells at concentrations ranging from 0.03 to 100 μM. In HFD obese mice, resveratrol treatment for 10 wk without decreased calories intake significantly attenuated HFD-induced weight gain in a dose-dependent manner. Resveratrol treatment also protected against HFD-induced lipid deposition in adipose tissues and liver. In cultured 3T3-L1 preadipocytes, high dosage (10 to 100 μM) resveratrol treatment produced cytotoxicity in both preadipocytes and mature adipocytes. In contrast, low concentration resveratrol treatment (1 to 10 μM) significantly inhibited the capacity of 3T3-L1 cells differentiated into mature adipocytes. Low dose resveratrol treatment also downregulated peroxisome proliferator-activated receptor gamma (PPARγ) and perilipin protein expressions in differentiated adipocytes. Additionally, tumor necrosis factor alpha (TNFα)-induced lipolysis was inhibited by low concentration resveratrol treatment in mature adipocytes. At concentrations of 10-100 μM, resveratrol exerted cytotoxicity. In contrast, at concentrations of 1-10 μM resveratrol inhibited adipogenic differentiation in preadipocytes and suppressed lipolysis in mature adipocytes. Our results suggest that resveratrol possessed anti-obesity effects by induction of cytotoxicity at high dosage and that it influences preadipocyte differentiation and mature adipocyte lipolysis at low concentration.

Topics: 3T3-L1 Cells; Adipogenesis; Animals; Anti-Obesity Agents; Cell Death; Cell Differentiation; Diet, High-Fat; Dose-Response Relationship, Drug; Lipolysis; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Resveratrol; Stilbenes

Low-grade inflammation is seen with obesity and is suggested to be a mediator of insulin resistance. The eliciting factor of low-grade inflammation is unknown but increased permeability of gut bacteria-derived lipopolysaccharides (LPS) resulting in endotoxemia could be a candidate. Here we test the effect of LPS and the anti-inflammatory compound resveratrol on glucose homeostasis, insulin levels and inflammation. Mice were subcutaneously implanted with osmotic mini pumps infusing either low-dose LPS or saline for 28 days. Half of the mice were treated with resveratrol delivered through the diet. LPS caused increased inflammation of the liver and adipose tissue (epididymal and subcutaneous) together with enlarged spleens and increased number of leukocytes in the blood. Resveratrol specifically reduced the inflammatory status in epididymal fat (reduced expression of TNFa and Il1b, whereas the increased macrophage infiltration was unaltered) without affecting the other tissues investigated. By LC-MS, we were able to quantitate resveratrol metabolites in epididymal but not subcutaneous adipose tissue. LPS induced insulin resistance as the glucose-stimulated insulin secretion during an oral glucose tolerance test was increased despite similar plasma glucose level resulting in an increase in the insulinogenic index (IGI; delta0-15insulin/delta0-15glucose) from 13.73 to 22.40 pmol/mmol (P < 0.001). This aberration in insulin and glucose homeostasis was normalized by resveratrol.. Low-dose LPS enhanced the glucose-stimulated insulin secretion without affecting the blood glucose suggesting increased insulin resistance. Resveratrol restored LPS-induced alteration of the insulin secretion and demonstrated anti-inflammatory effects specifically in epididymal adipose tissue possibly due to preferential accumulation of resveratrol metabolites pointing towards a possible important involvement of this tissue for the effects on insulin resistance and insulin secretion.

Topics: Adipose Tissue; Animals; Antioxidants; Blood Glucose; Body Weight; Epididymis; Gene Expression Profiling; Glucose; Glucose Tolerance Test; Homeostasis; Inflammation; Insulin; Insulin Resistance; Insulin Secretion; Leukocytes; Lipopolysaccharides; Liver; Male; Mice; Mice, Inbred C57BL; Obesity; Osmosis; Resveratrol; Stilbenes

Resveratrol is beneficial in obese and diabetic rodents. However, its low bioavailability raises questions about its therapeutic relevance for treating or preventing obesity complications. In this context, many related natural polyphenols are being tested for their putative antidiabetic and anti-obesity effects. This prompted us to study the influence of piceatannol, a polyhydroxylated stilbene, on the prevention of obesity complications in Zucker obese rats. A 6-week supplementation was followed by the determination of various markers in plasma, liver, adipose tissue and heart, together with a large-scale analysis of gut microbiota composition. When given in doses of 15 or 45 mg/kg body weight/day, piceatannol did not reduce either hyperphagia or fat accumulation. It did not modify the profusion of the most abundant phyla in gut, though slight changes were observed in the abundance of several Lactobacillus, Clostridium, and Bacteroides species belonging to Firmicutes and Bacteroidetes. This was accompanied by a tendency to reduce plasma lipopolysaccharides by 30 %, and by a decrease of circulating non-esterified fatty acids, LDL-cholesterol, and lactate. While piceatannol tended to improve lipid handling, it did not mitigate hyperinsulinemia and cardiac hypertrophy. However, it increased cardiac expression of ephrin-B1, a membrane protein that contributes to maintaining cardiomyocyte architecture. Lastly, ascorbyl radical plasma levels and hydrogen peroxide release by adipose tissue were similar in control and treated groups. Thus, piceatannol did not exhibit strong slimming capacities but did limit several obesity complications.

Topics: 3T3-L1 Cells; Adipose Tissue, White; Adiposity; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Biomarkers; Dietary Supplements; Dysbiosis; Heart Diseases; Hydrogen Peroxide; Hyperlipidemias; Liver; Male; Mice; Myocardium; Obesity; Random Allocation; Rats, Zucker; Stilbenes

Aberrant gene expression within the hippocampus has recently been implicated in the pathogenesis of obesity-induced memory impairment. Whether a dysregulation of epigenetic modifications mediates this disruption in gene transcription has yet to be established. Here we report evidence of obesity-induced alterations in DNA methylation of memory-associated genes, including Sirtuin 1 (Sirt1), within the hippocampus, and thus offer a novel mechanism by which SIRT1 expression within the hippocampus is suppressed during obesity. Forebrain neuron-specific Sirt1 knock-out closely recapitulated the memory deficits exhibited by obese mice, consistent with the hypothesis that the high-fat diet-mediated reduction of hippocampal SIRT1 could be responsible for obesity-linked memory impairment. Obese mice fed a diet supplemented with the SIRT1-activating molecule resveratrol exhibited increased hippocampal SIRT1 activity and preserved hippocampus-dependent memory, further strengthening this conclusion. Thus, our findings suggest that the memory-impairing effects of diet-induced obesity may potentially be mediated by neuroepigenetic dysregulation of SIRT1 within the hippocampus.. Previous studies have implicated transcriptional dysregulation within the hippocampus as being a relevant pathological concomitant of obesity-induced memory impairment, yet a deeper understanding of the basis for, and etiological significance of, transcriptional dysregulation in this context is lacking. Here we present the first evidence of epigenetic dysregulation (i.e., altered DNA methylation and hydroxymethylation) of memory-related genes, including Sirt1, within the hippocampus of obese mice. Furthermore, experiments using transgenic and pharmacological approaches strongly implicate reduced hippocampal SIRT1 as being a principal pathogenic mediator of obesity-induced memory impairment. This paper offers a novel working model that may serve as a conceptual basis for the development of therapeutic interventions for obesity-induced memory impairment.

Topics: Animals; Antioxidants; Diet, High-Fat; Dietary Supplements; Disease Models, Animal; DNA Methylation; Excitatory Postsynaptic Potentials; Exploratory Behavior; Gene Expression Regulation; Hippocampus; Insulin; Male; Memory Disorders; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurons; Obesity; Prosencephalon; Recognition, Psychology; Resveratrol; Sirtuin 1; Spatial Memory; Stilbenes; Time Factors

Diabetes-induced CVD is the most significant complication of prolonged hyperglycaemia. The aim of this study was to determine whether resveratrol, a polyphenol antioxidant compound, when administered at a dose that can be reasonably obtained through supplementation could prevent the development of cardiovascular complications in older, obese, diabetic rats. Diabetes was induced in 6-month old, obese, male Wistar rats via a single intravenous dose of streptozotocin (65 mg/kg). Randomly selected animals were administered resveratrol (2 mg/kg) via oral gavage daily for 8 weeks. Body weights, blood glucose levels, food intake and water consumption were monitored, and assessments of vascular reactivity, tactile allodynia and left ventricular function were performed. Resveratrol therapy significantly improved tactile allodynia and vascular contractile functionality in diabetic rats (P<0·05). There were no significant changes in standardised vasorelaxation responses, plasma glucose concentrations, water consumption, body weight, left ventricular hypertrophy, kidney hypertrophy, heart rate or left ventricular compliance with resveratrol administration. Resveratrol-mediated improvements in vascular and nerve function in old, obese, diabetic rats were associated with its reported antioxidant effects. Resveratrol did not improve cardiac function nor mitigate the classic clinical symptoms of diabetes mellitus (i.e. hyperglycaemia, polydypsia and a failure to thrive). This suggests that supplementation with resveratrol at a dose achievable with commercially available supplements would not produce significant cardioprotective effects in people with diabetes mellitus.

Topics: Analgesics; Animals; Antioxidants; Cardiovascular Diseases; Diabetes Mellitus, Experimental; Endothelium, Vascular; Hyperalgesia; Male; Muscle Contraction; Nervous System; Obesity; Plant Extracts; Polyphenols; Random Allocation; Rats, Wistar; Resveratrol; Stilbenes

This study investigated possible mechanisms for cardioprotective effects of lipoic acid (LA), quercetin (Q) and resveratrol (R) on oxidative stress related to thyroid hormone alterations in long-term obesity. Female C57BL/6 mice were fed on high-fat diet (HFD), HFD+LA, HFD+R, HFD+Q and normal diet for 26weeks. Body weight, blood pressure, thyroid hormones, oxidative stress markers, angiotensin converting enzyme (ACE), nitric oxide synthase (NOS) and ion pump activities were measured, and expression of cardiac genes was analyzed by real-time polymerase chain reaction. HFD induced marked increase (P<.05) in body weight, blood pressure and oxidative stress, while plasma triidothyronine levels reduced. ACE activity increased (P<.05) in HFD mice (0.69±0.225U/mg protein) compared with controls (0.28±0.114U/mg protein), HFD+LA (0.231±0.02U/mg protein) and HFD+Q (0.182±0.096U/mg protein) at 26weeks. Moreover, Na(+)/K(+)-ATPase and Ca(2+)-ATPase activities increased in HFD mice whereas NOS reduced. A 1.5-fold increase in TRα1 and reduction in expression of the deiodinase iodothyronine DIO1, threonine protein kinase and NOS3 as well as up-regulation of AT1α, ACE, ATP1B1, GSK3β and Cja1 genes also occurred in HFD mice. Conversely, LA, Q and R inhibited weight gain; reduced TRα1 expression as well as increased DIO1; reduced ACE activity and AT1α, ATP1B1 and Cja1 gene expression as well as inhibited GSK3β; increased total antioxidant capacity, GSH and catalase activity; and reduced blood pressure. In conclusion, LA, resveratrol and quercetin supplementation reduces obesity thereby restoring plasma thyroid hormone levels and attenuating oxidative stress in the heart and thus may have therapeutic potential in heart diseases.

Topics: Animals; Anti-Obesity Agents; Antihypertensive Agents; Antioxidants; Biomarkers; Cardiotonic Agents; Cardiovascular Diseases; Diet, High-Fat; Female; Gene Expression Regulation; Heart Ventricles; Hypertension; Hypothyroidism; Mice, Inbred C57BL; Obesity; Oxidative Stress; Quercetin; Random Allocation; Resveratrol; Stilbenes; Thioctic Acid; Thyroid Hormones; Weight Gain

The objective of the present work was to evaluate whether oral intake with resveratrol ameliorates overactive bladder in high-fat fed mice. Male C57BL6 mice fed with standard chow or high-fat diet to induce obesity received a two-week therapy with resveratrol (100mg/kg, given as a daily gavage). Weight and metabolic profile, together with cystometry and in vitro bladder contractions were evaluated. Measurements of gp91phox and SOD1 mRNA expressions and reactive-oxygen species (ROS) in bladder tissues, and serum TBARS were performed. Obese mice exhibited increases in body weight and epididymal fat mass, which were significantly reduced by oral treatment with resveratrol. Cystometric study in obese mice showed increases in non-voiding contractions, post-voiding pressure and voiding frequency that were reversed by resveratrol treatment. Likewise, the in vitro bladder overactivity in response to electrical-field stimulation (80V, 1-32Hz) or carbachol (1nM to 10mM) were normalized by resveratrol. The gp91phox and SOD1 mRNA expressions in bladder tissues were markedly higher in obese mice compared with lean group. In addition, ROS levels in bladder tissues and serum lipid peroxidation (TBARS assay) were markedly higher in obese compared with lean mice, all of which were reduced by resveratrol treatment. In lean group, resveratrol had no effect in any parameter evaluated. Our results show that two-week therapy of obese mice with resveratrol reduces the systemic and bladder oxidative stress, and greatly ameliorated the cystometry alterations and in vitro bladder overactivity. Resveratrol treatment could be an option to prevent obesity-associated overactive bladder.

Topics: Administration, Oral; Animals; Anti-Obesity Agents; Antioxidants; Body Weight; Diet, High-Fat; Gene Expression Regulation, Enzymologic; Male; Membrane Glycoproteins; Mice; Mice, Inbred C57BL; Muscle, Smooth; NADPH Oxidase 2; NADPH Oxidases; Obesity; Oxidative Stress; Resveratrol; RNA, Messenger; Stilbenes; Superoxide Dismutase-1; Time Factors; Urinary Bladder; Urinary Bladder, Overactive

Sirtuin type 1 (Sirt1) and protein kinase B (Akt2) are associated with development of obesity and inflammation, but the molecular mechanisms of Sirt1 and Akt2 interaction on adipose inflammation remain unclear. To explore these mechanisms, a mouse model was used. Mice were fed with a high-fat diet (HFD) for 8 weeks, with interventions of resveratrol (RES) or nicotinamide (NAM) during the last 15 days. The HFD reduced Sirt1 mRNA in adipose tissue and elevated interleukin-6 (IL-6) expression. RES reduced the adipose tissue weight, increased the Sirt1 mRNA level, and reduced both mRNA and protein levels of IL-6, MCP-1, inducible nitric oxide synthase, and TNF-α by inhibiting phosphorylation of Akt2 in adipose tissue. Additionally, macrophage type I marker genes were reduced while macrophage type II marker genes were elevated by RES addition. Moreover, activation of Akt2 signal by using insulin significantly blunted the inhibitory effect of RES on adipose inflammation. Immunoprecipitation assay demonstrated that RES enhances the protein-protein interaction between Sirt1 and Akt2, but NAM inhibits this interaction. Furthermore, Sirt1 significantly reduced the levels of raptor and inactivated mammalian target of rapamycin (mTOR)C1 signal by interacting with Akt2, and confirmed that RES attenuated adipose inflammation by inhibiting the mTOR/S6K1 pathway via rapamycin.

Topics: Adaptor Proteins, Signal Transducing; Animals; Anti-Obesity Agents; Cells, Cultured; Diet, High-Fat; Enzyme Activation; Inflammation; Insulin; Male; Mice; Niacinamide; Obesity; Proto-Oncogene Proteins c-akt; Regulatory-Associated Protein of mTOR; Resveratrol; Ribosomal Protein S6 Kinases, 90-kDa; Signal Transduction; Sirtuin 1; Stilbenes; Subcutaneous Fat; TOR Serine-Threonine Kinases

Obesity and insulin resistance have been associated with deterioration in asthma outcomes. High oxidative stress and deficient activation of AMP-activated protein kinase (AMPK) have emerged as important regulators linking insulin resistance and inflammation. This study aimed to evaluate the effects of resveratrol on obesity-associated allergic pulmonary inflammation. Male C57/Bl6 mice fed with high-fat diet to induce obesity (obese group) or standard-chow diet (lean group) were treated or not with resveratrol (100mg/kg/day, two weeks). Mice were sensitized and challenged with ovalbumin (OVA). At 48h thereafter, bronchoalveolar lavage fluid was performed, and lungs collected for morphological studies and Western blot analysis. Treatment of obese mice with resveratrol significantly reduced hyperglycemia and insulin resistance, as well as the body measures (body mass, fat mass, % fat, and body area). OVA-challenge promoted a higher increase in pulmonary eosinophil infiltration in obese compared with lean mice, which was nearly abrogated by resveratrol treatment. Resveratrol markedly increased the phosphorylated AMPK expression in lung tissues of obese compared with lean mice. Resveratrol reduced the p47phox expression and reactive-oxygen species (ROS) production, and elevated the superoxide dismutase (SOD) levels in lung tissues of obese mice. The increased pulmonary levels of TNF-α and inducible nitric oxide synthase (iNOS) in obese mice were also normalized after resveratrol treatment. In lean mice, resveratrol failed to affect the levels of fasting glucose, p47phox, ROS levels, TNF-α, iNOS and phosphorylated AMPK. Resveratrol exhibits protective effects in obesity-associated lung inflammation that is accompanied by local AMPK activation and antioxidant property.

Topics: AMP-Activated Protein Kinases; Animals; Antioxidants; Asthma; Cell Movement; Cells, Cultured; Disease Progression; Eosinophils; Lung; Mice; Mice, Inbred Strains; Obesity; Pneumonia; Resveratrol; Stilbenes

Arterial stiffness, a major cardiovascular risk factor, develops within 2 months in mice fed a high-fat, high-sucrose (HFHS) diet, serving as a model of human metabolic syndrome, and it is associated with activation of proinflammatory and oxidant pathways in vascular smooth muscle (VSM) cells. Sirtuin-1 (SirT1) is an NAD(+)-dependent deacetylase regulated by the cellular metabolic status. Our goal was to study the effects of VSM SirT1 on arterial stiffness in the context of diet-induced metabolic syndrome. Overnight fasting acutely decreased arterial stiffness, measured in vivo by pulse wave velocity, in mice fed HFHS for 2 or 8 months, but not in mice lacking SirT1 in VSM (SMKO). Similarly, VSM-specific genetic SirT1 overexpression (SMTG) prevented pulse wave velocity increases induced by HFHS feeding, during 8 months. Administration of resveratrol or S17834, 2 polyphenolic compounds known to activate SirT1, prevented HFHS-induced arterial stiffness and were mimicked by global SirT1 overexpression (SirT1 bacterial artificial chromosome overexpressor), without evident metabolic improvements. In addition, HFHS-induced pulse wave velocity increases were reversed by 1-week treatment with a specific, small molecule SirT1 activator (SRT1720). These beneficial effects of pharmacological or genetic SirT1 activation, against HFHS-induced arterial stiffness, were associated with a decrease in nuclear factor kappa light chain enhancer of activated B cells (NFκB) activation and vascular cell adhesion molecule (VCAM-1) and p47phox protein expressions, in aorta and VSM cells. In conclusion, VSM SirT1 activation decreases arterial stiffness in the setting of obesity by stimulating anti-inflammatory and antioxidant pathways in the aorta. SirT1 activators may represent a novel therapeutic approach to prevent arterial stiffness and associated cardiovascular complications in overweight/obese individuals with metabolic syndrome.

Topics: Animals; Blotting, Western; Cardiovascular Diseases; Diet, High-Fat; Disease Models, Animal; Glucose Tolerance Test; Male; Metabolic Syndrome; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Muscle, Smooth, Vascular; Obesity; Pulse Wave Analysis; Random Allocation; Real-Time Polymerase Chain Reaction; Resveratrol; Sirtuin 1; Stilbenes; Vascular Cell Adhesion Molecule-1; Vascular Stiffness

Adipose tissue inflammation is believed to play a pivotal role in the development obesity-related morbidities such as insulin resistance. However, it is not known how this (low-grade) inflammatory state develops. It has been proposed that the leakage of lipopolysaccharides (LPS), originating from the gut microbiota, through the gut epithelium could drive initiation of inflammation. To get a better understanding of which proteins and intracellular pathways are affected by LPS in adipocytes, we performed SILAC proteomic analysis and identified proteins that were altered in expression. Furthermore, we tested the anti-inflammatory compound resveratrol. A total of 927 proteins were quantified by the SILAC method and of these 57- and 64 were significantly up- and downregulated by LPS, respectively. Bioinformatic analysis (GO analysis) revealed that the upregulated proteins were especially involved in the pathways of respiratory electron transport chain and inflammation. The downregulated proteins were especially involved in protein glycosylation. One of the latter proteins, GALNT2, has previously been described to regulate the expression of liver lipases such as ANGPTL3 and apoC-III affecting lipid metabolism. Furthermore, LPS treatment reduced the protein levels of the insulin sensitizing adipokine, adiponectin, and proteins participating in the final steps of triglyceride- and cholesterol synthesis. Generally, resveratrol opposed the effect induced by LPS and, as such, functioning as an ameliorating factor in disease state. Using an unbiased proteomic approach, we present novel insight of how the proteome is altered in adipocytes in response to LPS as seen in obesity. We suggest that LPS partly exerts its detrimental effects by altering glycosylation processes of the cell, which is starting to emerge as important posttranscriptional regulators of protein expression. Furthermore, resveratrol could be a prime candidate in ameliorating dysfunctioning adipose tissue induced by inflammatory stimulation.

Topics: Adipocytes; Adipose Tissue; Angiopoietin-Like Protein 3; Angiopoietin-like Proteins; Angiopoietins; Gastrointestinal Microbiome; Gene Expression Regulation; Glycosylation; Humans; Inflammation; Insulin; Insulin Resistance; Lipid Metabolism; Lipogenesis; Lipopolysaccharides; N-Acetylgalactosaminyltransferases; Obesity; Polypeptide N-acetylgalactosaminyltransferase; Proteome; Proteomics; Resveratrol; Stilbenes

Alterations in the gut microbiota play a crucial role in host physiology and metabolism; however, the molecular pathways underlying these changes in diet-induced obesity are unclear. Mechanistic target of rapamycin (mTOR) signaling pathway is associated with metabolic disorders such as obesity and type 2 diabetes (T2D). Therefore, we examined whether changes in the regulation of mTOR signaling induced by diet (a high-fat diet [HFD] or normal-chow diet) and/or therapeutics (resveratrol [a specific inhibitor of mTOR complex 1] or rapamycin [an inhibitor of both mTOR complex 1 and 2]) altered the composition of the gut microbiota in mice. Oral administration of resveratrol prevented glucose intolerance and fat accumulation in HFD-fed mice, whereas rapamycin significantly impaired glucose tolerance and exacerbated intestinal inflammation. The abundance of Lactococcus, Clostridium XI, Oscillibacter, and Hydrogenoanaerobacterium increased under the HFD condition; however, the abundance of these species declined after resveratrol treatment. Conversely, the abundance of unclassified Marinilabiliaceae and Turicibacter decreased in response to a HFD or rapamycin. Taken together, these results demonstrated that changes in the composition of intestinal microbiota induced by changes in mTOR activity correlate with obese and diabetic phenotypes.

Topics: Animals; Bacteria; Blood Glucose; Clostridium; Diet, High-Fat; Gastrointestinal Microbiome; Glucose Intolerance; Glucose Tolerance Test; Insulin; Intestines; Lactococcus; Male; Mechanistic Target of Rapamycin Complex 1; Mechanistic Target of Rapamycin Complex 2; Mice; Mice, Inbred C57BL; Obesity; Resveratrol; Signal Transduction; Sirolimus; Stilbenes

Nicotinamide (NAM), or vitamin B3, is an essential coenzyme for ATP synthesis and an inhibitor of sirtuin 1. Recently, conflicting results were reported regarding the treatment of NAM in type 2 diabetes and obesity. The aim of this study was to determine whether and how long-term treatment with NAM at lower dose would affect insulin sensitivity in mice fed chow diet. We treated mice with NAM (100 mg/kg/day) and normal chow for 8 weeks. Strikingly, NAM induced glucose intolerance and skeletal muscle lipid accumulation in nonobese mice. NAM impaired mitochondrial respiration capacity and energy production in skeletal muscle, in combination with increased expression of the mediators for mitophagy (p62, PINK1, PARK2 and NIX) and autophagy (FOXO3, Bnip3, CTSL, Beclin1 and LC-3b). Next, we treated mice with high-fat diet (HFD) and resveratrol (RSV; 100 mg/kg/day) for 8 weeks. RSV protected against HFD-induced insulin resistance and obesity. HFD increased skeletal muscle lipid content as well as NAM, but this increase was attenuated by RSV. In contrast to NAM, HFD enhanced fatty acid oxidative capacity. Muscle transcript levels of genes for mitophagy and autophagy were largely suppressed by HFD, whereas RSV did not rescue these effects. These differences suggest that skeletal muscle autophagy may represent adaptive response to NAM-induced lipotoxicity, whereas reduced autophagy in skeletal muscle may promote HFD-induced lipotoxicity. Our results demonstrate that chronic NAM supplementation in healthy individuals, although at lower dose than previously reported, is still detrimental to glucose homeostasis and skeletal muscle lipid metabolism.

Topics: Animals; Antioxidants; Autophagy; Diet, High-Fat; Dietary Supplements; Gene Expression Regulation; Glucose Intolerance; Histone Deacetylase Inhibitors; Insulin Resistance; Lipid Metabolism; Male; Mice, Inbred C57BL; Mitophagy; Muscle Proteins; Muscle, Skeletal; Niacinamide; Obesity; Resveratrol; Sirtuin 1; Stilbenes; Time Factors

Catch up growth (CUG) motivated by under-nutrition can lead to insulin resistance (IR) and visceral fat over-accumulation. However, the precise mechanisms on IR induced by adipose tissue changes during CUG remain unresolved.. Experimental rats were divided into three groups: normal chow group, catch up growth group and resveratrol administrated group. The whole experiment was carried out in four stages: 4, 6, 8 and 12 weeks. Peroxisome-proliferator activated receptor gamma (PPAR-γ) and fat-specific protein 27 (FSP27) expression level in epididymal adipose tissues (EAT) and subcutaneous adipose tissues (SAT) were detected along with other IR indicators.. Calorie restriction (CR) significantly increased PPAR-γ expression in EAT while decreased FSP27 expression. During re-feeding, both of the expression of PPAR-γ and FSP27 increased, even FSP27 returned to normal level when CUG for 4 weeks. Although PPAR-γ expression declined slightly at 8 weeks, it was still much stronger than normal chow groups. However, no changes were seen in SAT. Relative insufficiency of FSP27 expression in EAT results in a decrease in lipid storage capacity, causing a series of path physiological changes that led to the formation of IR. Resveratrol inhibited the expression of PPAR-γ and promoted FSP27 expression, thus fundamentally improving IR.. The imbalance between adipose synthesis and storage mediated by PPAR-γ / FSP27 in the EAT plays a pivotal role in the formation of IR during CUG. Resveratrol can correct fat formation and storage imbalance status by up-regulating FSP27 and down-regulating PPAR-γ expression level, ameliorating insulin sensitivity.

Topics: Adipocytes; Adipose Tissue; Animals; Apoptosis Regulatory Proteins; Caloric Restriction; Energy Intake; Epididymis; Epididymitis; Gene Expression Regulation; Humans; Insulin Resistance; Intra-Abdominal Fat; Male; Obesity; PPAR gamma; Proteins; Rats; Resveratrol; Stilbenes; Subcutaneous Fat

Male infertility is a complex, multifactorial and polygenic disease that contributes to ~50% cases of infertility. Previous studies have demonstrated that excess weight and obesity factors serve an important role in the development of male infertility. An increasing number of studies have reported that resveratrol may regulate the response of cells to specific stimuli that induce cell injury, as well as decrease germ cell apoptosis in mice or rats. In the present study, the semen quality and serum sex hormone levels were evaluated in 324 men, which included 73 underweight, 82 normal weight, 95 overweight and 74 obese men. All patients were referred to The Reproductive Medicine Center of Shanxi Women and Infants Hospital (Taiyuan, China) between January 2013 and January 2015. The aim of the present study was to investigate the effects of resveratrol treatment on the motility, plasma zinc concentration and acrosin activity of sperm from obese males. The sperm concentration, normal sperm morphology, semen volumes, DNA fragmentation rates and testosterone levels in men from the overweight and obese groups were markedly decreased when compared with men in the normal weight group. In addition, the progressive motility, seminal plasma zinc concentration and spermatozoa acrosin activity were notably decreased in the obese group compared with the normal weight group. However, estradiol levels were significantly increased in the overweight, obese and underweight groups compared with the normal weight group. Notably, semen samples from obese males with astenospermia treated with 0‑100 µmol/l resveratrol for 30 min demonstrated varying degrees of improvement in sperm motility. When these semen samples were treated with 30 µmol/l resveratrol, sperm motility improved when compared to other doses of resveratrol. Therefore, 30 µmol/l resveratrol was selected for further experiments. Upon treatment of semen samples with resveratrol (30 µmol/l) for 30 min, the seminal plasma zinc concentration and spermatozoa acrosin activity increased significantly in the experimental group compared with the control group. These data suggest that male obesity negatively impacts on male reproductive potential, not only through altering hormone levels, but also by directly altering sperm function. In addition, resveratrol may have a therapeutic and protective effect against obesity-induced abnormalities in semen.

Topics: Acrosin; Adult; Cell Survival; Cytoplasm; Gonadal Steroid Hormones; Humans; Infertility, Male; Male; Obesity; Overweight; Protective Agents; Resveratrol; Semen Analysis; Spermatozoa; Stilbenes; Zinc

Obesity is a global health concern. Piceatannol (Pic), an analog of resveratrol (Res), has many reported biological activities. In this study, we investigated the anti-obesity effect of Pic in a high-fat diet (HFD)-induced obese animal model. The results showed that Pic significantly reduced mouse body weight in a dose-dependent manner without affecting food intake. Serum total cholesterol (TC), low-density lipoprotein (LDL), high-density lipoprotein (HDL) levels, and blood glucose (GLU) were significantly lowered in Pic-treated groups. Pic significantly decreased the weight of liver, spleen, perigonadal and retroperitoneal fat compared with the HFD group. Pic significantly reduced the adipocyte cell size of perigonadal fat and decreased the weight of liver. Pic-treated mice showed higher phosphorylated adenosine 5'-monophosphate-activated protein kinase (pAMPK) and phosphorylated acetyl-CoA carboxylase (pACC) protein levels and decreased protein levels of CCAAT/enhancer-binding protein C/EBPα, peroxisome proliferator-activated receptor PPARγ and fatty acid synthase (FAS), resulting in decreased lipid accumulation in adipocytes and the liver. Pic altered the composition of the gut microbiota by increasing Firmicutes and

Topics: Adipogenesis; Animals; Anti-Obesity Agents; Body Weight; Cholesterol; Diet, High-Fat; Disease Models, Animal; Dose-Response Relationship, Drug; Eating; Gastrointestinal Microbiome; Gene Expression Regulation; Lipoproteins, HDL; Lipoproteins, LDL; Mice; Mice, Inbred C57BL; Obesity; Organ Size; Stilbenes

In recent years, much attention has been paid by the scientific community to phenolic compounds as active biomolecules naturally present in foods. Pterostilbene is a resveratrol dimethylether derivative which shows higher bioavailability. The aim of the present study was to analyze the effect of pterostilbene on brown adipose tissue thermogenic markers in a model of genetic obesity, which shows reduced thermogenesis. The experiment was conducted with 30 Zucker (fa/fa) rats that were distributed in three experimental groups: control and two groups orally administered with pterostilbene at 15 and 30 mg/kg body weight/day for 6 weeks. Gene expression of uncoupling protein 1 (Ucp1), peroxisome proliferator-activated receptor γ co-activator 1 α (Pgc-1α), carnitine palmitoyl transferase 1b (Cpt1b), peroxisome proliferator-activated receptor α (Pparα), nuclear respiratory factor 1 (Nfr1), and cyclooxygenase-2 (Cox-2); protein expression of PPARα, PGC-1α, p38 mitogen-activated protein kinase (p38 MAPK), UCP1 and glucose transporter (GLUT4); and enzyme activity of CPT 1b and citrate synthase (CS) were assessed in interscapular brown adipose tissue. With the exception of Pgc-1α expression, all these parameters were significantly increased by pterostilbene administration. These results show for the first time that pterostilbene increases thermogenic and oxidative capacity of brown adipose tissue in obese rats. Whether these effects effectively contribute to the antiobesity properties of these compound needs further research.

Topics: Adipose Tissue, Brown; Adipose Tissue, White; Animals; Anti-Obesity Agents; Drug Evaluation, Preclinical; Energy Intake; Gene Expression; Male; Obesity; Organ Size; Rats, Zucker; Stilbenes; Thermogenesis

The detrimental effects on Leydig cells steroidogenesis in mice on high-calorie and high-cholesterol diet (HCD) were determined, and the possible protection conferred by resveratrol supplementation was investigated. Male C57BL/6J mice were fed high-calorie and alone (HCD group) or with resveratrol supplementation (HCD + Res group) for 18 weeks. Male C57BL/6J mice fed standard diet without or with the same dose of resveratrol served as controls. At the end of the experiment, there were significant declines of serum testosterone and luteinising hormone (LH) in HCD group as compared to controls. In line with the hormone alterations, the expressions of StAR and steroidogenic enzymes in testicular tissues were significantly down-regulated in HCD group. Resveratrol supplementation could significantly improve expressions of StAR and steroidogenic enzymes, and increase serum testosterone and LH concentrations in HCD + Res group. Mice in HCD group also showed a statistically significant down-regulation in the mRNA expressions of MnSOD and GPx4. Resveratrol supplementation improved testicular MnSOD and GPx4 expression in comparison with HCD group. We propose that resveratrol may attenuate detrimental effects on Leydig cells steroidogenesis in HCD-fed mice, and its upregulations of antioxidant defence mechanisms and LH level may play a role in its protection. Our data suggest resveratrol appears to have the potential for therapeutic approaches targeting male obesity-associated secondary hypogonadism.

Topics: Animals; Antioxidants; Cholesterol; Diet; Energy Intake; Glutathione Peroxidase; Leydig Cells; Male; Mice; Obesity; Oxidative Stress; Phospholipid Hydroperoxide Glutathione Peroxidase; Phosphoproteins; Resveratrol; RNA, Messenger; Stilbenes; Superoxide Dismutase; Testis; Testosterone

Sleep fragmentation (SF) increases food intake and the risk of obesity, and recruits macrophages to visceral white adipose tissue (VWAT) promoting tissue inflammation and insulin resistance. Administration of resveratrol (Resv) has been associated with significant improvements in high-fat diet-induced obesity, inflammation and insulin resistance.. Male mice were subjected to SF or sleep control conditions for 8 weeks, and treated with either Resv or vehicle (Veh). Fasting plasma levels of glucose, insulin and leptin were obtained and VWAT insulin sensitivity tests were performed (phosphorylated AKT/total AKT), along with flow-cytometric assessments for VWAT macrophages (M1 and M2) and T-cell lymphocytes (CD4+, CD8+ and T regulatory cell (Treg)).. SF-Veh and SF-Resv mice showed increased food consumption and weight gain. However, although SF-Veh mice exhibited increased fasting insulin and leptin levels, and reduced VWAT p-AKT/AKT responses to insulin, such alterations were abrogated in SF-Resv-treated mice. Increases in M1, reduced M2 counts and increased tumor necrosis factor-α release emerged in SF-Veh macrophages compared with all other three groups. Similarly, increased CD8+ and reduced Treg lymphocyte counts were apparent in SF-Veh.. Resveratrol does not reverse the SF-induced increases in food intake and weight gain, but markedly attenuates VWAT inflammation and insulin resistance, thereby providing a potentially useful adjunctive therapy in the context of sleep disorders manifesting metabolic morbidity.

Topics: Animals; Anti-Obesity Agents; Diet, High-Fat; Disease Models, Animal; Eating; Inflammation; Insulin Resistance; Intra-Abdominal Fat; Male; Mice; Mice, Inbred C57BL; Obesity; Resveratrol; Sleep Apnea Syndromes; Stilbenes; Tumor Necrosis Factor-alpha; Weight Gain

Diet-induced obesity is associated to an imbalance in the normal gut microbiota composition. Resveratrol and quercetin, widely known for their health beneficial properties, have low bioavailability, and when they reach the colon, they are targets of the gut microbial ecosystem. Hence, the use of these molecules in obesity might be considered as a potential strategy to modulate intestinal bacterial composition. The purpose of this study was to determine whether trans-resveratrol and quercetin administration could counteract gut microbiota dysbiosis produced by high-fat sucrose diet (HFS) and, in turn, improve gut health. Wistar rats were randomised into four groups fed an HFS diet supplemented or not with trans-resveratrol [15 mg/kg body weight (BW)/day], quercetin (30 mg/kg BW/day) or a combination of both polyphenols at those doses. Administration of both polyphenols together prevented body weight gain and reduced serum insulin levels. Moreover, individual supplementation of trans-resveratrol and quercetin effectively reduced serum insulin levels and insulin resistance. Quercetin supplementation generated a great impact on gut microbiota composition at different taxonomic levels, attenuating Firmicutes/Bacteroidetes ratio and inhibiting the growth of bacterial species previously associated to diet-induced obesity (Erysipelotrichaceae, Bacillus, Eubacterium cylindroides). Overall, the administration of quercetin was found to be effective in lessening HFS-diet-induced gut microbiota dysbiosis. In contrast, trans-resveratrol supplementation alone or in combination with quercetin scarcely modified the profile of gut bacteria but acted at the intestinal level, altering the mRNA expression of tight-junction proteins and inflammation-associated genes.

Topics: Animals; Bacillus; Bacteroidetes; Diet, High-Fat; Dietary Supplements; DNA, Bacterial; Fatty Acids, Volatile; Feces; Firmicutes; Gas Chromatography-Mass Spectrometry; Gastrointestinal Microbiome; Gastrointestinal Tract; Insulin Resistance; Obesity; Quercetin; Rats; Rats, Wistar; Resveratrol; Stilbenes; Sucrose; Weight Gain

Liver steatosis is characterized by an abnormal accumulation of triacylglycerols in this organ. This metabolic disorder is closely associated with obesity. In the present study, we aimed to analyse the effect of a combination of resveratrol and quercetin on liver steatosis in an animal model of dietetic obesity, and to compare it with one induced by the administration of each polyphenol separately. Rats were divided into four dietary groups of nine animals each and fed a high-fat, high-sucrose diet: an untreated control group and three groups treated either with resveratrol (RSV; 15 mg/kg/day), with quercetin (Q; 30 mg/kg/day), or with both (RSV + Q; 15 mg resveratrol/kg/day and 30 mg quercetin/kg/day) for 6 weeks. Liver weight and triacylglycerol content decreased only in the RSV + Q group. A significant reduction in acetyl-CoA carboxylase activity was observed in RSV and RSV + Q groups, without changes in fatty acid synthase activity. A significant increase in carnitine palmitoyltransferase-1a activity was observed only in rats treated with the combination of resveratrol and quercetin, suggesting increased fatty acid oxidation. Citrate synthase, a marker of mitochondrial density, remained unchanged in all groups. No significant changes were observed in the expression of peroxisome proliferator-activated receptor α (PPARα), nuclear respiratory factor 1 (NRF-1) and transcription factor A mitochondrial (TFAM). In conclusion, resveratrol and quercetin together, combining two doses which were shown to be ineffective singly, is an interesting tool to prevent liver steatosis associated with high-fat high-sucrose feeding. The delipidating effect seems to be mediated by increased fatty acid oxidation not associated with increased mitochondriogenesis, and by reduced de novo lipogenesis.

Topics: Alanine Transaminase; Animals; Aspartate Aminotransferases; Diet, High-Fat; Drug Evaluation, Preclinical; Energy Intake; Gene Expression; Lipid Metabolism; Liver; Male; Non-alcoholic Fatty Liver Disease; Obesity; Quercetin; Rats, Wistar; Resveratrol; Stilbenes

Resveratrol improves insulin sensitivity and lowers hepatic glucose production (HGP) in rat models of obesity and diabetes, but the underlying mechanisms for these antidiabetic effects remain elusive. One process that is considered a key feature of resveratrol action is the activation of the nicotinamide adenine dinucleotide (NAD(+))-dependent deacetylase sirtuin 1 (SIRT1) in various tissues. However, the low bioavailability of resveratrol raises questions about whether the antidiabetic effects of oral resveratrol can act directly on these tissues. We show here that acute intraduodenal infusion of resveratrol reversed a 3 d high fat diet (HFD)-induced reduction in duodenal-mucosal Sirt1 protein levels while also enhancing insulin sensitivity and lowering HGP. Further, we found that duodenum-specific knockdown of Sirt1 expression for 14 d was sufficient to induce hepatic insulin resistance in rats fed normal chow. We also found that the glucoregulatory role of duodenally acting resveratrol required activation of Sirt1 and AMP-activated protein kinase (Ampk) in this tissue to initiate a gut-brain-liver neuronal axis that improved hypothalamic insulin sensitivity and in turn, reduced HGP. In addition to the effects of duodenally acting resveratrol in an acute 3 d HFD-fed model of insulin resistance, we also found that short-term infusion of resveratrol into the duodenum lowered HGP in two other rat models of insulin resistance--a 28 d HFD-induced model of obesity and a nicotinamide (NA)-streptozotocin (STZ)-HFD-induced model of mild type 2 diabetes. Together, these studies highlight the therapeutic relevance of targeting duodenal SIRT1 to reverse insulin resistance and improve glucose homeostasis in obesity and diabetes.

Topics: Animals; Antioxidants; Blood Glucose; Diabetes Mellitus; Disease Models, Animal; Gene Expression Regulation; HEK293 Cells; Homeostasis; Humans; Insulin; Insulin Resistance; Male; Nerve Net; Neurons; Niacinamide; Obesity; Rats; Rats, Sprague-Dawley; Resveratrol; Sirtuin 1; Stilbenes; Streptozocin

Obesity, a sirtuin-1 (SIRT-1) -deficient state, increases morbidity and resource utilization in critically ill patients. SIRT-1 deficiency increases microvascular inflammation and mortality in early sepsis. The objective of the study was to study the effect of resveratrol (RSV), a SIRT-1 activator, on microvascular inflammation in obese septic mice.. ob/ob and C57Bl/6 (WT) mice were pretreated with RSV versus dimethyl sulfoxide (DMSO) (vehicle) prior to cecal ligation and puncture (sepsis). We studied (1) leukocyte/platelet adhesion, (2) E-selectin, ICAM-1, and SIRT-1 expression in small intestine, and (3) 7-day survival. A group of RSV-treated mice received SIRT-1 inhibitor (EX-527) with sepsis induction, and leukocyte/platelet adhesion and E-selectin/ICAM-1 expression were studied. We treated endothelial (HUVEC) cells with RSV to study E-selectin/ICAM-1 and p65-acetylation (AC-p65) in response to lipopolysaccharide (LPS).. RSV treatment decreased leukocyte/platelet adhesion and E-selectin/ICAM-1 expression with increased SIRT-1 expression in septic ob/ob and WT mice, decreased E-selectin/ICAM-1 expression via increased SIRT-1 expression, and decreased AC-p65 expression in HUVEC. EX-527 abolished RSV-induced attenuation of microvascular inflammation in ob/ob septic mice. Finally, ob/ob mice in the sepsis+RSV group had significantly increased 7-day survival versus the sepsis+vehicle group.. RSV increases SIRT-1 expression in ob/ob septic mice to reduce microvascular inflammation and improves survival.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Cecum; Cell Adhesion Molecules; Female; Inflammation; Intercellular Adhesion Molecule-1; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Platelet Adhesiveness; Resveratrol; Sepsis; Sirtuin 1; Stilbenes

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.

Topics: Animals; Cytokines; Diet, High-Fat; Dietary Sucrose; Dietary Supplements; Glucokinase; Glucose Transporter Type 4; Hypoglycemic Agents; Insulin Resistance; Liver; Male; Muscle, Skeletal; Obesity; Organ Specificity; Phosphorylation; Prediabetic State; Protein Processing, Post-Translational; Proto-Oncogene Proteins c-akt; Random Allocation; Rats, Wistar; Stilbenes; Up-Regulation

Melinjo (Gnetum gnemon L.) seed extracts (MSEs) are rich in resveratrol dimers (gnemonoside A, C, D, gnetin C), trans-resveratrol, and other resveratrol derivatives. trans-Resveratrol is a widely studied caloric restriction mimetic. In mice fed a high-fat diet (HFD), trans-resveratrol protects against obesity, type 2 diabetes, and premature death. Here, treatment of HFD-fed mice with 2.0% MSE significantly reduced body weight gain (p < 0.001), blood insulin (p < 0.01), and HOMA-IR (p < 0.05) after 8 weeks compared with untreated HFD-fed mice. Additionally, 0.2% MSE treatment of HFD-fed mice significantly improved physiological activity (p < 0.05) at 18 months of age and reduced risk of death due to HFD by 25% (hazard ratio = 0.75, p = 0.036). These data show that MSE can improve several aspects of metabolic syndrome and survival in mice and may have health benefits as a dietary supplement.

Topics: Animals; Diet, High-Fat; Gnetum; Insulin; Male; Mice; Mice, Inbred C57BL; Motor Activity; Obesity; Plant Extracts; Resveratrol; Seeds; Stilbenes; Survival Analysis

Ethanol extracts (Et) from the stem (S) and leaf (L) of Vitis thunbergii var. taiwaniana (VTT) were used to investigate yeast α-glucosidase and porcine kidney dipeptidyl peptidase-IV (DPP-IV) inhibitory activities. Both VTT-Et showed complete α-glucosidase inhibition at 0.1 mg/mL; VTT-S-Et and VTT-L-Et showed 26 and 11% DPP-IV inhibition, respectively, at 0.5 mg/mL. The VTT-Et interventions (20 and 50 mg/kg) resulted in improvements in impaired glucose tolerance of diet-induced obese rats. (+)-Hopeaphenol, (+)-vitisin A, and (-)-vitisin B were isolated from the ethyl acetate fractions of S-Et and showed yeast α-glucosidase inhibition (IC50 = 18.30, 1.22, and 1.02 μM) and porcine kidney DPP-IV inhibition (IC50 = 401, 90.75, and 15.3 μM) compared to acarbose (6.39 mM) and sitagliptin (47.35 nM), respectively. Both (+)-vitisin A and (-)-vitisin B showed mixed noncompetitive inhibition against yeast α-glucosidase and porcine kidney DPP-IV, respectively. These results proposed that VTT extracts might through inhibitions against α-glucosidase and DPP-IV improve the impaired glucose tolerance in diet-induced obese rats.

Topics: alpha-Glucosidases; Animals; Benzofurans; Dipeptidyl Peptidase 4; Dipeptidyl-Peptidase IV Inhibitors; Glucose Intolerance; Glycoside Hydrolase Inhibitors; Kinetics; Male; Obesity; Phenols; Plant Extracts; Plant Leaves; Rats; Rats, Wistar; Saccharomyces cerevisiae; Stilbenes; Swine; Vitis

Metabolic homeostasis is maintained by the coordinated regulation of several physiological processes and organ crosstalk. Especially, the interaction between adipose tissue and liver is critical for the regulation of glucose and lipid metabolism. This study investigated the involvement of resveratrol (RSV) in the crosstalk between adipokine adiponectin and hepatokine fetuin-A. Adipocytes-hepatocytes co-culture system and a high-fat (HF) diet-induced obesity (DIO) mouse model were utilized. Protein levels of adiponectin and fetuin-A were analyzed in adipocytes and hepatocytes with the knockdown of adiponectin and fetuin-A, respectively. After six weeks of the HF diet treatment, RSV was delivered via an osmotic pump for four weeks. The experimental groups were lean control fed with a standard diet, HF diet-induced obese control and HF_RSV (8 mg/kg/day). After 4 weeks of each treatment, blood and tissues were collected, and the levels of adiponectin and fetuin-A were analyzed. RNA interference during co-culture of adipocytes and hepatocytes demonstrated the existence of crosstalk between adiponectin and fetuin-A. The four-week RSV treatment resulted in increased serum adiponectin and decreased serum fetuin-A in diet-induced obesity mice. The serum levels of adiponectin and fetuin-A were inversely related. In epididymal fat depots, RSV increased adiponectin, peroxisome proliferator-activated receptor (PPAR) alpha, PPAR gamma, sirtuin1 and AMP-activated protein kinase (AMPK). RSV lowered fetuin-A and NF-κB, and increased liver AMPK. These results demonstrate the crosstalk between adiponectin and fetuin-A, and suggest that RSV may be involved in adipose tissue and liver crosstalk through the interaction between adiponectin and fetuin-A.

Topics: Adipocytes; Adiponectin; alpha-2-HS-Glycoprotein; Animals; Body Weight; Coculture Techniques; Diet, High-Fat; Hepatocytes; Lipids; Liver; Male; Mice, Inbred C57BL; Obesity; Resveratrol; Stilbenes

The increasing prevalence of obesity continues to gain more attention worldwide. In this study, diet-induced obese mice were used to evaluate the antiobesity effects of extracts, fractions, and purified compounds from Vitis thunbergii var. taiwaniana (VTT). The C57BL/6J mice were fed a 5-week high-fat diet (HF) concurrently with ethanol extracts (Et-ext, 80 mg/kg) from roots (R), stems (S), and leaves (L) by oral gavage daily. Only R-Et-ext interventions showed significant weight reduction in mice compared with those in the HF group; however, mouse plasma contents of total cholesterols (TC), total triglycerides (TG) and low-density lipoproteins (LDL) of all three Et-ext intervened groups showed significant reductions compared with those in the HF group. Furthermore, intervention with the ethyl acetate-partitioned fraction (EA-fra, 60 mg/kg) from R-Et-ext but not the n-butanol-partitioned fraction or water fraction from R-Et-ext showed significant weight reduction in mice compared with those in the HF group. The same molecular weights of three resveratrol tetramers, (+)-hopeaphenol, (+)-vitisin A, and (-)-vitisin B, were isolated from the EA-fra of VTT-R. The (+)-vitisin A and fenofibrate (25 mg/kg) but not the (+)-hopeaphenol and (-)-vitisin B interventions showed significant weight reduction in mice compared with those in the HF group. The total feed intake among the HF groups with or without interventions showed no significant differences. The mouse plasma contents of TC, TG, LDL, free fatty acid, and plasma lipase activity of the three resveratrol tetramer-intervened groups showed reductions in the mice compared with those in the HF group. It was proposed that the lipase inhibitory activities of VTT extracts and purified resveratrol tetramers might contribute in part to the antiobesity effect, and these results suggested that VTT may be developed as functional food for achieving antiobesity objectives and requires further investigation.

Topics: Animals; Cholesterol; Diet, High-Fat; Lipoproteins, LDL; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Phytotherapy; Plant Extracts; Plant Leaves; Plant Stems; Resveratrol; Stilbenes; Taiwan; Triglycerides; Vitis

Red wines are thought to be one of the major dietary sources of trans-resveratrol. The beneficial effects of t-resveratrol against metabolic disorders have been well characterized, however, red wines also contain various resveratrol derivatives whose health benefits have not been completely elucidated. In this report, we investigated ε-viniferin, a resveratrol dimer, which is present at comparable concentrations to t-resveratrol in red wines, and has higher anti-adipogenesis activity in 3T3-L1 cells. In addition, ε-viniferin was more effective than t-resveratrol in its anti-obesity and anti-inflammatory effects in high-fat diet fed mice. These results suggested ε-viniferin may be one of the active ingredients against metabolic disorders in red wines, in addition to t-resveratrol.

Topics: 3T3 Cells; Adipogenesis; Animals; Anti-Obesity Agents; Benzofurans; Diet, High-Fat; Dimerization; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred C57BL; Obesity; Resveratrol; Stilbenes; Treatment Outcome

This study was performed to investigate the hypolipidemic, antiobese, and antiatherogenic effects of resveratrol in apoE-deficient mice fed an atherogenic diet (20% fat and 1% cholesterol). These animals were fed an atherogenic diet containing 0.02% lovastatin (w/w) or 0.02% resveratrol (w/w) for 12 weeks. Resveratrol and lovastatin supplementation significantly reduced either the body weight or epididymal fat weight without altering the food intake and food efficiency ratio. Resveratrol significantly decreased the plasma total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C) concentrations, apoB/apoA-I ratio, hepatic cholesterol, and triglyceride (TG) contents, whereas significantly it increased the plasma HDL-C concentration compared with the control and lovastatin groups. Plasma and hepatic TG and plasma apoB levels were significantly lower in both the lovastatin and resveratrol groups than in the control group without altering the plasma apoA-I concentration. Both resveratrol and lovastatin significantly decreased hepatic fatty acid and TG synthesis, whereas they increased fatty acid oxidation (β-oxidation) except for the carnitine palmitoyltransferase activity compared with the control group. However, there was no difference in hepatic 3-hydroxyl-3-methylglutaryl-CoA reductase activity among the groups, although hepatic acyl-CoA: cholesterol acyltransferase activity was significantly lower in the lovastatin groups than in the control group. In epididymal adipose tissue, resveratrol supplementation led to an increase in β-oxidation and decrease in TG synthesis, compared with the control group. Tissue morphology revealed that there were dramatic decreases in hepatic lipid droplets and aortic fatty streaks by resveratrol and lovastatin supplementation. This study demonstrates that resveratrol exerts not only antiobesity and hypolipidemic effects, but also protective effects for the liver and aorta through the modulation of lipid metabolism in both the liver and white adipose tissues.

Topics: Animals; Anti-Obesity Agents; Anticholesteremic Agents; Aorta; Apolipoproteins E; Arteriosclerosis; Diet, Atherogenic; Humans; Lovastatin; Male; Mice; Mice, Knockout; Obesity; Protective Agents; Resveratrol; Stilbenes

Obesity is the most prevalent disease in the world which poses a serious risk for various chronic diseases. However, currently there are not any therapeutic agents that reduce body weight without causing serious side effects. In order to prevent and/or treat obesity and related diseases through a nutraceutical approach, we created a resveratrol-enriched transgenic rice accumulating 1.4 μg/g of resveratrol in its grain, DJ-526. Feeding of mice with the resveratrol-enriched rice DJ-526 showed excellent anti-obesity effect with reduction of body weights and abdominal fat volumes compared to the control by 20.0% and 31.3%, respectively. Also, the consumption of the resveratrol-enriched rice DJ526 significantly improved the blood lipid profiles and glucose levels in the animal experiments. Our resveratrol-enriched rice DJ-526 rice could provide both safe and convenient way for people with obesity and related diseases without major change of lifestyle or unwanted side effects from medication.

Topics: Abdominal Fat; Animals; Anti-Obesity Agents; Blood Glucose; Body Weight; Chromatography, High Pressure Liquid; Female; Lipids; Mice; Mice, Inbred C57BL; Obesity; Oryza; Plants, Genetically Modified; Resveratrol; Stilbenes

This study was designed to investigate the effects of bilateral ovariectomy and fructose diet on obesity-related metabolic parameters in female rats. The potential of resveratrol, alone and in combination with melatonin, to counter ensuing obesity and precipitated metabolic disturbances was explored.. Eight-week-old female Sprague-Dawley rats were subjected to bilateral ovariectomy (OVX) or sham operation and randomly assigned to standard diet (SD) or fructose diet (FD) groups (n = 6 rats per group) as follows: Sham; OVX + FD; OVX + SD; OVX + FD + resveratrol 50 mg/kg/day PO (RESV); OVX + SD + RESV; OVX + FD + melatonin 3 mg/kg/day PO in drinking water (M); OVX + SD + M; OVX + FD + RESV + M; OVX + SD + RESV + M. All treatments were given for 7 weeks. Biochemical, dietary, and anthropometrical parameters were estimated, and abdominal fat pads and the liver were examined for histopathological alterations.. Ovariectomy caused an increase in body weight, body mass index, feed efficiency, serum glucose, cholesterol, triglycerides, and free fatty acids, which was further exacerbated by fructose diet. These parameters were significantly decreased by resveratrol, alone and in combination with melatonin. Histopathological examination revealed reduced hypertrophy of adipocytes in adipose tissue and reduced macrophage infiltration in the liver.. Resveratrol/melatonin combination effectively normalizes anthropometrical, biochemical, and histopathological parameters in ovariectomized rats with fructose diet-induced obesity and associated metabolic alterations. The combination should be explored for potential benefits in postmenopausal women.

Topics: Administration, Oral; Animals; Antioxidants; Diabetes Mellitus; Diet; Disease Models, Animal; Female; Fructose; Melatonin; Obesity; Ovariectomy; Random Allocation; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes

Resveratrol inhibits lipid accumulation but suffers from limited bioavailability. The anti-depressive agent phenelzine limits adipogenesis in various models of cultured preadipocytes, and this hydrazine derivative also inhibits de novo lipogenesis in mature adipocytes. It was therefore tested whether resveratrol effects on adiposity reduction and glucose tolerance improvement could be reinforced by co-administration with phenelzine.. Mice fed a very-high-fat diet (VHFD, 60% calories as fat) were subjected to drinking solution containing low dose of resveratrol (0.003%) and/or 0.02% phenelzine for 12 weeks. Body fat content, glucose tolerance, food and water consumption were checked during treatment while fat depot mass was determined at the end of supplementation. Direct influence of the agents on lipogenesis and glucose uptake was tested in adipocytes.. Epididymal fat depots were reduced in mice drinking phenelzine alone or with resveratrol. No limitation of body weight gain or body fat content was observed in the groups drinking resveratrol or phenelzine, separately or in combination. The altered glucose tolerance and the increased fat body composition of VHFD-fed mice were not reversed by resveratrol and/or phenelzine. Such lack of potentiation between resveratrol and phenelzine prompted us to verify in vitro their direct effects on mouse adipocytes. Both molecules inhibited de novo lipogenesis, but did not potentiate each other at 10 or 100 μM. Only resveratrol inhibited hexose uptake in a manner that was not improved by phenelzine.. Phenelzine has no interest to be combined with low doses of resveratrol for treating/preventing obesity, when considering the VHFD mouse model.

Topics: Adipocytes; Adipogenesis; Animals; Blood Glucose; Body Composition; Diet, High-Fat; Dose-Response Relationship, Drug; Drinking Water; Glucose Tolerance Test; Lipogenesis; Male; Mice; Mice, Inbred C57BL; Obesity; Phenelzine; Resveratrol; Stilbenes; Weight Gain

Dysregulation of lipid homeostasis is intimately associated with obesity, type 2 diabetes, and cardiovascular diseases. Sterol regulatory-element binding proteins (SREBPs) are the master regulators of lipid biosynthesis. Previous studies have shown that the conserved transcriptional cofactor Mediator complex is critically required for the SREBP transcriptional activity, and recruitment of the Mediator complex to the SREBP transactivation domains (TADs) is through the MED15-KIX domain. Recently, we have synthesized several boron-containing small molecules. Among these novel compounds, BF175 can specifically block the binding of MED15-KIX to SREBP1a-TAD in vitro, resulting in an inhibition of the SREBP transcriptional activity and a decrease of SREBP target gene expression in cultured hepatocytes. Furthermore, BF175 can improve lipid homeostasis in the mouse model of diet-induced obesity. Compared with the control, BF175 treatment decreased the expression of SREBP target genes in mouse livers and decreased hepatic and blood levels of lipids. These results suggest that blocking the interaction between SREBP-TADs and the Mediator complex by small molecules may represent a novel approach for treating diseases with aberrant lipid homeostasis.

Topics: Animals; Boron Compounds; Boronic Acids; Cells, Cultured; Diet; Drosophila melanogaster; Drug Evaluation, Preclinical; HEK293 Cells; Hep G2 Cells; Homeostasis; Humans; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Obesity; Rats; Sterol Regulatory Element Binding Proteins; Stilbenes; Transcriptional Activation

Angiotensin-(1-7) and resveratrol have been described as new potential therapeutic tools on treating and preventing metabolic disorders. In the present study we aimed to evaluate the effect of an oral formulation of angiotensin-(1-7) [Ang-(1-7)] included in HPB-cyclodextrin and resveratrol (RSV), in modulation of sirtuin and renin-angiotensin system (RAS) in adipose tissue of mice treated with a high-fat diet (HFD). We observed that HFD+Ang-(1-7) and HFD+RSV groups presented marked decrease in the adipose tissue mass. Furthermore, these animals showed improved insulin-sensitivity and glucose tolerance as well as lower plasma levels of fasting glucose and lipids. The RT-PCR analysis revealed decreased expression of ACE and an increase of ACE2 [Ang-(1-7) marker] in group treated with resveratrol and also an increased expression of SIRT1 in groups that received Ang-(1-7). We showed for the first time that improved metabolic profile is associated with increased expression of GLUT4 and high expression of AMPK/FOXO1/PPAR-γ pathway in adipose-tissue. Finally, adipocyte primary cell-culture incubated with and without sirtuin and Ang-(1-7)/Mas antagonists pointed out for a cross-talking between RAS and sirtuins. We conclude that oral administration of Ang-(1-7) and RSV improved metabolic profile through a cross-modulation between RAS and Sirtuins.

Topics: Administration, Oral; Angiotensin I; Animals; Antimetabolites; Cells, Cultured; Diet, High-Fat; Drug Evaluation, Preclinical; Gene Expression; Glucose Intolerance; Hyperinsulinism; Insulin Resistance; Intra-Abdominal Fat; Lipolysis; Male; Mice; Obesity; Peptide Fragments; Primary Cell Culture; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Resistin; Resveratrol; Sirtuins; Stilbenes

Recent studies have investigated the anti-obesity effect of resveratrol, but the pathways through which resveratrol resists obesity are not clear. In the present study, we hypothesize that resveratrol exerts anti-obesity effects that are likely mediated by mechanisms of regulating gut microbes, and in turn, improving fat storage and metabolism. Gut microbes, glucose and lipid metabolism in high-fat diet (HF) mice in vivo are investigated after resveratrol treatment. Several biochemical markers are measured. Fluorescence in situ hybridization and flow cytometry are used to monitor and quantify the changes in gut microbiota. The key genes related to fat storage and metabolism in the liver and visceral adipose tissues are measured by real-time PCR. The results show that resveratrol (200 mg per kg per day) significantly lowers both body and visceral adipose weights, and reduces blood glucose and lipid levels in HF mice. Resveratrol improves the gut microbiota dysbiosis induced by the HF diet, including increasing the Bacteroidetes-to-Firmicutes ratios, significantly inhibiting the growth of Enterococcus faecalis, and increasing the growth of Lactobacillus and Bifidobacterium. Furthermore, resveratrol significantly increases the fasting-induced adipose factor (Fiaf, a key gene negatively regulated by intestinal microbes) expression in the intestine. Resveratrol significantly decreases mRNA expression of Lpl, Scd1, Ppar-γ, Acc1, and Fas related to fatty acids synthesis, adipogenesis and lipogenesis, which may be driven by increased Fiaf expression. The Pearson's correlation coefficient shows that there is a negative correlation between the body weight and the ratios of Bacteroidetes-to-Firmicutes. Therefore, resveratrol mediates the composition of gut microbes, and in turn, through the Fiaf signaling pathway, accelerates the development of obesity.

Topics: Acetyl-CoA Carboxylase; Adipose Tissue; Angiopoietin-Like Protein 4; Angiopoietins; Animals; Bifidobacterium; Blood Glucose; Body Weight; Diet, High-Fat; Enterococcus faecalis; fas Receptor; Gastrointestinal Tract; Lactobacillus; Lipids; Lipogenesis; Liver; Male; Mice; Microbiota; Obesity; PPAR gamma; Resveratrol; Signal Transduction; Stearoyl-CoA Desaturase; Stilbenes

Obesity is characterized by dysfunctional white adipose tissue (WAT) that ultimately may lead to metabolic diseases. Calorie restriction (CR) reduces the risk for age and obesity-associated complications. The impact of CR on obesity has been examined with human intervention studies, which showed alterations in circulating adipokines. However, a direct effect of CR on the human adipocyte secretome remains elusive. Therefore, the effect of a 96h low glucose CR on the secretion profile of in vitro cultured mature human SGBS adipocytes was investigated by using proteomics technology. Low-glucose CR decreased the adipocyte triglyceride contents and resulted in an altered secretion profile. Changes in the secretome indicated an improved inflammatory phenotype. In addition, several adipocyte-secreted proteins related to insulin resistance showed a reversed expression after low-glucose CR. Furthermore, 6 novel CR-regulated adipocyte-secreted proteins were identified. Since resveratrol (RSV) mimics CR we compared results from this study with data from our previous RSV study on the SGBS adipocyte secretome. The CR and RSV adipocyte secretomes partly differed from each other, although both treatment strategies lead to secretome changes indicating a less inflammatory phenotype. Furthermore, both treatments induced SIRT1 expression and resulted in a reversed expression of detrimental adipokines associated with metabolic complications.

Topics: Adipocytes; Adipokines; Adipose Tissue, White; Antioxidants; Arrhythmias, Cardiac; Caloric Restriction; Cells, Cultured; Electrophoresis, Gel, Two-Dimensional; Gene Expression Regulation; Genetic Diseases, X-Linked; Gigantism; Glucose; Heart Defects, Congenital; Humans; Insulin Resistance; Intellectual Disability; Molecular Sequence Annotation; Obesity; Proteome; Proteomics; Resveratrol; Sirtuin 1; Stilbenes; Tandem Mass Spectrometry

High-fat diet (HFD)-induced obesity is often associated with immune dysfunction. Resveratrol (trans-3,5,4'-trihydroxystilbene), which has well-founded immunity-related beneficial properties, was used to elucidate the regulatory effect on glucose metabolism and T-lymphocyte subsets in the development of HFD-induced obesity. Resveratrol, being associated with decreases of plasma leptin and plasma lipids and the release of oxidative stress, significantly decreased the body weight and fat masses in HF mice after 26 weeks of feeding. Furthermore, resveratrol decreased the fasting blood glucose and fasting plasma insulin and increased the CD3(+)CD4(+)/CD3(+)CD8(+) subsets percentages and the regulatory T cells (Tregs) production after 13 and 26 weeks of feeding. The results indicate that resveratrol, as an effective supplement for HFD, maintained glucose homeostasis by activating the PI3K and SIRT1 signaling pathways. Moreover, resveratrol activated the Nrf2 signaling pathway-mediated antioxidant enzyme expression to alleviate inflammation by protecting against oxidative damage and T-lymphocyte subset-related chronic inflammatory response in the development of HFD-induced obesity.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Blood Glucose; Body Weight; Diet, High-Fat; Fasting; Female; Inflammation; Insulin; Leptin; Mice; Mice, Inbred C57BL; NF-E2-Related Factor 2; Obesity; Oxidative Stress; Phosphatidylinositol 3-Kinases; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes; T-Lymphocyte Subsets

We have previously shown that early weaning in rats increases the risk of obesity and insulin resistance at adulthood, and leptin resistance can be a prime factor leading to these changes. Resveratrol is reported to decrease oxidative stress, insulin resistance, and cardiovascular risk. However, there is no report about its effect on leptin resistance. Thus, in this study we have evaluated resveratrol-preventing effect on the development of visceral obesity, insulin, and leptin resistance in rats programmed by early weaning. To induce early weaning, lactating dams were separated into 2 groups: early weaning (EW)--dams were wrapped with a bandage to interrupt lactation in the last 3 days of lactation and control (C)--dams whose pups had free access to milk during throughout lactation period (21 days). At 150 days-old, EW offspring were subdivided into 2 groups: EW+res--treated with resveratrol solution (30 mg/kg BW/day) or EW--receiving equal volume of vehicle solution, both given by gavage during 30 days. Control group received vehicle solution. Resveratrol prevented the higher body weight, hyperphagia, visceral obesity, hyperleptinemia, hyperglycemia, insulin resistance, and hypoadiponectinemia at adulthood in animals that were early weaned. Leptin resistance, associated with lower JAK2 and pSTAT3 and higher NPY in hypothalamus of EW rats were also normalized by resveratrol. The present results suggest that resveratrol is useful as therapeutic tool in treating obesity, mainly because it prevents the development of central leptin resistance.

Topics: Animals; Female; Humans; Insulin; Janus Kinase 2; Lactation; Leptin; Male; Obesity; Rats; Rats, Wistar; Resveratrol; Stilbenes; Weaning

Growth hormone (GH) secretion is reduced in obesity, despite normal serum insulin-like growth factor I (IGF-1) levels, but the association between obesity and the GH signaling is unknown. Furthermore, SIRT1, an nicotinamide adenine dinucleotide-dependent protein deacetylase, reduces hepatic IGF-1 production in mice via blunting of GH-induced STAT5 signaling.. To study GH signaling in muscle and fat in obese subjects and the interaction with concomitant administration of the putative SIRT1 activator resveratrol, and to assess the effects of inhibiting or knocking down SIRT1 on GH regulated genes in vitro.. Twenty-four obese males were examined in a randomized, double blinded, parallel-group study with resveratrol or placebo treatment for 5 weeks followed by a GH bolus. Muscle and fat biopsies were collected before and after GH. Body composition was assessed by DEXA and MRI.. (1) Effect of body composition and age on GH-stimulated STAT5b phosphorylation and IGF-1, SOCS2, and CISH mRNA in muscle and fat. (2) The impact of resveratrol treatment on GH activity. (3) Impact of inhibiting or knocking down SIRT1 on effects of GH in vitro.. Significant GH-induced STAT5b phosphorylation in muscle and fat in obese subjects was recorded together with increased CISH and SOCS2 mRNA. GH-induced STAT5b phosphorylation in muscle correlated positively with age [r = 0.53, p < 0.01], but not with body composition. Resveratrol administration had no impact on body composition, serum IGF-1, or GH signaling in vivo, and SIRT1 knock down or inhibition did not affect GH signaling in vitro.. (1) GH induced STAT5b phosphorylation is detectable in muscle and fat in adult males with simple obesity, but is not determined by body composition. (2) Resveratrol supplementation does not impact circulating IGF-1 levels or GH signaling in human muscle and fat. (3) Our data speak against a major impact of SIRT1on GH action in human subjects.

Topics: 3T3-L1 Cells; Adipose Tissue; Animals; Antioxidants; Body Composition; Double-Blind Method; Human Growth Hormone; Mice; Muscles; Obesity; Resveratrol; Signal Transduction; Sirtuin 1; STAT5 Transcription Factor; Stilbenes

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.

Topics: Acetyl-CoA Carboxylase; Animals; Diet, High-Fat; Fats; Fatty Acid Synthases; Fatty Acids; Humans; Insulin; Liver; Male; Mice; Obesity; Rats; Rats, Wistar; Stilbenes

We aimed to evaluate the in vitro effects of yerba maté, YGD (a herbal preparation containing yerba maté, guarana and damiana), and resveratrol on adipogenesis. The anti-adipogenic effects of yerba mate, YGD, resveratrol and YGD + resveratrol and yerba mate + resveratrol combinations were evaluated in 3T3-L1 cells by Oil Red staining, cellular triglyceride content, and PCR quantitative array. The results demonstrated that all of the tested compounds inhibited adipogenesis. Yerba maté extract significantly down-regulated the expression of genes that play an important role in regulating adipogenesis, such as Adig, Axin, Cebpa, Fgf10, Lep, Lpl, and Pparγ2. In addition, these genes, YGD also repressed Bmp2, Ccnd1, Fasn, and Srebf1. Resveratrol also modulated the expression of Adig, Bmp2, Ccnd1, C/EBPα, Fasn, Fgf10, Lep, Lpl, and Pparγ2. Moreover, resveratrol repressed Cebpb, Cdk4, Fgf2, and Klf15. The yerba maté extract and YGD up-regulated the expression of genes involved in inhibiting adipogenesis, such as Dlk-1, Klf2, and Ucp1. Resveratrol also induced the expression of Klf2 and Ucp1. In addition resveratrol modulated the Ddit3, Foxo1, Sirt1, and Sirt2. The combined effects of these compounds on gene expression showed similar results observed from individual treatments. Our data indicates that the synergy between the compounds favors the inhibition of adipogenesis.

Topics: 3T3-L1 Cells; Adipogenesis; Animals; Antioxidants; Biomarkers, Tumor; Blotting, Western; Cell Differentiation; Cell Proliferation; Drug Combinations; Gene Expression Profiling; Gene Expression Regulation; Ilex paraguariensis; Mice; Obesity; Oligonucleotide Array Sequence Analysis; Plant Extracts; Real-Time Polymerase Chain Reaction; Resveratrol; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Stilbenes

The effect of the intake of antioxidant polyphenols such as resveratrol and others on survival and different parameters of life quality has been a matter of debate in the last years. We have studied here the effects of the polyphenols resveratrol and kaempferol added to the diet in a murine model undergoing long-term hypercaloric diet. Using 50 mice for each condition, we have monitored weight, survival, biochemical parameters such as blood glucose, insulin, cholesterol, triglycerides and aspartate aminotransferase, neuromuscular coordination measured with the rotarod test and morphological aspect of stained sections of liver and heart histological samples. Our data show that mice fed since they are 3-months-old with hypercaloric diet supplemented with any of these polyphenols reduced their weight by about 5-7% with respect to the controls fed only with hypercaloric diet. We also observed that mice fed with any of the polyphenols had reduced levels of glucose, insulin and cholesterol, and better marks in the rotarod test, but only after 1 year of treatment, that is, during senescence. No effect was observed in the rest of the parameters studied. Furthermore, although treatment with hypercaloric diets induced large changes in the pattern of gene expression in liver, we found no significant changes in gene expression induced by the presence of any of the polyphenols. Thus, our data indicate that addition of resveratrol or kaempferol to mice food produces an initial decrease in weight in mice subjected to hypercaloric diet, but beneficial effects in other parameters such as blood glucose, insulin and cholesterol, and neuromuscular coordination, only appear after prolonged treatments.

Topics: Alanine Transaminase; Animals; Blood Glucose; Body Weight; Cholesterol; Gene Expression Regulation; Insulin; Kaempferols; Liver; Male; Mice, Inbred C57BL; Obesity; Resveratrol; Rotarod Performance Test; Stilbenes; Survival Rate; Triglycerides

Topics: Antioxidants; Body Composition; Humans; Insulin Resistance; Male; Obesity; Resveratrol; Stilbenes

The exact mechanisms of the relationship between obesity and cardiovascular events are not yet fully understood; however, oxidative stress may be involved. Thus, the aim of the present study was to evaluate the effects of resveratrol and fish oil on catecholamine-induced mortality in obese rats. To begin with, rats were divided into five groups: (1) lean, (2) obese, (3) obese supplemented with resveratrol, (4) obese supplemented with fish oil and (5) obese supplemented with resveratrol and fish oil (n 18 rats per group), for 2 months. After supplementation, the groups were subdivided as with (n 10) and without (n 8) cardiovascular catecholaminergic stress after isoproterenol (60 mg/kg) injection. At 24 h later, the survival rate was analysed. The obese group showed lower survival rates (10 %) when compared with the lean group (70 %). On the other hand, resveratrol (50 %) and fish oil (40 %) increased the survival rate of obese rats (χ(2) test, P= 0·019). Biochemical analyses of the myocardium and aorta revealed that obese rats had higher levels of superoxide and oxidative damage to lipids and protein. This was associated with reduced superoxide dismutase and glutathione peroxidase activity in both the myocardium and aorta. The supplementation increased antioxidant enzyme activities and reduced oxidative damage. We also evaluated the nuclear factor-erythroid 2 p45-related factor 2 (Nrf2)/Kelch-like ECH-associated protein 1 antioxidant pathway. Nrf2 protein levels that were reduced in obese rats were increased by the antioxidant treatment. Taken together, these results showed that resveratrol and fish oil reduce catecholamine-induced mortality in obese rats, partly through the reduction of oxidative stress.

Topics: Animals; Antioxidants; Aorta; Catecholamines; Dietary Fats; Dietary Supplements; Fish Oils; Isoproterenol; Male; Microfilament Proteins; Myocardium; NF-E2-Related Factor 2; Obesity; Oxidative Stress; Rats; Rats, Wistar; Resveratrol; Stilbenes

Obesity is associated with an increased risk of infectious diseases. It has been shown to have deleterious effects on cell-mediated immunity, including reducing thymocyte numbers and altering responses of thymocytes to pathogens. In the current study, we examined the efficacy of the antiobesity phytochemical resveratrol in preventing the deleterious effects of a high-fat diet on thymic anatomy and function. Compared to C57Bl/6 male mice fed a low-fat diet, mice on a high-fat diet had a significant increase in thymic weight and lipid content, and a disrupted anatomy, including a reduction of the medullary compartment and absence of a corticomedullary junction. There were a decrease in thymic cellularity and mature T-cell output, and a disrupted T-cell maturation, as evidenced by increased double-negative and decreased single- and double-positive thymocytes. Mice that had been fed resveratrol along with a high-fat diet had a dose-dependent reversal in all these parameters. Western blots from thymi showed that obese mice had lower levels of the key stimulators of lipid metabolism, phospho-5' adenosine monophosphate-activated protein kinase and its downstream target, carnitine palmitoyl transferase-1; this was restored to normal levels in resveratrol-fed mice. Resveratrol also reversed an increase in glycerol-3-phosphate acyltransferase-1, the enzyme that catalyzes the first step in triglycerol synthesis. Taken together, these results indicate that resveratrol is a potent inhibitor of the deleterious effects of diet-induced obesity on thymic anatomy and function, and this may hold promise in preventing obesity-related deficits in cell-mediated immunity.

Topics: Adipose Tissue; Animals; Anti-Obesity Agents; Body Weight; Carnitine O-Palmitoyltransferase; Diet, High-Fat; Dose-Response Relationship, Drug; Lipid Metabolism; Male; Mice; Mice, Inbred C57BL; Obesity; Organ Size; Resveratrol; Stilbenes; T-Lymphocytes; Thymus Gland

Resveratrol (RSV), 3,5,4'-trihydroxy-trans-stilbene, is known to have many beneficial physiological activities. We have synthesized several stilbene analogues and have reported that the hydroxyl group in the 4' position of RSV exhibited strong radical scavenging action. Using stilbene analogs, we investigated the structure of RSV to explain its protective effect against obesity and type 2 diabetes. All six analogs used in this study inhibited the differentiation of 3T3-L1 adipocytes. 3-Hydroxy-trans stilbene (3(OH)ST), and 3,4'-dihydroxy-trans stilbene (3,4'(OH)2ST) increased glucose uptake and induced adenosine monophosphate kinase (AMPK) phosphorylation in C2C12 myotubes independently of insulin. An in vivo study using mice fed high-fat diets indicated that 3(OH)ST was more effective than RSV in improving insulin resistance. In conclusion, RSV and its derivatives, particularly 3(OH)ST, inhibited adipocyte differentiation and enhanced glucose uptake in the myotubes, resulting in a reduction of obesity and an improvement in glucose tolerance in vivo.

Topics: 3T3-L1 Cells; Adipocytes; AMP-Activated Protein Kinases; Animals; Diabetes Mellitus, Type 2; Disease Models, Animal; Glucose; Humans; Insulin; Insulin Resistance; Mice; Obesity; Resveratrol; Stilbenes

Topics: Animals; Diet, High-Fat; Humans; Hyperinsulinism; Male; Obesity; Sirolimus; Stilbenes

The effect of resveratrol on thermogenesis in skeletal muscle and interscapular brown adipose tissue (IBAT) was investigated. Rats were fed an obesogenic diet supplemented with resveratrol (30mg/kg/day) or not supplemented for 6weeks. Resveratrol intake led to increased gene expression of mitochondrial-transcription-factor-A (TFAM), mitochondrial-protein-cytochrome-C-oxidase subunit-2 (COX2), sirtuin-1 (SIRT1), peroxisome-proliferator-activated-receptor-β/δ (PPARβ/δ) and proliferator-activated-receptor-gamma-coactivator1-α (PGC-1α) in IBAT and increased UCP1protein expression; however, peroxisome-proliferator-activated-receptor-α (PPARα) expression remained unchanged. In gastrocnemius muscle, resveratrol increased the gene expression of TFAM and COX2; however, no changes were observed in levels of SIRT1, PGC-1α and PPARβ/δ. Acetylated-PGC-1α was decreased in the resveratrol-treated group, indicating a higher level of activation, and a significant increase of UCP3 protein expression was observed in this group. The increases in UCP protein expression in two important thermogenic tissues after resveratrol treatment may contribute to increased whole-body energy dissipation, which may help to better understand the body-fat lowering effect of this polyphenol.

Topics: Adipose Tissue, Brown; Animals; Electron Transport Complex IV; Gene Expression Regulation; Humans; Male; Muscle, Skeletal; Obesity; PPAR alpha; Rats; Rats, Sprague-Dawley; Resveratrol; Sirtuin 1; Stilbenes; Thermogenesis

Resveratrol (RSV) is a polyphenolic compound suggested to have anti-diabetic properties. Surprisingly, little is known regarding the effects of RSV supplementation on adipose tissue (AT) metabolism in vivo. The purpose of this study was to assess the effects of RSV on mitochondrial content and respiration, glyceroneogenesis (GNG), and adiponectin secretion in adipose tissue from Zucker diabetic fatty (ZDF) rats. Five-week-old ZDF rats were fed a chow diet with (ZDF RSV) or without (ZDF chow) RSV (200 mg/kg body wt) for 6 wk. Changes in adipose tissue metabolism were assessed in subcutaneous (scAT) and intra-abdominal [retroperitoneal (rpWAT), epididymal (eWAT)] adipose tissue depots. ZDF RSV rats showed lower fasting glucose and higher circulating adiponectin, as well as lower glucose area under the curve during intraperitoneal glucose and insulin tolerance tests than ZDF chow. [¹⁴C]pyruvate incorporation into triglycerides and adiponectin secretion were higher in scAT from ZDF RSV rats, concurrent with increases in adipose tissue triglyceride lipase (ATGL), hormone-sensitive lipase (HSL), and the phosphorylation of pyruvate dehydrogenase-E1α (PDH) (Ser293) protein content in this depot. Moreover, uncoupled mitochondrial respiration and complex I and II-supported respiration were increased in both scAT and rpWAT, which correlated with increases in cytochrome c oxidase subunit IV (COX4) protein content. In vitro treatment of scAT with RSV (50 μmol/l; 24 h) induced pyruvate dehydrogenase kinase 4 (PDK4) and peroxisome proliferator-activated receptor (PPAR)-γ coactivator-1α (PGC-1α) mRNA expression. Collectively, these data demonstrate that RSV can induce adipose tissue mitochondrial biogenesis in parallel with increases in GNG and adiponectin secretion.

Topics: Adipose Tissue, White; Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Diabetes Mellitus; Dietary Supplements; Male; Obesity; Rats; Rats, Zucker; Resveratrol; Stilbenes; Treatment Outcome

Obesity is associated with a chronic, low-grade, systemic inflammation that may contribute to the development of insulin resistance and type 2 diabetes. Resveratrol, a natural compound with anti-inflammatory properties, is shown to improve glucose tolerance and insulin sensitivity in obese mice and humans. Here, we tested the effect of a 2-year resveratrol administration on proinflammatory profile and insulin resistance caused by a high-fat, high-sugar (HFS) diet in white adipose tissue (WAT) from rhesus monkeys. Resveratrol supplementation (80 and 480 mg/day for the first and second year, respectively) decreased adipocyte size, increased sirtuin 1 expression, decreased NF-κB activation, and improved insulin sensitivity in visceral, but not subcutaneous, WAT from HFS-fed animals. These effects were reproduced in 3T3-L1 adipocytes cultured in media supplemented with serum from monkeys fed HFS ± resveratrol diets. In conclusion, chronic administration of resveratrol exerts beneficial metabolic and inflammatory adaptations in visceral WAT from diet-induced obese monkeys.

Topics: Adipocytes; Adipose Tissue, White; Animals; Anti-Inflammatory Agents, Non-Steroidal; Carbohydrates; Cell Line; Diet, High-Fat; Inflammation; Insulin; Macaca mulatta; Male; Mice; NF-kappa B; Obesity; Resveratrol; Signal Transduction; Sirtuin 1; Stilbenes; Transcriptome; Viscera

Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a polyphenolic phytoalexin that exerts cardioprotective, neuroprotective, and antioxidant effects. Recently it has been shown that obesity is associated with an increase in cerebral oxidative stress levels, which may enhance neurodegeneration. The present study evaluates the neuroprotective action of resveratrol in brain of obese (ob/ob) mice. Resveratrol was administered orally at the dose of 25 mg kg(-1) body weight daily for three weeks to lean and obese mice. Resveratrol had no effect on body weight or blood glucose levels in obese mice. Lipid peroxides were significantly increased in brain of obese mice. The enzymatic antioxidants superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase, glucose-6-phosphate dehydrogenase and nonenzymatic antioxidants tocopherol, ascorbic acid, and glutathione were decreased in obese mice brain. Administration of resveratrol decreased lipid peroxide levels and upregulated the antioxidant activities in obese mice brain. Our findings indicate a neuroprotective effect of resveratrol by preventing oxidative damage in brain tissue of obese mice.

Topics: Animals; Antioxidants; Blood Glucose; Body Weight; Brain; Hydrogen Peroxide; Lipid Peroxidation; Male; Malondialdehyde; Mice; Mice, Obese; Neuroprotective Agents; Obesity; Oxidative Stress; Resveratrol; Stilbenes; Thinness

Consumption of a high-fat diet (HFD) is correlated with increased oxidative stress and chronic inflammation in many organs. Regulatory T cells (Tregs) are essential negative regulators of inflammation. We hypothesized that resveratrol (trans-3,5,4'-trihydroxystilbene) could protect against HFD-induced oxidative stress and inflammation. Therefore, we examined the effect of resveratrol on oxidative stress and the relevant peripheral immune-regulating mechanisms in HFD-induced obese (DIO) and diet-resistant mice. C57BL/6 mice were fed a normal diet and an HFD for 13 weeks. Then the experimental group was subdivided into DIO and diet-resistant groups according to their body weights, which were further supplemented with 0.03% resveratrol and 0.06% resveratrol, respectively, for an additional 13 weeks. Resveratrol prevented the accumulation of chronic oxidative stress and suppression of Tregs production in HFD mice, modulated changes of cytokines in the plasma and spleen, and decreased expressions of inflammatory mediators compared with those of the DIO group. Our results indicate that resveratrol, as a feasible effective supplement for HFD, can relieve oxidative stress, inhibit inflammatory genes expression, and increase Tregs number via aryl hydrocarbon receptor activation inhibited by HFD, especially in DIO mice.

Topics: Animals; Anti-Inflammatory Agents; Antioxidants; Body Weight; Cytokines; Diet, High-Fat; Dietary Fats; Dietary Supplements; Inflammation; Inflammation Mediators; Male; Mice; Mice, Inbred C57BL; Obesity; Oxidative Stress; Phytotherapy; Plant Extracts; Receptors, Aryl Hydrocarbon; Resveratrol; Spleen; Stilbenes; T-Lymphocytes, Regulatory

We hypothesized that resveratrol, a natural phytoalexin found in grapes, can prevent oxidative stress, obesity and its related disturbances in obese rats programmed by early weaning. Lactating Wistar rats were separated into two groups: early weaning (EW) - dams who were wrapped with a bandage to interrupt the lactation in the last 3 days of lactation; control - dams whose pups had free access to milk during all lactation. At the 150th day, EW offspring were randomly subdivided into EW+resveratrol (EW+Res) - resveratrol (30 mg/kg/day); EW+vehicle (EW) - rats that received 0.5% (w/v) aqueous methylcellulose. The control group received vehicle. Rats were treated by gavage daily for 30 days. EW offspring developed hyperphagia, higher body weight, visceral obesity, higher systolic (SBP) and diastolic blood pressure (DBP) (+15% and +20%, respectively; P<.05) and higher serum triglycerides (TG) and low-density lipoprotein but lower high-density lipoprotein (+55%, +33% and -13%, respectively; P<.05). Resveratrol normalized food intake, SBP and DBP and prevented obesity and dyslipidemia in EW+Res. EW rats had higher plasma and liver thiobarbituric-acid-reactive substances (TBARS) and lower plasma superoxide dismutase (SOD) and liver glutathione peroxidase activities (+51%, +18%, -58%, -31%, respectively; P<.05), and resveratrol normalized both plasma and liver TBARS and increased the activity of SOD and catalase in plasma. EW rats presented liver steatosis and higher liver TG, and resveratrol prevented these hepatic alterations. In conclusion, this study demonstrated a potential therapeutic use of resveratrol in preventing obesity and oxidative stress and reducing the risk of hypertension, dyslipidemia and steatosis in adult rats programmed by early weaning.

Topics: Animals; Antioxidants; Blood Glucose; Dyslipidemias; Fatty Liver; Female; Glutathione Peroxidase; Hyperphagia; Hypertension; Insulin Resistance; Liver; Obesity; Oxidative Stress; Rats; Rats, Wistar; Resveratrol; Stilbenes; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Weaning

The scientific community is on the look-out for safe biomolecules useful in the prevention of obesity and related aberrations such as fatty liver. This study analyzed the influence of resveratrol on hepatic triacylglycerol metabolism.. Male Sprague-Dawley rats were divided into control and resveratrol-treated groups (30 mg/kg of body weight per day) and fed a commercial obesogenic diet for 6 wk. Liver triacylglycerol content and the activity of carnitine palmitoyl transferase-Ia (CPT-Ia), acyl-coenzyme A oxydase (ACO), fatty acid synthase (FAS), glucose-6-phosphate dehydrogenase (G6PDH), malic enzyme (ME), acetyl-coenzyme A carboxylase (ACC), adenosine monophosphate-activated protein kinase (AMPK), and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) activation were measured. Mitochondrial protein cytochrome C oxidase subunit 2 (COXII), mitochondrial transcription factor A (TFAM), sterol regulatory element-binding protein-1c (SREBP-1c), peroxisome proliferator-activated receptor-α (PPAR-α), sirtuin-1 (SIRT1), hepatocyte nuclear factor receptor-4α (HNF-4α), and PGC-1α mRNA levels were also analyzed. Serum insulin was quantified.. Resveratrol decreased liver fat accumulation, increased CPT-Ia and ACO, and decreased ACC activities. Other lipogenic enzymes, FAS, ME, and G6PDH were not modified. The polyphenol activated AMPK and PGC-1α. The expression of SRBP-1c, PPAR-α, SIRT1, PGC-1α, HNF-4α, TFAM, and COXII was not modified. No changes in serum insulin levels were observed.. Resveratrol partly prevents the increase in liver fat accumulation induced by high-fat high-sucrose feeding by increasing fatty acid oxidation and decreasing lipogenesis. These effects are mediated by the activation of the AMPK/SIRT1 axis.

Topics: Acetylation; Acyl-CoA Oxidase; Adenylate Kinase; Adipose Tissue; Animals; Carnitine O-Palmitoyltransferase; Diet, High-Fat; Dietary Sucrose; Enzyme Activation; Fatty Acids; Lipid Metabolism; Liver; Male; Obesity; Oxidation-Reduction; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Rats; Rats, Sprague-Dawley; Resveratrol; RNA-Binding Proteins; Sirtuin 1; Stilbenes; Transcription Factors; Triglycerides

High doses of rapamycin, an antiaging agent, can prevent obesity in mice on high fat diet (HFD). Obesity is usually associated with hyperinsulinemia. Here, we showed that rapamycin given orally, at doses that did not affect weight gain in male mice on HFD, tended to decrease fasting insulin levels. Addition of resveratrol, which alone did not affect insulin levels, potentiated the effect of rapamycin, so that the combination decreased obesity and prevented hyperinsulinemia. Neither rapamycin nor resveratrol, and their combination affected fasting levels of glucose (despite lowering insulin levels), implying that the combination might prevent insulin resistance. We and others previously reported that resveratrol at high doses inhibited the mTOR (Target of Rapamycin) pathway in cell culture. Yet, as we confirmed here, this effect was observed only at super-pharmacological concentrations. At pharmacological concentrations, resveratrol did not exert 'rapamycin-like effects' on cellular senescence and did not inhibit the mTOR pathway in vitro, indicating nonoverlapping therapeutic mechanisms of actions of rapamycin and resveratrol in vivo. Although, like rapamycin, resveratrol decreased insulin-induced HIF-1-dependent transcription in cell culture, resveratrol did not inhibit mTOR at the same concentrations. Given distinct mechanisms of action of rapamycin and resveratrol at clinically relevant doses, their combination warrants further investigation as a potential antiaging, antiobesity and antidiabetic modality.

Topics: Animals; Cell Line, Tumor; Cellular Senescence; Diet, High-Fat; Humans; Hyperinsulinism; Hypoxia-Inducible Factor 1, alpha Subunit; Insulin; Insulin Resistance; Male; Mice; Obesity; Resveratrol; Sirolimus; Stilbenes; TOR Serine-Threonine Kinases; Transcription, Genetic; Weight Gain

Resveratrol (trans-3,4',5-trihydroxystilbene) is a naturally occurring phytoalexin produced by plants in response to various stresses. Several studies have shown that resveratrol is present in significant amounts in a variety of human diets, including wines, grapes, berries, and peanuts, and it possesses several beneficial health properties, such as atheroprotective, anti-obesity, anti-cancer, anti-inflammatory and antioxidant activities. In this study, we evaluated the effect of resveratrol on the pathogenesis of obesity and the metabolic profile of nutrients in non-high fat-fed obese OLETF rats.. Although lipid parameters in the serum and liver were not changed, the accumulation of abdominal white adipose tissues was markedly prevented in resveratrol diet-fed OLETF rats after 4 weeks of feeding. The results of the respiratory gas analysis indicated that dietary resveratrol induced the partial enhancement of fat metabolism and sparing actions for carbohydrate and protein at 1 week and 3 weeks of feeding in OLETF rats. Additionally, the adipose mRNA level of carnitine palmitoyltransferase in the resveratrol diet-fed OLETF rats was higher than the control rats after 4 weeks of feeding.. Our study demonstrated that dietary resveratrol can prevent obesity through a change in the metabolic profile of nutrients in obese OLETF rats.

Topics: Adipose Tissue, White; Animals; Body Weight; Carnitine O-Palmitoyltransferase; Cholesterol; Food, Formulated; Gene Expression; Glycogen; Lipid Metabolism; Liver; Male; Metabolome; Obesity; Rats; Rats, Inbred OLETF; Resveratrol; RNA, Messenger; Stilbenes; Triglycerides; Up-Regulation

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 in fa/fa Zucker 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.

Topics: Acyl-CoA Oxidase; Animals; Antioxidants; Carnitine O-Palmitoyltransferase; Dose-Response Relationship, Drug; Fatty Acids; Fatty Liver; Isoenzymes; Lipid Metabolism; Lipids; Liver; Male; Obesity; Organ Size; Oxidative Stress; Random Allocation; Rats; Rats, Zucker; Resveratrol; Stilbenes; Up-Regulation

Resveratrol (RSV) has various metabolic effects, especially with relatively high-dose therapy. However, the ability of RSV to modulate insulin signaling has not been completely evaluated. Here, we determined whether RSV alters insulin signaling in insulin-responsive cells and tissues. The effects of RSV on insulin signaling in 3T3-L1 adipocytes under both insulin-sensitive and insulin-resistant states and in insulin-sensitive tissues of high fat-fed diet-induced obese (DIO) mice were investigated. Insulin-stimulated insulin receptor substrate-1 tyrosine phosphorylation (Y612) was suppressed in RSV-treated adipocytes compared with untreated adipocytes, as was the insulin-stimulated Akt phosphorylation (Ser473). However, under an insulin-resistant condition that was made by incubating 3T3-L1 adipocytes in the conditioned medium from lipopolysaccharide-stimulated LAW264.7 cells, RSV reduced inducible nitric oxide synthase expression and IκBα protein degradation and improved insulin-stimulated Akt phosphorylation (Ser473). In DIO mice, relatively low-dose RSV (30 mg/kg daily for 2 weeks) therapy lowered fasting blood glucose level and serum insulin, increased hepatic glycogen content, and ameliorated fatty liver without change in body weight. The insulin-stimulated Akt phosphorylation was decreased in the liver and white adipose tissue of DIO mice, but it was completely normalized by RSV treatment. However, in the skeletal muscle of DIO mice, insulin signaling was not improved by RSV treatment, whereas the phosphorylation of adenosine monophosphate-activated protein kinase α (Thr172) was improved by it. Our results show that RSV enhances insulin action only under insulin-resistant conditions and suggest that the effect of RSV may depend on the type of tissue being targeted and its metabolic status.

Topics: 3T3-L1 Cells; Adipocytes; AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents; Blotting, Western; Cells, Cultured; Culture Media, Conditioned; Dietary Fats; Inflammation; Insulin; Insulin Resistance; Liver; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Phosphorylation; Real-Time Polymerase Chain Reaction; Resveratrol; Signal Transduction; Stilbenes

We hypothesized that a low-dose resveratrol will reverse cardiovascular abnormalities in rats fed a high-fat (HF) diet. Obese prone (OP) and obese resistant (OR) rats were fed an HF diet for 17 weeks; Sprague-Dawley rats fed laboratory chow served as control animals. During the last 5 weeks of study, treatment group received resveratrol daily by oral gavage at a dosage of 2.5 mg/kg body weight. Assessments included echocardiography, blood pressure, adiposity, glycemia, insulinemia, lipidemia, and inflammatory and oxidative stress markers. Body weight and adiposity were significantly higher in OP rats when compared to OR rats. Echocardiographic measurements showed prolonged isovolumic relaxation time in HF-fed OP and OR rats. Treatment with resveratrol significantly improved diastolic function in OP but not in OR rats without affecting adiposity. OP and OR rats had increased blood pressure which remained unchanged with treatment. OP rats had elevated fasting serum glucose and insulin, whereas OR rats had increased serum glucose and normal insulin concentrations. Resveratrol treatment significantly reduced serum glucose while increasing serum insulin in both OP and OR rats. Inflammatory and oxidative stress markers, serum triglycerides and low-density lipoprotein were higher in OP rats, which were significantly reduced with treatment. In conclusion, HF induced cardiac dysfunction in both OP and OR rats. Treatment reversed abnormalities in diastolic heart function associated with HF feeding in OP rats, but not in OR rats. The beneficial effects of resveratrol may be mediated through regression of hyperglycemia, oxidative stress and inflammation.

Topics: Animals; Anti-Inflammatory Agents, Non-Steroidal; Antioxidants; Biomarkers; Blood Glucose; Diet, High-Fat; Disease Resistance; Disease Susceptibility; Echocardiography; Heart; Heart Diseases; Hyperglycemia; Hyperinsulinism; Male; Obesity; Oxidative Stress; Random Allocation; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes

Resveratrol, a polyphenol in red wine, has been reported as a calorie restriction mimetic with potential antiaging and antidiabetogenic properties. It is widely consumed as a nutritional supplement, but its mechanism of action remains a mystery. Here, we report that the metabolic effects of resveratrol result from competitive inhibition of cAMP-degrading phosphodiesterases, leading to elevated cAMP levels. The resulting activation of Epac1, a cAMP effector protein, increases intracellular Ca(2+) levels and activates the CamKKβ-AMPK pathway via phospholipase C and the ryanodine receptor Ca(2+)-release channel. As a consequence, resveratrol increases NAD(+) and the activity of Sirt1. Inhibiting PDE4 with rolipram reproduces all of the metabolic benefits of resveratrol, including prevention of diet-induced obesity and an increase in mitochondrial function, physical stamina, and glucose tolerance in mice. Therefore, administration of PDE4 inhibitors may also protect against and ameliorate the symptoms of metabolic diseases associated with aging.

Topics: 3',5'-Cyclic-AMP Phosphodiesterases; Adipose Tissue, White; Aging; AMP-Activated Protein Kinase Kinases; Animals; Caloric Restriction; Cyclic Nucleotide Phosphodiesterases, Type 4; Diet; Glucose Intolerance; Guanine Nucleotide Exchange Factors; Mice; Models, Molecular; Muscle, Skeletal; NAD; Obesity; Protein Kinases; Resveratrol; Rolipram; Ryanodine Receptor Calcium Release Channel; Signal Transduction; Sirtuin 1; Stilbenes

Obesity-induced diabetes is associated with chronic inflammation and is considered a risk factor for neurodegeneration. We tested the hypothesis that an AMP-activated protein kinase activator, resveratrol (RES), which is known to exert potent anti-inflammatory effects, would attenuate peripheral and central inflammation and improve memory deficit in mice fed a high-fat diet (HFD). C57BL/6J mice were fed an HFD or an HFD supplemented with RES for 20 weeks. Metabolic parameters in serum were evaluated, and Western blot analysis and immunohistochemistry in peripheral organs and brain were completed. We used the Morris water maze test to study the role of RES on memory function in HFD-treated mice. RES treatment reduced hepatic steatosis, macrophage infiltration, and insulin resistance in HFD-fed mice. In the hippocampus of HFD-fed mice, the protein levels of tumor necrosis factor-α and Iba-1 expression were reduced by RES treatment. Choline acetyltransferase was increased, and the phosphorylation of tau was decreased in the hippocampus of HFD-fed mice upon RES treatment. In particular, we found that RES significantly improved memory deficit in HFD-fed mice. These findings indicate that RES reverses obesity-related peripheral and central inflammation and metabolic derangements and improves memory deficit in HFD-fed diabetic mice.

Topics: Adipose Tissue; Animals; Anti-Inflammatory Agents, Non-Steroidal; Diet, High-Fat; Fatty Liver; Glucose Tolerance Test; Inflammation; Insulin Resistance; Male; Maze Learning; Memory Disorders; Mice; Obesity; Resveratrol; Stilbenes

Consumption of a high-fat diet (HFD) enriched in saturated fat induces excessive weight gain due to adiposity, which can lead to metabolic complications, as well as increased risk of fatty liver disease and CVD. The present study investigated the underlying mechanism and dose-response effects of resveratrol (RV) on obesity, hepatic steatosis and dyslipidaemia in mice fed a HFD. Male C57BL/6J mice were fed a normal diet or a HFD (20 % fat, w/w) combined with 0·005 or 0·02 % (w/w) RV for 10 weeks. As expected, mice fed a HFD developed obesity, as shown by increased body weight gain, visceral fat, hepatic fat and plasma cholesterol. RV significantly reduced visceral fat and plasma NEFA. In the liver of HFD-fed mice, RV significantly reduced TAG and cholesterol, as well as lipid droplet number and size. A low dose of RV (0·005 %) appeared to be more effective than a higher dose of RV (0·02 %) for suppressing adiposity and hepatic steatosis development with a significant decrease in body weight gain, plasma TAG and total cholesterol levels. These changes were seemingly attributable to a suppression of the fatty acid (FA) synthase, glucose-6-phosphate dehydrogenase, and phosphatidate phosphohydrolase and/or an activation of FA oxidation in the liver and epididymal adipose tissue. In conclusion, daily consumption of a low dose of RV is effective for protecting against diet-induced obesity, hepatic steatosis and dyslipidaemia in HFD-fed mice.

Topics: Adiposity; Animals; Cholesterol; Diet; Diet, High-Fat; Dose-Response Relationship, Drug; Enzyme Inhibitors; Fatty Acid Synthases; Fatty Liver; Glucosephosphate Dehydrogenase; Hyperlipidemias; Liver; Male; Mice; Mice, Inbred C57BL; Obesity; Phosphatidate Phosphatase; Resveratrol; Stilbenes; Triglycerides; Weight Gain

In obesity, there is an increase in reactive oxygen species (ROS) within adipose tissue caused by increases in inflammation and overnutrition. Hormone sensitive lipase (HSL) is part of the canonical lipolytic pathway and critical for complete lipolysis. This study hypothesizes that ROS is a signal that integrates regulation of lipolysis by targeting HSL. Experiments were performed with human differentiated adipocytes from the subcutaneous depot. Antioxidants were employed as a tool to decrease ROS, and it was found that scavenging ROS with diphenyliodonium, N-acetyl cysteine, or resveratrol decreased lipolysis in adipocytes. HSL phosphorylation of a key serine residue, Ser552, as well as translocation of this enzyme from the cytosol to the lipid droplet upon lipolytic stimulation were both abrogated by scavenging ROS. The phosphorylation status of other serine residues on HSL were not affected. These findings are significant because they document that ROS contributes to the physiological regulation of lipolysis via an effect on translocation. Such regulation could be useful in developing new obesity therapies.

Topics: Acetylcysteine; Adipocytes; Adipose Tissue; Adult; Antioxidants; Biphenyl Compounds; Colforsin; Female; Humans; Lipids; Lipolysis; Middle Aged; Obesity; Onium Compounds; Phosphorylation; Primary Cell Culture; Protein Transport; Reactive Oxygen Species; Resveratrol; Serine; Signal Transduction; Sterol Esterase; Stilbenes

Brown adipose tissue (BAT) can disperse stored energy as heat. Promoting BAT-like features in white adipose (WAT) is an attractive, if elusive, therapeutic approach to staunch the current obesity epidemic. Here we report that gain of function of the NAD-dependent deacetylase SirT1 or loss of function of its endogenous inhibitor Deleted in breast cancer-1 (Dbc1) promote "browning" of WAT by deacetylating peroxisome proliferator-activated receptor (Ppar)-γ on Lys268 and Lys293. SirT1-dependent deacetylation of Lys268 and Lys293 is required to recruit the BAT program coactivator Prdm16 to Pparγ, leading to selective induction of BAT genes and repression of visceral WAT genes associated with insulin resistance. An acetylation-defective Pparγ mutant induces a brown phenotype in white adipocytes, whereas an acetylated mimetic fails to induce "brown" genes but retains the ability to activate "white" genes. We propose that SirT1-dependent Pparγ deacetylation is a form of selective Pparγ modulation of potential therapeutic import.

Topics: 3T3 Cells; Acetylation; Adipose Tissue, Brown; Adipose Tissue, White; Adult; Amino Acid Sequence; Animals; Cells, Cultured; Energy Metabolism; Female; Humans; Insulin Resistance; Ligands; Lysine; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Models, Molecular; Molecular Sequence Data; Mutagenesis, Site-Directed; Mutation; Obesity; PPAR gamma; Resveratrol; Sequence Alignment; Sirtuin 1; Stilbenes; Thermogenesis; Thiazolidinediones

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.

Topics: Adipose Tissue, White; Animals; Area Under Curve; Blood Glucose; Body Weight; Drug Evaluation, Preclinical; Drug Therapy, Combination; Energy Intake; Glucose Tolerance Test; Linoleic Acids, Conjugated; Lipids; Male; Obesity; Organ Size; Rats; Rats, Wistar; Resveratrol; Stilbenes; Treatment Failure

Resveratrol (Res) is a natural polyphenolic compound with anti-inflammatory and antioxidant properties. Also, Res can inhibit lipogenesis and adipocyte differentiation. However, the underlying mechanisms of Res's functions remain largely unknown. AMP-activated protein kinase (AMPK) is a key player in adipocyte differentiation. Therefore, the purpose of our study was to determine the role played by AMPK in the Res-mediated regulation of adipocyte differentiation. Incubation of 3T3-L1 cells with Res confirmed that Res inhibited adipocyte differentiation. The phosphorylation of AMPKα was increased by Res in a dose-dependent manner, while total AMPKα levels were unchanged, and peroxisome proliferator-activated receptor γ (PPARγ), CCAAT-enhancer-binding protein α (C/EBPα), and sterol regulatory element-binding protein 1c (SREBP-1c) levels were decreased. Interestingly, pretreatment with AMPKα siRNA and Res promoted adipocyte differentiation, while the decrease of p-AMPKα increased PPARγ, C/EBPα, and SREBP-1c protein expression. Our study shows that Res is capable of inhibiting lipogenesis and differentiation of 3T3-L1 adipocytes via activation of AMPK, suggesting its potential therapeutic application in the treatment or prevention of obesity.

Topics: 3T3-L1 Cells; Adipocytes; AMP-Activated Protein Kinases; Animals; Anti-Inflammatory Agents, Non-Steroidal; CCAAT-Enhancer-Binding Protein-alpha; Cell Differentiation; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Lipogenesis; Mice; Obesity; Phosphorylation; PPAR gamma; Resveratrol; Sterol Regulatory Element Binding Protein 1; Stilbenes

Topics: AMP-Activated Protein Kinases; Animals; Cardiovascular Diseases; Enzyme Inhibitors; Humans; Insulin Resistance; Obesity; Resveratrol; Sirtuin 1; Stilbenes

Human obesity is closely associated with a state of chronic low-grade inflammation, which also involves the adipose tissue with enhanced production of bioactive substances (adipokines). Calorie restriction (CR) reduces adipocytokine production and improves metabolic profile in rodents. Some of these effects are mediated through activation of the sirtuin 1 (Sirt1) enzyme, and in this study, we investigate whether the natural phytoalexin, resveratrol (RSV), which is a potent Sirt1 activator, has anti-inflammatory effects in human adipose tissue explants.. The effect of RSV on interleukin 1β (IL1β)-induced change of adipokine mRNA gene expression and secretion were measured in human adipose tissue explants.. Exposure of human adipose tissue in vitro to IL1β for 24 h increased secretion of the proinflammatory adipokines IL6, IL8 and monocyte chemoattractant protein 1 (MCP-1) 3-7.7-fold (P<0.05) and increased IL6, IL8, MCP-1, IL1β and PAI-1 mRNA expression 1.3-7.2-fold (P<0.05) accordingly. Concomitant incubations with RSV reversed the IL1β-stimulated secretion (16-36%) and gene expression (25-48%) of these adipokines. IL1β reduced adiponectin mRNA expression (40%), a decrement that was reversed by RSV treatment. Similar effects were observed in differentiated human preadipocytes in primary culture, indicating that human adipocytes are a potential target for RSV effects. Finally, the effects were neutralized by sirtinol, a Sirt1 inhibitor.. This study is the first to show anti-inflammatory effects of RSV on adipokine expression and secretion in human adipose tissue in vitro through the SIRT1 pathway. Thus, RSV is hypothesized to possess beneficial effects and might improve the metabolic profile in human obesity.

Topics: Adipocytes; Adipose Tissue; Adult; Anti-Inflammatory Agents, Non-Steroidal; Female; Gene Expression; Humans; Inflammation; Male; Obesity; Resveratrol; RNA, Messenger; Stilbenes

Dietary supplementation with resveratrol may produce calorie restriction-like effects on metabolic and longevity endpoints in mice. In this study, we sought to determine whether resveratrol treatment elicited other hallmark changes associated with calorie restriction, namely bradycardia and decreased body temperature. We found that during short-term treatment, wild-type mice on a calorie-restricted diet experienced significant decreases in both heart rate and body temperature after only 1 day whereas those receiving resveratrol exhibited no such change after 1 wk. We also used ob/ob mice to study the effects of long-term treatment because previous studies had indicated the therapeutic value of resveratrol against the linked morbidities of obesity and diabetes. After 12 wk, resveratrol treatment had produced no changes in either heart rate or body temperature. Strikingly, and in contrast to previous findings, we found that resveratrol-treated mice had significantly reduced endurance in a treadmill test. Quantitative reverse transcriptase-polymerase chain reaction suggested that a proposed target of resveratrol, Sirt1, was activated in resveratrol-treated ob/ob mice. Thus, we conclude that the bradycardia and hypothermia associated with calorie restriction occur through mechanisms unaffected by the actions of resveratrol and that further studies are needed to examine the differential effects of resveratrol in a leptin-deficient background.

Topics: Animals; Anti-Obesity Agents; Bradycardia; Caloric Restriction; Exercise Test; Hypothermia; Male; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Physical Endurance; Random Allocation; Resveratrol; Stilbenes; Time Factors

Resveratrol is a natural polyphenolic stilbene derivative found in several human diet components that possess important and wide-ranging effects in biological systems including anticancer, anti-inflammatory, antioxidant, cardio-protective, and anti-ageing actions and beneficial properties against metabolic diseases. This study addresses the effects of long-term administration of resveratrol on several functional alterations arising from the metabolic syndrome experimental model of obese Zucker rats, and the possible mechanisms involved. The high plasma concentrations of triglycerides, total cholesterol, free fatty acids, insulin and leptin found in obese Zucker rats were reduced in obese rats that received resveratrol. Furthermore, the elevated hepatic lipid content was significantly lower in obese rats treated with resveratrol, an effect which was related to the increased phosphorylation of 5'-AMP-activated protein kinase (AMPK) and acetyl-CoA carboxylase (ACC) in the liver of these animals. Resveratrol treatment also improved the inflammatory status peculiar to this model, as it increased the concentration of adiponectin and lowered tumor necrosis factor-alpha production in the visceral adipose tissue (VAT) of obese Zucker rats. Moreover, chronic intake of resveratrol enhanced VAT eNOS expression among obese Zucker rats. These effects parallel the activation of AMPK and inhibition by phosphorylation of ACC in this tissue. The raised systolic blood pressure and reduced aortic eNOS expression found in obese Zucker rats were significantly improved in the resveratrol-treated obese rats. In conclusion, resveratrol improved dyslipidemia, hyperinsulinemia, hyperleptinemia and hypertension in obese Zucker rats, and produced anti-inflammatory effects in VAT, effects that seem to be mediated by AMPK activation.

Topics: Adipose Tissue; Animals; Blood Pressure; Disease Models, Animal; Drug Administration Schedule; Humans; Hypertension; Lipid Metabolism; Male; Metabolic Syndrome; Obesity; Random Allocation; Rats; Rats, Zucker; Resveratrol; Stilbenes

Calorie restriction increases the life span in a number of different organisms. This effect is dependent upon activation of the Sirt1 enzyme, and many of the beneficial effects of calorie restriction can be mimicked using resveratrol, which activates the Sirt1 enzyme. Nothing is known about this system in human adipose tissue; therefore, we investigated this system in human adipose tissue.. Sirt1 mRNA was measured in adipose tissue biopsies from human volunteers before and after 6 days of total fasting. In addition, adipose tissue from lean and obese individuals was compared and in vitro investigations were performed.. Long-term total fasting (6 days) of nine human volunteers increased Sirt1 mRNA expression in subcutaneous adipose tissue more than twofold (0.197-0.454 arbitrary units, P<0.05). Likewise, lean women (n=12) had more than twofold higher Sirt1 expression in subcutaneous adipose tissue compared to obese women (n=12; 0.33-0.73 arbitrary units, P<0.05). Sirt1 was equally expressed in the stroma-vascular fraction and the isolated adipocyte fraction. Finally, in vitro, we demonstrated that resveratrol (a Sirt1 activator) significantly enhanced the lipolytic effect of epinephrine in human adipose tissue (P<0.05).. Human adipose tissue contains Sirt1 and the expression of Sirt1 can be regulated by calorie restriction as in other species. Furthermore, we demonstrated that resveratrol affects human fat-cell metabolism similar to the effects in rodents (that is, increased epinephrine induced lipolysis). These findings indicated that the beneficial effects of calorie restriction in humans might involve the activation of Sirt1. Thus, based on these findings, we propose that Sirt1 might play important roles for the beneficial effects of calorie restriction in humans.

Topics: Adipocytes; Adult; Cell Differentiation; Cells, Cultured; Enzyme Activation; Fasting; Female; Humans; Lipolysis; Middle Aged; Obesity; Resveratrol; RNA, Messenger; Sirtuin 1; Sirtuins; Stilbenes; Subcutaneous Fat; Thinness; Up-Regulation

Disalicylic acid derivatives with stilbene and bis-styrylbenzene skeleton were synthesized as PTP1B inhibitors. The most potent in this series exhibited a submicromolar IC(50) value. One of the compounds 7b was tested in an animal model for its efficacy as an anti-diabetic or an anti-obesity agent. In feeding compound 7b to diet-induced obese mice, no significant differences in weight gain and food consumption were observed between the drug-treated and the obese control mice. However, 7b significantly lowered the fasting glucose level and improved the glucose tolerance in the obesity-induced diabetic mice.

Topics: Animals; Anti-Obesity Agents; Blood Glucose; Disease Models, Animal; Fasting; Glucose Tolerance Test; Hyperglycemia; Mice; Mice, Inbred C57BL; Mice, Obese; Obesity; Salicylates; Stilbenes; Structure-Activity Relationship; Styrenes; Weight Gain

The natural compounds genistein (G), quercetin (Q), and resveratrol (R) have been reported to each exhibit anti-adipogenic activities in adipocytes and antiproliferative and pro-apoptotic activities in several cell types. We studied the combined effects of G, Q, and R on adipogenesis and apoptosis in primary human adipocytes (HAs) and 3T3-L1 murine adipocyte (MAs). Combined treatment with 6.25 microM G, 12.5 microM Q, and 12.5 microM R during the 14-day differentiation period caused an enhanced inhibition of lipid accumulation in maturing HAs that was greater than the responses to individual compounds and to the calculated additive response. Glycerol 3-phosphate dehydrogenase activity, a marker of late adipocyte differentiation, was decreased markedly in HAs treated with the combination of G+Q+R. In addition, combined treatment with 50 microM G, 100 microM Q, and 100 microM R for 3 days decreased cell viability and induced apoptosis in early- and mid- phase maturing and lipid-filled mature HAs. In contrast, no compound alone induced apoptosis. Oil Red O stain and Hoechst 33342 stain were performed to confirm the effects on lipid accumulation and apoptosis, respectively. We also determined whether MAs responded to the combination treatment similarly to HAs. As in HAs, G+Q+R treatment decreased lipid accumulation in maturing MAs and increased apoptosis in pre- and lipid-filled mature MAs more than the responses to G, Q, and R when used separately. These results show that lower concentrations of combined treatments with several natural compounds may be useful for treatments for obesity through the suppression of adipogenesis and enhanced adipocyte apoptosis.

Topics: 3T3-L1 Cells; Adipocytes; Adipogenesis; Animals; Anti-Obesity Agents; Antioxidants; Apoptosis; Cells, Cultured; Drug Synergism; Drug Therapy, Combination; Female; Genistein; Glycerolphosphate Dehydrogenase; Humans; Lipids; Mice; Obesity; Phytoestrogens; Quercetin; Resveratrol; Stilbenes

The resveratrol-induced cardiac protection was studied in Zucker obese rats. Rats were divided into five groups: group 1, lean control; group 2, obese control (OC); group 3, obese rats treated orally with 5 mg kg(-1) day(-1) of resveratrol (OR) for 2 wk; group 4, obese rats received 10% glucose solution ad libitum for 3 wk (OG); and group 5, obese rats received 10% glucose for 3 wk and resveratrol (OGR) during the 2nd and 3rd wk. Body weight, serum glucose, and insulin were measured, and then hearts were isolated and subjected to 30 min of ischemia followed by 120 min of reperfusion. Heart rate, coronary flow, aortic flow, developed pressure, the incidence of reperfusion-induced ventricular fibrillation, and infarct size were measured. Resveratrol reduced body weight and serum glucose in the OR compared with the OC values (414 +/- 10 g and 7.08 +/- 0.41 mmol/l, respectively, to 378 +/- 12 g and 6.11 +/- 0.44 mmol/l), but insulin levels were unchanged. The same results were obtained for the OG vs. OGR group. Resveratrol improved postischemic cardiac function in the presence or absence of glucose intake compared with the resveratrol-free group. The incidence of ventricular fibrillation and infarct size was reduced by 83 and 20% in the OR group, and 67 and 16% in the OGR group, compared with the OC and OG groups, respectively. Resveratrol increased GLUT-4 expression and reduced endothelin expression and cardiac apoptosis in ischemic-reperfused hearts in the presence or absence of glucose intake. Thus the protective effect of resveratrol could be related to its direct effects on the heart.

Topics: Animals; Antioxidants; Apoptosis; Blood Glucose; Blood Pressure; Electrocardiography; Endothelin-1; Glucose Transporter Type 4; Heart Rate; In Situ Nick-End Labeling; In Vitro Techniques; Insulin; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Obesity; Rats; Rats, Zucker; Resveratrol; Signal Transduction; Stilbenes

It remains presently unknown whether vascular reactivity is impaired and whether maladaptive cardiac remodeling occurs before the onset of overt obesity and in the absence of hyperlipidemia. Normal female rats were fed a high-fat diet for 8 weeks and were associated with a modest nonsignificant increase of body weight (standard diet, 300 +/- 10, versus high-fat diet, 329 +/- 14 g) and a normal plasma lipid profile. In rats fed a high-fat diet, systolic (171 +/- 7 mm Hg) and diastolic blood pressures (109 +/- 3) were increased compared to a standard diet (systolic blood pressure, 134 +/- 8; diastolic blood pressure, 96 +/- 5 mm Hg), and acetylcholine-dependent relaxation of isolated aortic rings (high-fat diet, 22 +/- 5%, versus standard diet, 53 +/- 8%) was significantly reduced. Furthermore, perivascular fibrosis was detected in the heart of rats fed a high-fat diet. The exogenous addition of resveratrol (trans-3,5,4'-trihydroxystilbene) (0.1 microM) to aortic rings isolated from rats fed a high-fat diet restored acetylcholine-mediated relaxation (47 +/- 9%). The administration of resveratrol (20 mg/kg/day for 8 weeks) to rats fed a high-fat diet prevented the increase in blood pressure and preserved acetylcholine-dependent relaxation of isolated aortic rings. However, resveratrol therapy failed to attenuate the perivascular fibrotic response. These data have demonstrated that a high-fat diet fed to normal female rats can elicit a hypertensive response and induce perivascular fibrosis before the development of overt obesity and in the absence of hyperlipidemia. Resveratrol therapy can prevent the hypertensive response in female rats fed a high-fat diet but is without effect on the progression of perivascular fibrosis.

Topics: Acetylcholine; Animals; Antioxidants; Aorta; Blood Pressure; Dietary Fats; Female; Fibrosis; Hyperlipidemias; Myocardium; Nitroprusside; Obesity; Rats; Rats, Sprague-Dawley; Resveratrol; Stilbenes; Vasodilation; Vasodilator Agents; Ventricular Dysfunction, Left

Topics: Animals; Diet; Enzyme Activation; Flavonoids; Humans; Mice; Obesity; Phenols; Polyphenols; Resveratrol; Sirtuins; Stilbenes; Vitis

Topics: Animals; Clinical Trials as Topic; Health; Humans; Mice; Obesity; Reproducibility of Results; Resveratrol; Sirtuins; Stilbenes

Resveratrol (3,5,4'-trihydroxystilbene) extends the lifespan of diverse species including Saccharomyces cerevisiae, Caenorhabditis elegans and Drosophila melanogaster. In these organisms, lifespan extension is dependent on Sir2, a conserved deacetylase proposed to underlie the beneficial effects of caloric restriction. Here we show that resveratrol shifts the physiology of middle-aged mice on a high-calorie diet towards that of mice on a standard diet and significantly increases their survival. Resveratrol produces changes associated with longer lifespan, including increased insulin sensitivity, reduced insulin-like growth factor-1 (IGF-I) levels, increased AMP-activated protein kinase (AMPK) and peroxisome proliferator-activated receptor-gamma coactivator 1alpha (PGC-1alpha) activity, increased mitochondrial number, and improved motor function. Parametric analysis of gene set enrichment revealed that resveratrol opposed the effects of the high-calorie diet in 144 out of 153 significantly altered pathways. These data show that improving general health in mammals using small molecules is an attainable goal, and point to new approaches for treating obesity-related disorders and diseases of ageing.

Topics: Acetylation; Adenylate Kinase; Animals; Energy Intake; Health; Insulin; Liver; Male; Mice; Mice, Inbred C57BL; Mitochondria, Liver; Obesity; Oligonucleotide Array Sequence Analysis; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Resveratrol; Stilbenes; Survival Rate; Trans-Activators; Transcription Factors

Topics: Animals; Caloric Restriction; Energy Intake; Health; Humans; Insulin Resistance; Longevity; Mice; Obesity; Resveratrol; Stilbenes

Diminished mitochondrial oxidative phosphorylation and aerobic capacity are associated with reduced longevity. We tested whether resveratrol (RSV), which is known to extend lifespan, impacts mitochondrial function and metabolic homeostasis. Treatment of mice with RSV significantly increased their aerobic capacity, as evidenced by their increased running time and consumption of oxygen in muscle fibers. RSV's effects were associated with an induction of genes for oxidative phosphorylation and mitochondrial biogenesis and were largely explained by an RSV-mediated decrease in PGC-1alpha acetylation and an increase in PGC-1alpha activity. This mechanism is consistent with RSV being a known activator of the protein deacetylase, SIRT1, and by the lack of effect of RSV in SIRT1(-/-) MEFs. Importantly, RSV treatment protected mice against diet-induced-obesity and insulin resistance. These pharmacological effects of RSV combined with the association of three Sirt1 SNPs and energy homeostasis in Finnish subjects implicates SIRT1 as a key regulator of energy and metabolic homeostasis.

Topics: Acetylation; Adult; Animals; Dietary Fats; Energy Metabolism; Gene Expression Regulation; Humans; Insulin Resistance; Male; Metabolic Diseases; Mice; Mice, Inbred C57BL; Mice, Inbred Strains; Mitochondria, Muscle; Motor Activity; Muscle Fibers, Skeletal; Obesity; Oxidative Phosphorylation; Oxygen Consumption; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Polymorphism, Single Nucleotide; Resveratrol; Sirtuin 1; Sirtuins; Specific Pathogen-Free Organisms; Stilbenes; Trans-Activators; Transcription Factors

Resveratrol increases life span in lower organisms by activating the NAD(+)-dependent histone deacetylase Sirt1. Studies by and now show that resveratrol promotes longevity and improves glucose homeostasis in mice by stimulating the Sirt1-mediated deacetylation of the transcriptional coactivator PGC-1alpha.

Topics: Acetylation; Administration, Oral; Aging; Animals; Diabetes Mellitus, Type 2; Energy Metabolism; Glucose; Homeostasis; Humans; Insulin; Longevity; Male; Mice; Obesity; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Resveratrol; Signal Transduction; Sirtuin 1; Sirtuins; Stilbenes; Trans-Activators; Transcription Factors

Resveratrol has been shown to induce vasorelaxation. In this study, we investigated the mechanism(s) of resveratrol-induced vasorelaxation in resistance mesenteric arteries from male lean and dietary-induced obese rats. Compared with lean rats, arteries from dietary-obese rats showed significant (P<0.001) endothelial dysfunction, as indicated by a decrease (>20%) in maximal acetylcholine-induced vasorelaxation. Resveratrol (5-35 micromol/l) induced concentration-dependent relaxation of mesenteric arteries preconstricted with noradrenaline (8 micromol/l) or KCl (125 mmol/l) from both lean and dietary-obese rats. There were no significant differences between the two groups, achieving a maximum relaxation of >95% at a concentration of 35 micromol/l. In noradrenaline-preconstricted arteries from lean rats, N(G)-nitro-L-arginine methyl ester (L-NAME; 100 and 300 micromol/l) caused a significant (P<0.01) concentration-dependent rightward shift in reseveratrol activity, with no effect on maximal responses. However, L-NAME (100 and 300 micromol/l) did not alter the effects of reseveratrol on arteries from dietary-obese rats, giving superimposed concentration-responses curves. Indomethacin was also ineffective in altering resveratrol activity in arteries from both lean and dietary-obese rats. In noradrenaline-precontracted arteries from dietary-obese rats, responses to resveratrol were not attenuated by endothelial denudation, indicating an action independent of the endothelium. This study indicates that: (a) the maximal effects of resveratrol on resistance arteries from lean and dietary-obese rats are not effected by endothelial dysfunction, and (b) the effects of resveratrol in lean animals (where endothelial function is not impaired), but not in dietary-obese rats, are mediated via NO.

Topics: Acetylcholine; Animals; Body Weight; Dose-Response Relationship, Drug; Drug Interactions; Endothelium, Vascular; Indomethacin; Male; Mesenteric Arteries; NG-Nitroarginine Methyl Ester; Norepinephrine; Obesity; Rats; Rats, Wistar; Resveratrol; Stilbenes; Vasoconstrictor Agents; Vasodilation; Vasodilator Agents

Topics: Adolescent; Amenorrhea; Child; Clomiphene; Diagnosis, Differential; Environment; Female; Hirsutism; Humans; Hypothyroidism; Menstruation Disturbances; Norethindrone; Obesity; Stilbenes

Topics: Female; Follicle Stimulating Hormone; Hormones; Humans; Obesity; Stilbenes; Vagina; Vaginitis