Article:Dietary Strategies Implicated in the Prevention and Treatment of Metabolic Syndrome (5133877)

From ScienceSource
Jump to: navigation, search

This page is the ScienceSource HTML version of the scholarly article described at Its title is Dietary Strategies Implicated in the Prevention and Treatment of Metabolic Syndrome and the publication date was 2016-11-10. The initial author is Rocio de la Iglesia.

Fuller metadata can be found in the Wikidata link, which lists all authors, and may have detailed items for some or all of them. There is further information on the article in the footer below. This page is a reference version, and is protected against editing.

Converted JATS paper:

Journal Information

Title: International Journal of Molecular Sciences

Dietary Strategies Implicated in the Prevention and Treatment of Metabolic Syndrome

  • Rocio de la Iglesia
  • Viviana Loria-Kohen
  • Maria Angeles Zulet
  • Jose Alfredo Martinez
  • Guillermo Reglero
  • Ana Ramirez de Molina
  • Maurizio Battino (Academic Editor)

1GENYAL Platform on Nutrition and Health, IMDEA Food Institute, CEI UAM + CSIC, 28049 Madrid, Spain; (V.L.-K.); (G.R.)

2Department of Nutrition, Food Science and Physiology, University of Navarra, 31008 Pamplona, Spain; (M.A.Z.); (J.A.M.)

3CIBER Fisiopatología de la Obesidad y la Nutrición (CIBERobn), 28029 Madrid, Spain

Publication date (epub): 11/2016

Publication date (collection): 11/2016


Metabolic syndrome (MetS) is established as the combination of central obesity and different metabolic disturbances, such as insulin resistance, hypertension and dyslipidemia. This cluster of factors affects approximately 10%–50% of adults worldwide and the prevalence has been increasing in epidemic proportions over the last years. Thus, dietary strategies to treat this heterogenic disease are under continuous study. In this sense, diets based on negative-energy-balance, the Mediterranean dietary pattern, n-3 fatty acids, total antioxidant capacity and meal frequency have been suggested as effective approaches to treat MetS. Furthermore, the type and percentage of carbohydrates, the glycemic index or glycemic load, and dietary fiber content are some of the most relevant aspects related to insulin resistance and impaired glucose tolerance, which are important co-morbidities of MetS. Finally, new studies focused on the molecular action of specific nutritional bioactive compounds with positive effects on the MetS are currently an objective of scientific research worldwide. The present review summarizes some of the most relevant dietary approaches and bioactive compounds employed in the treatment of the MetS to date.


1. The Metabolic Syndrome

It was during the period between 1910 and 1920 when it was suggested for the first time that a cluster of associated metabolic disturbances tended to coexist together [[1]]. Since then, different health organisms have suggested diverse definitions for metabolic syndrome (MetS) but there has not yet been a well-established consensus. The most common definitions are summarized in Table 1. What is clear for all of these is that the MetS is a clinical entity of substantial heterogeneity, commonly represented by the combination of obesity (especially abdominal obesity), hyperglycemia, dyslipidemia and/or hypertension [[2],[3],[4],[5],[6]].

Obesity consists of an abnormal or excessive fat accumulation, for which the main cause is a chronic imbalance between energy intake and energy expenditure [[7],[8]]. The excess of energy consumed is primarily deposited in the adipose tissue as triglycerides (TG) [[9]].

Dyslipidemia encompasses elevated serum TG levels, increased low density lipoprotein-cholesterol (LDL-c) particles, and reduced levels of high density lipoprotein-cholesterol (HDL-c) [[10]]. It is associated with hepatic steatosis [[11]], dysfunction of pancreatic β-cells [[12]] and elevated risk of atherosclerosis [[13]], among others.

Another main modifiable MetS manifestation is hypertension, which is mainly defined as a resting systolic blood pressure (SBP) ≥ 140 mmHg or diastolic blood pressure (DBP) ≥ 90 mmHg or drug prescription to lower hypertension [[14]]. It usually involves narrowed arteries and is identified as a major cardiovascular and renal risk factor, related to heart and vascular disease, stroke and myocardial infarction [[13],[15],[16],[17]].

Hyperglycemia, related insulin resistance and type 2 diabetes mellitus are characterized by an impaired uptake of glucose by the cells, that lead to elevated plasma glucose levels, glycosuria and ketoacidosis [[18]]. It is responsible for different tissue damage that shortens the life expectancy of diabetics, involving cardiovascular diseases (CVD), atherosclerosis, hypertension [[19]], β-cell dysfunction [[12]], kidney disease [[20]] or blindness [[21]]. Currently, diabetes is considered the leading cause of death in developed countries [[22]].

Moreover, oxidative stress and low grade inflammation are two important mechanisms implicated in the etiology, pathogenesis, and development of MetS [[23]]. Oxidative stress is defined as an imbalance between the pro-oxidants and antioxidants in the body [[24]]. It plays a key role in the development of atherosclerosis by different mechanisms such as the oxidation of LDL-c particles [[25]] or impairment of HDL-c functions [[26]]. Inflammation is an immune system response to injury hypothesized to be a major mechanism in the pathogenesis and progression of obesity related disorders and the link between adiposity, insulin resistance, MetS and CVD [[27]].

Although the prevalence of the MetS varies broadly around the word and depends on the source used for its definition, it is clear that over the last 40–50 years the number of people presenting with this syndrome has risen in epidemic proportions [[28]]. Moreover, the frequency of this syndrome is increased in developed countries, sedentary people, smokers, low socioeconomic status population, as well as in individuals with unhealthy dietary habits [[29],[30]].

For all of this, there is currently a wide concern to find effective strategies to detect, treat and control the comorbidities associated with MetS. This is a complex challenge as MetS is a clinical entity of substantial heterogeneity and therefore, the different cornerstones implicated in its development should be addressed. In this review we compiled and examined different dietary patterns and bioactive compounds that have pointed out to be effective in MetS treatment.

2. Dietary Patterns

Several dietary strategies and their potential positive effects on the prevention and treatment of the different metabolic complications associated to the MetS, are described below and summarized in Table 2.

2.1. Energy-Restricted Diets

Energy restricted diets are probably the most commonly used and studied dietary strategies for combating excess weight and related comorbidities. They consist in personalized regimes that supply less calories than the total energy expended by a specific individual [[31]].

A hypocaloric diet results in a negative energy balance and subsequently, in body weight reduction [[31]]. Weight loss is achieved via fat mobilization from different body compartments as a consequence of the lipolysis process necessary to provide energy substrate [[32],[33]]. In people who are overweight or suffering from obesity, as is the case of most people with MetS, weight loss is important as it is associated with improvement of related disorders such as abdominal obesity (visceral adipose tissue), type 2 diabetes, CVD or inflammation [[32],[33],[34],[35],[36]].

Moreover, as described above, low grade inflammation is associated with MetS and obesity. Therefore, of particular importance is the fact that in obese individuals following a hypocaloric diet, a depletion of plasma inflammatory markers such as interleukin (IL)-6 has been observed [[34]]. Thus, caloric restriction in obese people suffering MetS may improve the whole-body pro-inflammatory state.

At the same time, body weight reduction is associated with improvements in cellular insulin signal transduction, increments in peripheral insulin sensitivity and higher robustness in insulin secretory responses [[32],[36]]. People with excess body weight who are at risk of developing type 2 diabetes, may benefit from a hypocaloric regime by improving plasma glucose levels and insulin resistance.

In addition, different intervention trials have reported a relationship between energy restricted diets and lower risk of developing CVD. In this sense, in studies with obese people following a hypocaloric diet, improvements in lipid profile variables such as reductions of LDL-c and plasma TG levels, as well as improvements in hypertension via depletion of SBP and DBP levels have been observed [[35],[37]].

Among the different nutritional intervention trials, a reduction of 500–600 kcal a day of the energy requirements is a well-established hypocaloric dietary strategy, which has demonstrated to be effective in weight reduction [[38],[39]]. However, the challenge lies in maintaining the weight loss over time, as many subjects can follow a prescribed diet for a few months, but most people have difficulty in maintaining the acquired habits over the long term [[40],[41]].

2.2. Diets Rich in Omega-3 Fatty Acids

The very long-chain eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are essential omega-3 polyunsaturated fatty acids (n-3 PUFAs) for human physiology. Their main dietary sources are fish and algal oils and fatty fish, but they can also be synthesized by humans from α-linolenic acid [[40]].

There is a moderate body of evidence suggesting that n-3 PUFAs, mainly EPA and DHA, have a positive role in the prevention and treatment of the pathologies associated to MetS [[42]].

In this context, it has been described that EPA and DHA have the ability to reduce the risk of developing CVD and cardiometabolic abnormalities as well as CVD-related mortality [[42]]. These beneficial effects are thought to be mainly due to the ability of these essential fatty acids to reduce plasma TG levels [[43]].

Moreover, different studies have shown that people following an increased n-3 PUFA diet have reduced plasma levels of the pro-inflammatory cytokines IL-6 and tumor necrosis factor-alpha (TNFα), as well as plasma C-reactive protein (CRP) [[44]]. These effects are probably mediated by resolvins, maresins and protectins, which are EPA and DHA metabolic products with anti-inflammatory properties [[44]].

There are some studies that have observed an association between n-3 ingestion and improvements or prevention of type 2 diabetes development. However, other studies found opposite results [[44]]. Thus, it cannot be made any specific affirmation in this respect.

The European Food Safety Authority recommends and intake of 250 mg EPA + DHA a day, in the general healthy population as a primary prevention of CVD [[45]]. These amounts can be achieved with an ingestion of 1–2 fatty fish meals per week [[45]].

2.3. Diets Based on Low Glycemic Index/Load

Over the last ten years, the concern about the quality of the carbohydrates (CHO) consumed has risen [[46]]. In this context, the glycemic index (GI) is used as a CHO quality measure. It consists in a ranking on a scale from 0 to 100 that classifies carbohydrate-containing foods according to the postprandial glucose response [[47]]. The higher the index, the more promptly the postprandial serum glucose rises and the more rapid the insulin response. A quick insulin response leads to rapid hypoglycemia, which is suggested to be associated with an increment of the feeling of hunger and to a subsequent higher caloric intake [[47]]. The glycemic load (GL) is equal to the GI multiplied by the number of grams of CHO in a serving [[48]].

There is a theory which states that MetS is a consequence of an elevated intake of high GI foods over time, among others unhealthy dietary habits [[49]]. In this sense, following a diet rich in high GI CHO has been associated with hyperglycemia, insulin resistance, type 2 diabetes, hypertriglyceridemia, CVD, and obesity [[47],[50],[51]], abnormalities directly related to MetS.

On the contrary, a low GI diet has been associated with slower absorption of the CHO and subsequently smaller blood glucose fluctuations, which indicate better glycemic control [[46]]. In patients with type 2 diabetes, diets based on low GI are associated with reductions in glycated hemoglobin (HbA1c) and fructosamine blood levels, two biomarkers used as key monitoring factors in diabetes management [[52],[53]].

For all of this, it is common to find the limitation of CHO at high GI among the advice for MetS treatment [[28]], in particular with respect to “ready-to-eat processed foods” including sweetened beverages, soft drinks, cookies, cakes, candy, juice drinks, and other foods which contain high amounts of added sugars [[54]].

2.4. Diets with High Total Antioxidant Capacity

Dietary total antioxidant capacity (TAC) is an indicator of diet quality defined as the sum of antioxidant activities of the pool of antioxidants present in a food [[55]]. These antioxidants have the capacity to act as scavengers of free radicals and other reactive species produced in the organisms [[56]]. Taking into account that oxidative stress is one of the remarkable unfortunate physiological states of MetS, dietary antioxidants are of main interest in the prevention and treatment of this multifactorial disorder [[57]]. Accordingly, it is well-accepted that diets with a high content of spices, herbs, fruits, vegetables, nuts and chocolate, are associated with a decreased risk of oxidative stress-related diseases development [[58],[59],[60]]. Moreover, several studies have analyzed the effects of dietary TAC in individuals suffering from MetS or related diseases [[61],[62]]. In the Tehran Lipid and Glucose Study it was demonstrated that a high TAC has beneficial effects on metabolic disorders and especially prevents weight and abdominal fat gain [[61]]. In the same line, research conducted in our institutions also evidenced that beneficial effects on body weight, oxidative stress biomarkers and other MetS features were positively related with higher TAC consumption in patients suffering from MetS [[63],[64],[65]].

In this sense, the World Health Organization (WHO) recommendation for fruit and vegetables consumption (high TAC foods) for the general population is a minimum of 400 g a day [[66]]. Moreover, cooking with spices is recommended in order to increase the TAC dietary intake and, at the same time, maintain flavor while reducing salt [[67]].

2.5. Moderate-High Protein Diets

The macronutrient distribution set in a weight loss dietary plan has commonly been 50%–55% total caloric value from CHO, 15% from proteins and 30% from lipids [[57],[68]]. However, as most people have difficulty in maintaining weight loss achievements over time [[69],[70]], research on increment of protein intake (>20%) at the expense of CHO was carried out [[71],[72],[73],[74],[75],[76],[77]].

Two mechanisms have been proposed to explain the potential beneficial effects of high-moderate protein diets: the increment of diet-induced thermogenesis [[73]] and the increase of satiety [[78]]. The increment of the thermogenesis is explained by the synthesis of peptide bonds, production of urea and gluconeogenesis, which are processes with a higher energy requirement than the metabolism of lipids or CHO [[75]]. An increment of different appetite-control hormones such as insulin, cholecystokinin or glucagon-like peptide 1, may clarify the satiety effect [[79]].

Other beneficial effects attributed to moderate-high protein diets in the literature are the improvement of glucose homeostasis [[80]], the possibility of lower blood lipids [[81]], the reduction of blood pressure [[82]], the preservation of lean body mass [[83]] or the lower of cardiometabolic disease risk [[84],[85]]. However, there are other studies that have not found benefits associated to a moderate-high protein diet [[76]]. This fact may be explained by the different type of proteins and their amino acid composition [[80]], as well as by the different type of populations included in each study [[85]]. Therefore, more research in the field is needed in order to make these results consistent.

In any case, when a hypocaloric diet is implemented, it is necessary to slightly increase the amount of proteins. Otherwise it would be difficult to reach the protein energy requirements, established as 0.83 g/kg/day for isocaloric diets and which should probably be at least 1 g/kg/day for energy-restricted diets [[86]].

2.6. High Meal Frequency Pattern

The pattern of increasing meal frequency in weight loss and weight control interventions has currently become popular among professionals [[87],[88]]. The idea is to distribute the total daily energy intake into more frequently and smaller meals. However, there is no strong evidence about the efficacy of this habit yet [[89]]. While some investigations have found an inverse association between the increment of meals per day and body weight, body mass index (BMI), fat mass percentage or metabolic diseases such as coronary heart disease or type 2 diabetes [[71],[88],[90],[91],[92]], others have found no association [[93],[94],[95]].

Different mechanisms by which high meal frequency can have a positive effect on weight and metabolism management have been proposed. An increment of energy expenditure was hypothesized; however, the studies carried out in this line have concluded that total energy expenditure does not differ among different meal frequencies [[96],[97]]. Another postulated hypothesis is that the greater the number of meals a day, the higher the fat oxidation, but again no consensus has been achieved [[89],[98]]. An additional suggested mechanism is that increasing meal frequency leads to plasma glucose levels with lower oscillations and reduced insulin secretion which is thought to contribute to a better appetite control. However, these associations have been found in population with overweight or high glucose levels but in normal-weight or normoglycaemic individuals the results are still inconsistent [[93],[99],[100],[101]].

2.7. The Mediterranean Diet

The concept of the Mediterranean Diet (MedDiet) was for the first time defined by the scientific Ancel Keys who observed that those countries around the Mediterranean Sea, which had a characteristic diet, had less risk of suffering coronary heart diseases [[102],[103]].

The traditional MedDiet is characterized by a high intake of extra-virgin olive oil and plant foods (fruits, vegetables, cereals, whole grains, legumes, tree nuts, seeds and olives), low intakes of sweets and red meat and moderate consumption of dairy products, fish and red wine [[104]].

There is a lot of literature supporting the general health benefits of the MedDiet. In this sense, it has been reported that a high adherence to this dietary pattern protects against mortality and morbidity from several causes [[105]]. Thus, different studies suggested the MedDiet as a successful tool for the prevention and treatment of MetS and related comorbidities [[106],[107],[108]]. Moreover, recent meta-analysis concluded that the MedDiet is associated with less risk of developing type 2 diabetes and with a better glycemic control in people with this metabolic disorder [[107],[109],[110]]. Other studies have found a positive correlation between the adherence to a MedDiet pattern and reduced risk of developing CVD [[111],[112],[113],[114]]. In fact, many studies have found a positive association between following a MedDiet and improvements in lipid profile by reduction of total cholesterol, LDL-c and TG, and an increase in HDL-c [[111],[112],[113],[114],[115]]. Finally, different studies also suggest that the MedDiet pattern may be a good strategy for obesity treatment as it has been associated with significant reductions in body weight and waist circumference [[108],[116],[117]].

The high amount of fiber which, among other beneficial effects, helps to weight control providing satiety; and the high antioxidants and anti-inflammatory nutrients such as n-3 fatty acids, oleic acid or phenolic compounds, are thought to be the main contributors to the positive effects attributed to the MedDiet [[118]].

For all these reasons, efforts to maintain the MedDiet pattern in Mediterranean countries and to implement this dietary habits in westernized countries with unhealthy nutritional patterns should be made.

3. Single Nutrients and Bioactive Compounds

New studies focused on the molecular action of nutritional bioactive compounds with positive effects on MetS are currently an objective of scientific research worldwide with the aim of designing more personalized strategies in the framework of molecular nutrition. Among them, flavonoids and antioxidant vitamins are some of the most studied compounds with different potential benefits such as antioxidant, vasodilatory, anti-atherogenic, antithrombotic, and anti-inflammatory effects [[119]]. Table 3 summarizes different nutritional bioactive compounds with potential positive effects on MetS, including the possible molecular mechanism of action involved.

3.1. Ascorbate

Vitamin C, ascorbic acid or ascorbate is an essential nutrient as human beings cannot synthesize it. It is a water-soluble antioxidant mainly found in fruits, especially citrus (lemon, orange), and vegetables (pepper, kale) [[120]]. Several beneficial effects have been associated to this vitamin such as antioxidant and anti-inflammatory properties and prevention or treatment of CVD and type 2 diabetes [[121],[122],[123]].

This dietary component produces its antioxidant effect primarily by quenching damaging free radicals and other reactive oxygen and nitrogen species and therefore preventing molecules such as LDL-c from oxidation [[122]]. It can also regenerate other oxidized antioxidants like tocopherol [[124]].

Moreover, it has been described that ascorbic acid may reduce inflammation as it is associated with depletion of CRP levels [[125]]. This is an important outcome to take in consideration in the treatment of MetS sufferers, as they usually present low grade inflammation [[27]].

Supplementation with vitamin C have also been associated with prevention of CVD by improving the endothelial function [[126]] and probably by lowering blood pressure [[121]]. These effects are thought to be exerted by the ability of vitamin C to enhance the endothelial nitric oxide synthase enzyme (eNOS) activity and to reduce HDL-c glycation [[127]].

Additionally, several studies have attributed to ascorbate supplementation an antidiabetic effect by improving whole body insulin sensitivity and glucose control in people with type 2 diabetes [[123]]. These antidiabetic properties are thought to be mediated by optimization of the insulin secretory function of the pancreatic islet cells by increasing muscle sodium-dependent vitamin C transporters (SVCTs) [[128]].

Despite all of this, it should be taken into account that most people reach ascorbic acid requirements (established at 95–110 mg/day in the general population) from diet and do not need supplementation [[122],[129]]. Besides, it should be considered that an excess of vitamin C ingestion leads to the opposite effect and oxidative particles are formed [[130],[131]].

3.2. Hydroxytyrosol

Hydroxytyrosol (3,4-dihydroxyphenylethanol) is a phenolic compound mainly found in olives [[132]].

It is considered the strongest antioxidant of olive oil and one of the main antioxidants in nature [[133]]. It acts as a powerful scavenger of free radicals, as a radical chain breaker and as metal chelator [[134]]. It has the ability of inhibiting LDL-c oxidation by macrophages [[132]]. In this sense, it is the only phenol recognized by the European Food Safety Authority (EFSA) as a protector of blood lipids from oxidative damage [[135]].

Hydroxytyrosol has also been reported to have anti-inflammatory effects, probably by suppressing cyclooxygenase activity and inducing eNOS expression [[136]]. Thus, enhancement of olives/olive oil intakes or hydroxytyroxol supplementation in people suffering from MetS may be a good strategy in order to improve inflammatory status.

Another beneficial effect attributed to this phenolic compound is its cardiovascular protective effect. It presents anti-atherogenic properties by decreasing the expression of vascular cell adhesion protein 1 (VCAM-1) and intercellular adhesion molecule 1 (ICAM-1) [[132],[137]], which are probably the result of an inactivation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NFκB), activator protein 1 (AP-1), GATA transcription factor and nicotinamide adenine dinucleotide phosphate (NAD(P)H) oxidase [[138],[139]]. Hydroxytyrosol also provides antidyslipidemic effects by lowering plasma levels of LDL-c, total cholesterol and TG, and by rising HDL-c [[138]].

Despite the beneficial effects attributed to hydfroxytyrosol as an antioxidant, for its antiinflamatory properties and as cardiovascular protector, it should be taken into account that most studies focused on this compound have been performed with mixtures of olive phenols, thus a synergic effect cannot be excluded [[140]].

3.3. Quercetin

Quercetin is a predominant flavanol naturally present in vegetables, fruits, green tea or red wine. It is commonly found as glycoside forms, where rutin is the most common and important structure found in nature [[141]].

Many beneficial effects that can contribute to MetS improvement have been attributed to quercetin. Among them, its antioxidant capacity should be highlighted, as it has been reported to inhibit lipid peroxidation and increase antioxidant enzymes such as superoxide dismutase (SOD), catalase (CAT) or glutathione peroxidase (GPX) [[142]].

Moreover, an anti-inflammatory effect mediated via attenuation of tumor necrosis factor α (TNF-α), NFκB and mitogen-activated protein kinases (MAPK), as well as depletion of IL-6, IL-1β, IL-8 or monocyte chemoattractant protein-1 (MCP-1) gene expression has also been attributed to this polyphenol [[143]].

As most people with MetS are overweight or obese, the role of quercetin in body weight reduction and obesity prevention has been of special interest. In this sense, it stands out the capacity of quercetin to inhibit adipogenesis through inducing the activation of AMP-activated protein kinase (AMPK) and decreasing the expression of CCAAT-enhancer-binding protein-α (C/EBPα), peroxisome proliferator-activated receptor gamma (PPARγ), and sterol regulatory element-binding protein 1 (SREBP-1) [[141],[144]].

According to the antidiabetic effects, it is proposed that quercetin may act as an agonist of peroxisome proliferator-activated receptor gamma (PPARγ), and thus improve insulin-stimulated glucose uptake in mature adipocytes [[145]]. Moreover, quercetin may ameliorate hyperglycemia by inhibiting glucose transporter 2 (GLUT2) and insulin dependent phosphatidylinositol-3-kinase (PI3K) and blocking tyrosine kinase (TK) [[142]].

Finally, different studies observed that quercetin has the ability to reduce blood pressure [[146],[147],[148]]. However, the mechanisms of action are not clear, since some authors have suggested that quercetin increases eNOS, contributing to inhibition of platelet aggregation and improvement of the endothelial function [[146],[147]], but there are other studies that have not come across these results [[148]].

3.4. Resveratrol

Resveratrol (3,5,4′-trihidroxiestilben) is a phenolic compound mainly found in red grapes and derived products (red wine, grape juice) [[149]]. It has shown antioxidant and anti-inflammatory activities, and cardioprotective, anti-obesity and antidiabetic capacities [[150],[151],[152],[153],[154],[155],[156]].

The antioxidant effects of resveratrol have been reported to be carried out by scavenging of hydroxyl, superoxide, and metal-induced radicals as well as by antioxidant effects in cells producing reactive oxygen species (ROS) [[150]].

Moreover, it has been reported that the anti-inflammatory effects of resveratrol are mediated by inhibiting NFκB signaling [[151]]. Furthermore, this polyphenol reduces the expression of proinflammatory cytokines such as interleukin 6 (IL-6), interleukin 8 (IL-8), TNF-α, monocyte chemoattractant protein-1 (MCP-1) and eNOS [[152]]. In addition, resveratrol inhibits the cyclooxygenase (COX) expression and activity, a pathway involved in the synthesis of proinflammatory lipid mediators [[152]].

Concerning the effects of resveratrol against development of type 2 diabetes, it has been reported that treatment of diabetes patients with this polyphenol provides significant improvements in the status of multiple clinically relevant biomarkers such as fasting glucose levels, insulin concentrations or glycated hemoglobin and Homeostasis Model Assessment Insulin Resistance (HOMA-IR) [[153],[154]].

Additionally, cardioprotective effects have been attributed to resveratrol. In this sense, it is suggested that resveratrol improves the endothelial function by producing nitric oxide (NO) through increasing the activity and expression of eNOS. This effect is thought to be conducted through activation of nicotinamide adenine dinucleotide-dependent deacetylase sirtuin-1 (Sirt 1) and 5′ AMP-activated protein kinase (AMPK) [[155]]. Besides, resveratrol exerts endothelial protection by stimulation of NF-E2-related factor 2 (Nrf2) [[156]] and decreasing the expression of adhesion proteins such as ICAM-1 and VCAM-1 [[152]].

Finally, it has been described that resveratrol may have a role in preventing obesity as it has been related with energy metabolism improvement, increasing lipolysis and reducing lipogenesis [[157]]. However, more studies are needed in order to corroborate these findings.

3.5. Tocopherol

Tocopherols, also known as vitamin E, are a family of eight fat-soluble phenolic compounds whose main dietary sources are vegetable oils, nuts and seeds [[130],[158]].

For a long time, it has been suggested that vitamin E could prevent different metabolic diseases as a potent antioxidant, acting as scavenger of lipid peroxyl radicals by hydrogen donating [[159]]. In this sense, it was described that tocopherols inhibit peroxidation of membrane phospholipids and prevent generation of free radicals in cell membranes [[160]].

Moreover, it has been shown that supplementation with α-tocopherol or γ-tocopherol, two of the different isoforms of vitamin E, could have an effect on inflammation status by reducing CRP levels [[161]]. Additionally, inhibition of COX and protein kinase C (PKC) and reduction of cytokines such as IL-8 or plasminogen activator inhibitor-1 (PAI-1) are other mechanisms that may contribute to these anti-inflammatory effects [[162],[163]].

However, the beneficial effects attributed to this vitamin previously have lately became controversial as different clinical trials have not come across such benefits, but ineffective or even harmful effects have been observed [[164]]. It has been recently suggested that this may be explained by the fact that vitamin E may lose most of the antioxidant capacity when ingested by human beings through different mechanisms [[162]].

3.6. Anthocyanins

Anthocyanins are water-soluble polyphenolic compounds responsible for the red, blue and purple colors of berries, black currants, black grapes, peaches, cherries, plums, pomegranate, eggplant, black beans, red radishes, red onions, red cabbage, purple corn or purple sweet potatoes [[165],[166],[167]]. Actually, they are the most abundant polyphenols in fruits and vegetables [[167]]. Moreover, they can also be found in teas, honey, nuts, olive oil, cocoa, and cereals [[168]].

These compounds have high antioxidant capacity inhibiting or decreasing free radicals by donating or transferring electrons from hydrogen atoms [[167]].

Regarding clinical studies, it has been shown that these bioactive compounds may prevent type 2 diabetes development by improving insulin sensitivity [[169]]. The exact mechanisms by which anthocyanins exert their antidiabetic effect are not yet clear, but an enhancement of the glucose uptake by muscle and adipocyte cells in an insulin-independent manner has been suggested [[169]].

Moreover, it has been shown that anthocyanins may have the capacity to prevent CVD development by improving endothelial function via increasing brachial artery flow-mediated dilation and HDL-c, and decreasing serum VCAM-1 and LDL-c concentrations [[170],[171],[172],[173]].

Finally, these polyphenolic compounds may exert anti-inflamatory effects via reducing proinflamatory molecules such as IL-8, IL-1β or CRP [[172],[174]].

However, most studies have used anthocyanin-rich extracts instead of purified anthocyanins; thus, a synergic effect with other polyphenols cannot be discarded.

3.7. Catechins

Catechins are polyphenols that can be found in a variety of foods including fruits, vegetables, chocolate, wine, and tea [[175]]. The epigallocatechin 3-gallate present in tea leaves is the catechin class most studied [[176]].

Anti-obesity effects have been attributed to these polyphenols in different studies [[176]]. The mechanisms of action suggested to explain these beneficial effects on body weight are: increasing energy expenditure and fat oxidation, and reducing fat absorption [[177]]. It is thought that energy expenditure is enhanced by catechol-O-methyltransferase and phosphodiesterase inhibition, which stimulates the sympathetic nervous system causing an activation of the brown adipose tissue [[178]]. Fat oxidation is mediated by upregulation of acyl-CoA dehydrogenase and peroxisomal b-oxidation enzymes [[178],[179]].

Moreover, catechin intake has also been associated with lower risk of CVD development by improving lipid biomarkers. Thus, it has been reported that consumption of this kind of polyphenols may increase HDL-c and decrease LDL-c and total cholesterol [[180]].

Finally, and antidiabetic effect has also been related to catechin comsumption, lowering fasting glucose levels [[175]] and improving insulin sensitivity [[178]].

4. Conclusions

As the prevalence of MetS reaches epidemic rates, the finding of an effective and easy-to-follow dietary strategy to combat this heterogenic disease is still a pending subject. This work recompiled different dietary nutrients and nutritional patterns with potential benefits in the prevention and treatment of MetS and related comorbidities (Figure 1) with the aim of facilitating future clinical studies in this area. The challenge now is to introduce precision bioactive compounds in personalized nutritional patterns in order to gain the most benefits for prevention and treatment of this disease through nutrition.


  1. P.A. SarafidisP.M. NilssonThe metabolic syndrome: A glance at its historyJ. Hypertens.20062462162610.1097/01.hjh.0000217840.26971.b616531786
  2. K.G. AlbertiP.Z. ZimmetDefinition, diagnosis and classification of diabetes mellitus and its complications. Part 1: Diagnosis and classification of diabetes mellitus provisional report of a WHO consultationDiabet. Med.19981553955310.1002/(SICI)1096-9136(199807)15:7<539::AID-DIA668>3.0.CO;2-S9686693
  3. B. BalkauM.A. CharlesComment on the provisional report from the WHO consultation. European Group for the Study of Insulin Resistance (EGIR)Diabet. Med.19991644242310342346
  4. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in AdultsExecutive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III)JAMA20012852486249711368702
  5. S.M. GrundyJ.I. CleemanS.R. DanielsK.A. DonatoR.H. EckelB.A. FranklinD.J. GordonR.M. KraussP.J. SavageS.C. Smith Jr.Diagnosis and management of the metabolic syndrome: An American Heart Association/National Heart, Lung, and Blood Institute Scientific StatementCirculation20051122735275210.1161/CIRCULATIONAHA.105.16940416157765
  6. K.G. AlbertiP. ZimmetJ. ShawThe metabolic syndrome—A new worldwide definitionLancet20053661059106210.1016/S0140-6736(05)67402-816182882
  7. M. SelassieA.C. SinhaThe epidemiology and aetiology of obesity: A global challengeBest Pract. Res. Clin. Anaesthesiol.2011251910.1016/j.bpa.2011.01.00221516909
  8. WHO, W.H.O.Available online: on 4 June 2016)
  9. H. ShimanoNovel qualitative aspects of tissue fatty acids related to metabolic regulation: Lessons from Elovl6 knockoutProg. Lipid Res.20125126727110.1016/j.plipres.2011.12.00422266797
  10. N.J. BosomworthApproach to identifying and managing atherogenic dyslipidemia: A metabolic consequence of obesity and diabetesCan. Fam. Phys.20135911691180
  11. A. Vidal-PuigThe Metabolic Syndrome and its Complex PathophysiologyA Systems Biology Approach to Study Metabolic SyndromeM. OresicSpringerNew York, NY, USA2014316
  12. V. PoitoutR.P. RobertsonGlucolipotoxicity: Fuel excess and beta-cell dysfunctionEndocr. Rev.20082935136610.1210/er.2007-002318048763
  13. W. RizzaN. VeroneseL. FontanaWhat are the roles of calorie restriction and diet quality in promoting healthy longevity?Ageing Res. Rev.201413384510.1016/j.arr.2013.11.00224291541
  14. D.M. Lloyd-JonesD. LevyEpidemiology of HypertensionHypertension: A Companion to Braunwald’s Heart DiseaseH.R. BlackW.J. ElliottElsevierPhiladephia, PA, USA2013111
  15. A. ZanchettiChallenges in hypertension: Prevalence, definition, mechanisms and managementJ. Hypertens.20143245145310.1097/HJH.000000000000011624440993
  16. G. ThomasM. ShishehborD. BrillJ.V. Nally Jr.New hypertension guidelines: One size fits most?Clevel. Clin. J. Med.20148117818810.3949/ccjm.81a.1400324591473
  17. P.A. JamesS. OparilB.L. CarterW.C. CushmanC. Dennison-HimmelfarbJ. HandlerD.T. LacklandM.L. LeFevreT.D. MacKenzieO. Ogedegbe2014 evidence-based guideline for the management of high blood pressure in adults: Report from the panel members appointed to the Eighth Joint National Committee (JNC 8)JAMA201431150752010.1001/jama.2013.28442724352797
  18. H. KlandorfA.R. ChirraA. DeGruccioD.J. GirmanDimethyl sulfoxide modulation of diabetes onset in NOD miceDiabetes19893819419710.2337/diab.38.2.1942914623
  19. K.D. BallardE. MahY. GuoR. PeiJ.S. VolekR.S. BrunoLow-fat milk ingestion prevents postprandial hyperglycemia-mediated impairments in vascular endothelial function in obese individuals with metabolic syndromeJ. Nutr.20131431602161010.3945/jn.113.17946523966328
  20. G. PuglieseA. SoliniE. BonoraE. OrsiG. ZerbiniC. FondelliG. GrudenF. CavalotO. LamacchiaR. TrevisanDistribution of cardiovascular disease and retinopathy in patients with type 2 diabetes according to different classification systems for chronic kidney disease: A cross-sectional analysis of the renal insufficiency and cardiovascular events (RIACE) Italian multicenter studyCardiovasc. Diabetol.2014135924624891
  21. M. AsifThe prevention and control the type-2 diabetes by changing lifestyle and dietary patternJ. Educ. Health Promot.20143110.4103/2277-9531.12754124741641
  22. W.R. RussellA. BakaI. BjorckN. DelzenneD. GaoH.R. GriffithsE. HadjilucasK. JuvonenS. LahtinenM. LansinkImpact of Diet Composition on Blood Glucose RegulationCrit. Rev. Food Sci. Nutr.20165654159010.1080/10408398.2013.79277224219323
  23. R. SoaresC. CostaOxidative Stress, Inflammation and Angiogenesis in the Metabolic SyndromeSpringerHeidelberg, Germany2009
  24. A. RahalA. KumarV. SinghB. YadavR. TiwariS. ChakrabortyK. DhamaOxidative Stress, Prooxidants, and Antioxidants: The InterplayBioMed Res. Int.2014201476126410.1155/2014/76126424587990
  25. S. ParthasarathyD. LitvinovK. SelvarajanM. GarelnabiLipid peroxidation and decomposition—Conflicting roles in plaque vulnerability and stabilityBiochim. Biophys. Acta2008178122123110.1016/j.bbalip.2008.03.00218406361
  26. D. McGrowderC. RileyE.Y. MorrisonL. GordonThe role of high-density lipoproteins in reducing the risk of vascular diseases, neurogenerative disorders, and cancerCholesterol2011201149692510.1155/2011/49692521490772
  27. N. FerriM. RuscicaProprotein convertase subtilisin/kexin type 9 (PCSK9) and metabolic syndrome: Insights on insulin resistance, inflammation, and atherogenic dyslipidemiaEndocrine201610.1007/s12020-016-0939-0
  28. M. OresicA. Vidal-PuigA Systems Biology Approach to Study Metabolic SyndromeSpringerHeidelberg, Germany2014
  29. E.G. LeeJ.H. ChoiK.E. KimJ.H. KimEffects of a Walking Program on Self-management and Risk Factors of Metabolic Syndrome in Older Korean AdultsJ. Phys. Ther. Sci.20142610510910.1589/jpts.26.10524567686
  30. G.J. BernabeR.P. ZafrillaC.J. MuleroJ.P. GomezH.M. LealA.J. AbellanBiochemical and nutritional markers and antioxidant activity in metabolic syndromeEndocrinol. Nutr.201361302308
  31. C.W. BalesW.E. KrausCaloric restriction: Implications for human cardiometabolic healthJ. Cardiopulm. Rehabil. Prev.20133320120810.1097/HCR.0b013e318295019e23748374
  32. J. GramsW.T. GarveyWeight Loss and the Prevention and Treatment of Type 2 Diabetes Using Lifestyle Therapy, Pharmacotherapy, and Bariatric Surgery: Mechanisms of ActionCurr. Obes. Rep.2015428730210.1007/s13679-015-0155-x26627223
  33. M. LazoS.F. SolgaA. HorskaS. BonekampA.M. DiehlF.L. BrancatiL.E. WagenknechtF.X. Pi-SunyerS.E. KahnJ.M. ClarkEffect of a 12-month intensive lifestyle intervention on hepatic steatosis in adults with type 2 diabetesDiabetes Care2010332156216310.2337/dc10-085620664019
  34. L. RossmeislovaL. MalisovaJ. KracmerovaV. StichAdaptation of human adipose tissue to hypocaloric dietInt. J. Obes.20133764065010.1038/ijo.2012.8022641066
  35. R.R. WingW. LangT.A. WaddenM. SaffordW.C. KnowlerA.G. BertoniJ.O. HillF.L. BrancatiA. PetersL. WagenknechtBenefits of modest weight loss in improving cardiovascular risk factors in overweight and obese individuals with type 2 diabetesDiabetes Care2011341481148610.2337/dc10-241521593294
  36. A. GolayE. BrockR. GabrielT. KonradN. LalicM. LavilleG. MingroneJ. PetrieT.M. PhanK.H. PietilainenTaking small steps towards targets—Perspectives for clinical practice in diabetes, cardiometabolic disorders and beyondInt. J. Clin. Pract.20136732233210.1111/ijcp.1211423521324
  37. K.M. FockJ. KhooDiet and exercise in management of obesity and overweightJ. Gastroenterol. Hepatol.201328596310.1111/jgh.1240724251706
  38. I. AbeteD. ParraJ.A. MartinezEnergy-restricted diets based on a distinct food selection affecting the glycemic index induce different weight loss and oxidative responseClin. Nutr.20082754555110.1016/j.clnu.2008.01.00518308431
  39. K.G. AlbertiR.H. EckelS.M. GrundyP.Z. ZimmetJ.I. CleemanK.A. DonatoJ.C. FruchartW.P. JamesC.M. LoriaS.C. Smith Jr.Harmonizing the metabolic syndrome: A joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of ObesityCirculation20091201640164519805654
  40. J.A. FlemingP.M. Kris-EthertonThe evidence for alpha-linolenic acid and cardiovascular disease benefits: Comparisons with eicosapentaenoic acid and docosahexaenoic acidAdv. Nutr.20145863S876S10.3945/an.114.00585025398754
  41. B. GrayF. SteynP.S. DaviesL. VitettaOmega-3 fatty acids: A review of the effects on adiponectin and leptin and potential implications for obesity managementEur. J. Clin. Nutr.2013671234124210.1038/ejcn.2013.19724129365
  42. Y.T. WenJ.H. DaiQ. GaoEffects of Omega-3 fatty acid on major cardiovascular events and mortality in patients with coronary heart disease: A meta-analysis of randomized controlled trialsNutr. Metab. Cardiovasc. Dis.20142447047510.1016/j.numecd.2013.12.00424472636
  43. E. Lopez-HuertasThe effect of EPA and DHA on metabolic syndrome patients: A systematic review of randomised controlled trialsBr. J. Nutr.201210718519410.1017/S000711451200157222591892
  44. M.I. MaiorinoP. ChiodiniG. BellastellaD. GiuglianoK. EspositoSexual dysfunction in women with cancer: A systematic review with meta-analysis of studies using the Female Sexual Function IndexEndocrine20165432934110.1007/s12020-015-0812-626643312
  45. EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies)Scientific Opinion on Dietary Reference Values for fats, including saturated fatty acids, polyunsaturated fatty acids, monounsaturated fatty acids, trans fatty acids, and cholesterol1EFSA J.2010814611566
  46. G. BellastellaA. BizzarroE. AitellaM. BarrassoD. CozzolinoS. di MartinoK. EspositoA. de BellisPregnancy may favour the development of severe autoimmune central diabetes insipidus in women with vasopressin cell antibodies: Description of two casesEur. J. Endocrinol.2015172K11K1710.1530/EJE-14-076225501964
  47. F.H. SunC. LiY.J. ZhangS.H. WongL. WangEffect of Glycemic Index of Breakfast on Energy Intake at Subsequent Meal among Healthy People: A Meta-AnalysisNutrients201683710.3390/nu801003726742058
  48. A.W. BarclayJ.C. Brand-MillerT.M. WoleverGlycemic index, glycemic load, and glycemic response are not the sameDiabetes Care2005281839184010.2337/diacare.28.7.183915983358
  49. T. NakagawaH. HuS. ZharikovK.R. TuttleR.A. ShortO. GlushakovaX. OuyangD.I. FeigE.R. BlockJ. Herrera-AcostaA causal role for uric acid in fructose-induced metabolic syndromeAm. J. Physiol. Ren. Physiol.2006290F625F63110.1152/ajprenal.00140.200516234313
  50. D. Symons DownsH.A. HausenblasWomen’s exercise beliefs and behaviors during their pregnancy and postpartumJ. Midwifery Women Health200449138144
  51. J. Brand-MillerJ. McMillan-PriceK. SteinbeckI. CatersonDietary glycemic index: Health implicationsJ. Am. Coll. Nutr.200928446S449S10.1080/07315724.2009.1071811020234031
  52. D. ThomasE.J. ElliottLow glycaemic index, or low glycaemic load, diets for diabetes mellitusCochrane Database Syst. Rev.200910.1002/14651858.CD006296.pub2
  53. L. BarreaN. BalatoC. di SommaP.E. MacchiaM. NapolitanoM.C. SavanelliK. EspositoA. ColaoS. SavastanoNutrition and psoriasis: Is there any association between the severity of the disease and adherence to the Mediterranean diet?J. Transl. Med.2015131810.1186/s12967-014-0372-125622660
  54. K.C. MathiasS.W. NgB. PopkinMonitoring changes in the nutritional content of ready-to-eat grain-based dessert products manufactured and purchased between 2005 and 2012J. Acad. Nutr. Diet.201511536036810.1016/j.jand.2014.10.01825541065
  55. M. SerafiniD. del RioUnderstanding the association between dietary antioxidants, redox status and disease: Is the Total Antioxidant Capacity the right tool?Redox Rep.2004914515210.1179/13510000422500481415327744
  56. G. BellastellaM.I. MaiorinoL. OlitaE. della VolpeD. GiuglianoK. EspositoPremature ejaculation is associated with glycemic control in Type 1 diabetesJ. Sex. Med.201512939910.1111/jsm.1275525424355
  57. M.A. ZuletM.J. Moreno-AliagaJ.A. MartinezDietary Determinants of Fat Mass and Body CompositionAdipose Tissue BiologyM.E. SymondsSpringerNew York, NY, USA2012271315
  58. M.H. CarlsenB.L. HalvorsenK. HolteS.K. BohnS. DraglandL. SampsonC. WilleyH. SenooY. UmezonoC. SanadaThe total antioxidant content of more than 3100 foods, beverages, spices, herbs and supplements used worldwideNutr. J.20109310.1186/1475-2891-9-320096093
  59. J. HarasymR. OledzkiEffect of fruit and vegetable antioxidants on total antioxidant capacity of blood plasmaNutrition20143051151710.1016/j.nut.2013.08.01924698344
  60. M.I. MaiorinoG. BellastellaM. PetrizzoE. della VolpeR. OrlandoD. GiuglianoK. EspositoCirculating endothelial progenitor cells in type 1 diabetic patients with erectile dysfunctionEndocrine20154941542110.1007/s12020-014-0478-525411101
  61. Z. BahadoranM. GolzarandP. MirmiranN. ShivaF. AziziDietary total antioxidant capacity and the occurrence of metabolic syndrome and its components after a 3-year follow-up in adults: Tehran Lipid and Glucose StudyNutr. Metab.201297010.1186/1743-7075-9-7022849424
  62. C. ChrysohoouK. EspositoD. GiuglianoD.B. PanagiotakosPeripheral Arterial Disease and Cardiovascular Risk: The Role of Mediterranean DietAngiology20156670871010.1177/000331971455665125354501
  63. R. De la IglesiaP. Lopez-LegarreaP. CeladaF.J. Sanchez-MunizJ.A. MartinezM.A. ZuletBeneficial effects of the RESMENA dietary pattern on oxidative stress in patients suffering from metabolic syndrome with hyperglycemia are associated to dietary TAC and fruit consumptionInt. J. Mol. Sci.2013146903691910.3390/ijms1404690323535332
  64. P. Lopez-LegarreaR. de la IglesiaI. AbeteI. Bondia-PonsS. Navas-CarreteroL. ForgaJ.A. MartinezM.A. ZuletShort-term role of the dietary total antioxidant capacity in two hypocaloric regimes on obese with metabolic syndrome symptoms: The RESMENA randomized controlled trialNutr. Metab.2013102210.1186/1743-7075-10-2223406163
  65. B. PuchauM.A. ZuletA.G. de EchavarriH.H. HermsdorffJ.A. MartinezDietary total antioxidant capacity is negatively associated with some metabolic syndrome features in healthy young adultsNutrition20102653454110.1016/j.nut.2009.06.01719783122
  66. World Health OrganizationObesity: Preventing and Managing the Global EpidemicReport of a WHO ConsultationWorld Health Organization Technical Report SeriesWHOGeneva, Switzerland2000
  67. L.C. TapsellI. HemphillL. CobiacC.S. PatchD.R. SullivanM. FenechS. RoodenrysJ.B. KeoghP.M. CliftonP.G. WilliamsHealth benefits of herbs and spices: The past, the present, the futureMed. J. Aust.2006185S4S2417022438
  68. I. AbeteA. AstrupJ.A. MartinezI. ThorsdottirM.A. ZuletObesity and the metabolic syndrome: Role of different dietary macronutrient distribution patterns and specific nutritional components on weight loss and maintenanceNutr. Rev.20106821423110.1111/j.1753-4887.2010.00280.x20416018
  69. C.B. EbbelingJ.F. SwainH.A. FeldmanW.W. WongD.L. HacheyE. Garcia-LagoD.S. LudwigEffects of dietary composition on energy expenditure during weight-loss maintenanceJAMA20123072627263410.1001/jama.2012.660722735432
  70. I. AbeteE. GoyenecheaM.A. ZuletJ.A. MartinezObesity and metabolic syndrome: Potential benefit from specific nutritional componentsNutr. Metab. Cardiovasc. Dis.201121B1B1510.1016/j.numecd.2011.05.00121764273
  71. P.J. ArcieroM.J. OrmsbeeC.L. GentileB.C. NindlJ.R. BrestoffM. RubyIncreased protein intake and meal frequency reduces abdominal fat during energy balance and energy deficitObesity2013211357136610.1002/oby.2029623703835
  72. T. WikarekJ. ChudekA. OwczarekM. Olszanecka-GlinianowiczEffect of dietary macronutrients on postprandial incretin hormone release and satiety in obese and normal-weight womenBr. J. Nutr.201411123624610.1017/S000711451300238923920407
  73. G.A. BrayS.R. SmithL. de JongeH. XieJ. RoodC.K. MartinM. MostC. BrockS. MancusoL.M. RedmanEffect of dietary protein content on weight gain, energy expenditure, and body composition during overeating: A randomized controlled trialJAMA2012307475510.1001/jama.2011.191822215165
  74. M.S. Westerterp-PlantengaA. NieuwenhuizenD. TomeS. SoenenK.R. WesterterpDietary protein, weight loss, and weight maintenanceAnnu. Rev. Nutr.200929214110.1146/annurev-nutr-080508-14105619400750
  75. L.L. KoppesN. BoonA.C. NooyensW. van MechelenW.H. SarisMacronutrient distribution over a period of 23 years in relation to energy intake and body fatnessBr. J. Nutr.200910110811510.1017/S000711450898686418466652
  76. L. De JongeG.A. BrayS.R. SmithD.H. RyanR.J. de SouzaC.M. LoriaC.M. ChampagneD.A. WilliamsonF.M. SacksEffect of diet composition and weight loss on resting energy expenditure in the POUNDS LOST studyObesity2012202384238910.1038/oby.2012.12722627912
  77. T. StocksL. AngquistJ. HagerC. CharonC. HolstJ.A. MartinezW.H. SarisA. AstrupT.I. SorensenL.H. LarsenTFAP2B-dietary protein and glycemic index interactions and weight maintenance after weight loss in the DiOGenes trialHum. Hered.20137521321910.1159/00035359124081236
  78. D. GiuglianoM.I. MaiorinoK. EspositoLinking prediabetes and cancer: A complex issueDiabetologia20155820120210.1007/s00125-014-3426-225344392
  79. L.Q. BendtsenJ.K. LorenzenN.T. BendsenC. RasmussenA. AstrupEffect of dairy proteins on appetite, energy expenditure, body weight, and composition: A review of the evidence from controlled clinical trialsAdv. Nutr.2013441843810.3945/an.113.00372323858091
  80. M. HeerS. EgertNutrients other than carbohydrates: Their effects on glucose homeostasis in humansDiabetes Metab. Res. Rev.201531143510.1002/dmrr.253324510463
  81. D.K. LaymanE.M. EvansD. EricksonJ. SeylerJ. WeberD. BagshawA. GrielT. PsotaP. Kris-EthertonA moderate-protein diet produces sustained weight loss and long-term changes in body composition and blood lipids in obese adultsJ. Nutr.200913951452110.3945/jn.108.09944019158228
  82. A.N. PedersenJ. KondrupE. BorsheimHealth effects of protein intake in healthy adults: A systematic literature reviewFood Nutr. Res.2013572124510.3402/fnr.v57i0.2124523908602
  83. R.M. DalyS.L. O’ConnellN.L. MundellC.A. GrimesD.W. DunstanC.A. NowsonProtein-enriched diet, with the use of lean red meat, combined with progressive resistance training enhances lean tissue mass and muscle strength and reduces circulating IL-6 concentrations in elderly women: A cluster randomized controlled trialAm. J. Clin. Nutr.20149989991010.3945/ajcn.113.06415424477043
  84. P.J. ArcieroC.L. GentileR. PressmanM. EverettM.J. OrmsbeeJ. MartinJ. SantamoreL. GormanP.C. FehlingM.D. VukovichModerate protein intake improves total and regional body composition and insulin sensitivity in overweight adultsMetab. Clin. Exp.20085775776510.1016/j.metabol.2008.01.01518502257
  85. S.M. GregoryS.A. HeadleyR.J. WoodEffects of dietary macronutrient distribution on vascular integrity in obesity and metabolic syndromeNutr. Rev.20116950951910.1111/j.1753-4887.2011.00390.x21884131
  86. Consenso FESNAD-SEEDORecomendaciones nutricionales basadas en la evidencia para la prevención y el tratamiento del sobrepeso y la obesidad en adultos (Consenso FESNAD-SEEDO)Rev. Esp. Obes.20111036
  87. D. JakubowiczO. FroyJ. WainsteinM. BoazMeal timing and composition influence ghrelin levels, appetite scores and weight loss maintenance in overweight and obese adultsSteroids20127732333110.1016/j.steroids.2011.12.00622178258
  88. N.A. SchwarzB.R. RigbyP. La BountyB. ShelmadineR.G. BowdenA review of weight control strategies and their effects on the regulation of hormonal balanceJ. Nutr. Metab.2011201123793210.1155/2011/23793221822485
  89. K. OhkawaraM.A. CornierW.M. KohrtE.L. MelansonEffects of increased meal frequency on fat oxidation and perceived hungerObesity20132133634310.1002/oby.2003223404961
  90. C. EkmekciogluY. TouitouChronobiological aspects of food intake and metabolism and their relevance on energy balance and weight regulationObes. Rev.201112142510.1111/j.1467-789X.2010.00716.x20122134
  91. S. LioretM. TouvierL. LafayJ.L. VolatierB. MaireAre eating occasions and their energy content related to child overweight and socioeconomic status?Obesity2008162518252310.1038/oby.2008.40418772863
  92. S. BhutaniK.A. VaradyNibbling versus feasting: Which meal pattern is better for heart disease prevention?Nutr. Rev.20096759159810.1111/j.1753-4887.2009.00231.x19785690
  93. H.J. LeidyM. TangC.L. ArmstrongC.B. MartinW.W. CampbellThe effects of consuming frequent, higher protein meals on appetite and satiety during weight loss in overweight/obese menObesity20111981882410.1038/oby.2010.20320847729
  94. J.P. MillsC.D. PerryM. ReicksEating frequency is associated with energy intake but not obesity in midlife womenObesity20111955255910.1038/oby.2010.26520966909
  95. J.D. CameronM.J. CyrE. DoucetIncreased meal frequency does not promote greater weight loss in subjects who were prescribed an 8-week equi-energetic energy-restricted dietBr. J. Nutr.20101031098110110.1017/S000711450999298419943985
  96. A.J. SmeetsM.P. LejeuneM.S. Westerterp-PlantengaEffects of oral fat perception by modified sham feeding on energy expenditure, hormones and appetite profile in the postprandial stateBr. J. Nutr.20091011360136810.1017/S000711450807959218814804
  97. M.A. TaylorJ.S. GarrowCompared with nibbling, neither gorging nor a morning fast affect short-term energy balance in obese patients in a chamber calorimeterInt. J. Obes. Relat. Metab. Disord.20012551952810.1038/sj.ijo.080157211319656
  98. A.J. SmeetsM.S. Westerterp-PlantengaAcute effects on metabolism and appetite profile of one meal difference in the lower range of meal frequencyBr. J. Nutr.2008991316132110.1017/S000711450787764618053311
  99. T.D. HedenJ.D. LeCheminantJ.D. SmithInfluence of weight classification on walking and jogging energy expenditure prediction in womenRes. Q. Exerc. Sport20128339139910.1080/02701367.2012.1059987322978188
  100. J.L. BachmanH.A. RaynorEffects of manipulating eating frequency during a behavioral weight loss intervention: A pilot randomized controlled trialObesity20122098599210.1038/oby.2011.36022173575
  101. M.M. PerrigueA. DrewnowskiC.Y. WangM.L. NeuhouserHigher Eating Frequency Does Not Decrease Appetite in Healthy AdultsJ. Nutr.2016146596410.3945/jn.115.21697826561409
  102. A. KeysCoronary heart disease in seven countries. 1970Nutrition19971324925310.1016/S0899-9007(96)00410-89131697
  103. A. KeysA. MenottiC. AravanisH. BlackburnB.S. DjordevicR. BuzinaA.S. DontasF. FidanzaM.J. KarvonenN. KimuraThe seven countries study: 2289 deaths in 15 yearsPrev. Med.19841314115410.1016/0091-7435(84)90047-16739443
  104. C. DavisJ. BryanJ. HodgsonK. MurphyDefinition of the Mediterranean Diet; a Literature ReviewNutrients201579139915310.3390/nu711545926556369
  105. F. SofiC. MacchiR. AbbateG.F. GensiniA. CasiniMediterranean diet and health status: An updated meta-analysis and a proposal for a literature-based adherence scorePublic Health Nutr.2014172769278210.1017/S136898001300316924476641
  106. J. Mayneris-PerxachsA. Sala-VilaM. ChisaguanoA.I. CastelloteR. EstruchM.I. CovasM. FitoJ. Salas-SalvadoM.A. Martinez-GonzalezR. Lamuela-RaventosEffects of 1-year intervention with a Mediterranean diet on plasma fatty acid composition and metabolic syndrome in a population at high cardiovascular riskPLoS ONE20149e8520210.1371/journal.pone.008520224651160
  107. K. EspositoM.I. MaiorinoG. BellastellaP. ChiodiniD. PanagiotakosD. GiuglianoA journey into a Mediterranean diet and type 2 diabetes: A systematic review with meta-analysesBMJ Open20155e00822210.1136/bmjopen-2015-00822226260349
  108. C.M. KastoriniH.J. MilionisK. EspositoD. GiuglianoJ.A. GoudevenosD.B. PanagiotakosThe effect of Mediterranean diet on metabolic syndrome and its components: A meta-analysis of 50 studies and 534,906 individualsJ. Am. Coll. Cardiol.2011571299131310.1016/j.jacc.2010.09.07321392646
  109. L. SchwingshacklB. MissbachJ. KonigG. HoffmannAdherence to a Mediterranean diet and risk of diabetes: A systematic review and meta-analysisPublic Health Nutr.2015181292129910.1017/S136898001400154225145972
  110. E. KoloverouK. EspositoD. GiuglianoD. PanagiotakosThe effect of Mediterranean diet on the development of type 2 diabetes mellitus: A meta-analysis of 10 prospective studies and 136,846 participantsMetab. Clin. Exp.20146390391110.1016/j.metabol.2014.04.01024931280
  111. J. Salas-SalvadoA. Garcia-ArellanoR. EstruchF. Marquez-SandovalD. CorellaM. FiolE. Gomez-GraciaE. VinolesF. ArosC. HerreraComponents of the Mediterranean-type food pattern and serum inflammatory markers among patients at high risk for cardiovascular diseaseEur. J. Clin. Nutr.20086265165910.1038/sj.ejcn.160276217440519
  112. M.A. Martinez-GonzalezM. Garcia-LopezM. Bes-RastrolloE. ToledoE.H. Martinez-LapiscinaM. Delgado-RodriguezZ. VazquezS. BenitoJ.J. BeunzaMediterranean diet and the incidence of cardiovascular disease: A Spanish cohortNutr. Metab. Cardiovasc. Dis.20112123724410.1016/j.numecd.2009.10.00520096543
  113. M. FitoR. EstruchJ. Salas-SalvadoM.A. Martinez-GonzalezF. ArosJ. VilaD. CorellaO. DiazG. SaezR. de la TorreEffect of the Mediterranean diet on heart failure biomarkers: A randomized sample from the PREDIMED trialEur. J. Heart Fail.20141654355010.1002/ejhf.6124574190
  114. R. EstruchE. RosJ. Salas-SalvadoM.I. CovasD. CorellaF. ArosE. Gomez-GraciaV. Ruiz-GutierrezM. FiolJ. LapetraPrimary prevention of cardiovascular disease with a Mediterranean dietN. Engl. J. Med.20133681279129010.1056/NEJMoa120030323432189
  115. L. Serra-MajemB. RomanR. EstruchScientific evidence of interventions using the Mediterranean diet: A systematic reviewNutr. Rev.200664S27S4710.1111/j.1753-4887.2006.tb00232.x16532897
  116. K. EspositoC.M. KastoriniD.B. PanagiotakosD. GiuglianoMediterranean diet and weight loss: Meta-analysis of randomized controlled trialsMetab. Syndr. Relat. Disord.2011911210.1089/met.2010.003120973675
  117. C. RazquinJ.A. MartinezM.A. Martinez-GonzalezM.T. MitjavilaR. EstruchA. MartiA 3 years follow-up of a Mediterranean diet rich in virgin olive oil is associated with high plasma antioxidant capacity and reduced body weight gainEur. J. Clin. Nutr.2009631387139310.1038/ejcn.2009.10619707219
  118. S. BertoliA. SpadafrancaM. Bes-RastrolloM.A. Martinez-GonzalezV. PonissiV. BeggioA. LeoneA. BattezzatiAdherence to the Mediterranean diet is inversely related to binge eating disorder in patients seeking a weight loss programClin. Nutr.20153410711410.1016/j.clnu.2014.02.00124559856
  119. A. Rios-HoyoM.J. CortesH. Rios-OntiverosE. MeaneyG. CeballosG. Gutierrez-SalmeanObesity, Metabolic Syndrome, and Dietary Therapeutical Approaches with a Special Focus on Nutraceuticals (Polyphenols): A Mini-ReviewInt. J. Vitam. Nutr. Res.20148411312310.1024/0300-9831/a00019826098475
  120. S.P. JuraschekE. GuallarL.J. AppelE.R. Miller 3rd.Effects of vitamin C supplementation on blood pressure: A meta-analysis of randomized controlled trialsAm. J. Clin. Nutr.2012951079108810.3945/ajcn.111.02799522492364
  121. A.J. MichelsB. FreiMyths, artifacts, and fatal flaws: Identifying limitations and opportunities in vitamin C researchNutrients201355161519210.3390/nu512516124352093
  122. B. FreiI. Birlouez-AragonJ. LykkesfeldtAuthors’ perspective: What is the optimum intake of vitamin C in humans?Crit. Rev. Food Sci. Nutr.20125281582910.1080/10408398.2011.64914922698272
  123. S.A. MasonP.A. della GattaR.J. SnowA.P. RussellG.D. WadleyAscorbic acid supplementation improves skeletal muscle oxidative stress and insulin sensitivity in people with type 2 diabetes: Findings of a randomized controlled studyFree Radic. Biol. Med.20169322723810.1016/j.freeradbiomed.2016.01.00626774673
  124. S. ChambialS. DwivediK.K. ShuklaP.J. JohnP. SharmaVitamin C in Disease Prevention and Cure: An OverviewIndian J. Clin. Biochem.20132831432810.1007/s12291-013-0375-324426232
  125. G. BlockC.D. JensenT.B. DalviE.P. NorkusM. HudesP.B. CrawfordN. HollandE.B. FungL. SchumacherP. HarmatzVitamin C treatment reduces elevated C-reactive proteinFree Radic. Biol. Med.200946707710.1016/j.freeradbiomed.2008.09.03018952164
  126. A.W. AshorM. SiervoJ. LaraC. OggioniS. AfsharJ.C. MathersEffect of vitamin C and vitamin E supplementation on endothelial function: A systematic review and meta-analysis of randomised controlled trialsBr. J. Nutr.20151131182119410.1017/S000711451500022725919436
  127. S.M. KimS.M. LimJ.A. YooM.J. WooK.H. ChoConsumption of high-dose vitamin C (1250 mg per day) enhances functional and structural properties of serum lipoprotein to improve anti-oxidant, anti-atherosclerotic, and anti-aging effects via regulation of anti-inflammatory microRNAFood Funct.201563604361210.1039/C5FO00738K26333284
  128. S. MonfaredB. LarijaniM. AbdollahiIslet transplantation and antioxidant management: A comprehensive reviewWorld J. Gastroenterol.2009151153116110.3748/wjg.15.115319291814
  129. German Nutrition Society (DGE)New Reference Values for Vitamin C IntakeAnn. Nutr. Metab.201567132026227083
  130. A.C. MamedeS.D. TavaresA.M. AbrantesJ. TrindadeJ.M. MaiaM.F. BotelhoThe role of vitamins in cancer: A reviewNutr. Cancer20116347949410.1080/01635581.2011.53931521541902
  131. M.A. MoserO.K. ChunVitamin C and Heart Health: A Review Based on Findings from Epidemiologic StudiesInt. J. Mol. Sci.201617132810.3390/ijms1708132827529239
  132. C. Vilaplana-PerezD. AunonL.A. Garcia-FloresA. Gil-IzquierdoHydroxytyrosol and potential uses in cardiovascular diseases, cancer, and AIDSFront. Nutr.201411825988120
  133. Y. AchmonA. FishmanThe antioxidant hydroxytyrosol: Biotechnological production challenges and opportunitiesAppl. Microbiol. Biotechnol.2015991119113010.1007/s00253-014-6310-625547836
  134. S. BulottaM. CelanoS.M. LeporeT. MontalciniA. PujiaD. RussoBeneficial effects of the olive oil phenolic components oleuropein and hydroxytyrosol: Focus on protection against cardiovascular and metabolic diseasesJ. Transl. Med.20141221910.1186/s12967-014-0219-925086598
  135. EFSA NDA Panel (EFSA Panel on Dietetic Products, Nutrition and Allergies)Scientific Opinion on the substantiation of health claims related to polyphenols in olive and protection of LDL particles from oxidative damage (ID 1333, 1638, 1639, 1696, 2865), maintenance of normal blood HDL cholesterol concentrations (ID 1639)EFSA J.2011920332058
  136. E. ScodittiA. NestolaM. MassaroN. CalabrisoC. StorelliR. De CaterinaM.A. CarluccioHydroxytyrosol suppresses MMP-9 and COX-2 activity and expression in activated human monocytes via PKCalpha and PKCbeta1 inhibitionAtherosclerosis2014232172410.1016/j.atherosclerosis.2013.10.01724401212
  137. E. GiordanoO. DanglesN. RakotomanomanaS. BaracchiniF. Visioli3-O-Hydroxytyrosol glucuronide and 4-O-hydroxytyrosol glucuronide reduce endoplasmic reticulum stress in vitroFood Funct.201563275328110.1039/C5FO00562K26238415
  138. S. Granados-PrincipalJ.L. QuilesC.L. Ramirez-TortosaP. Sanchez-RoviraM.C. Ramirez-TortosaHydroxytyrosol: From laboratory investigations to future clinical trialsNutr. Rev.20106819120610.1111/j.1753-4887.2010.00278.x20416016
  139. M.A. CarluccioL. SiculellaM.A. AncoraM. MassaroE. ScodittiC. StorelliF. VisioliA. DistanteR. De CaterinaOlive oil and red wine antioxidant polyphenols inhibit endothelial activation: Antiatherogenic properties of Mediterranean diet phytochemicalsArterioscler. Thromb. Vasc. Biol.20032362262910.1161/01.ATV.0000062884.69432.A012615669
  140. F. VisioliE. BernardiniExtra virgin olive oil’s polyphenols: Biological activitiesCurr. Pharm. Des.20111778680410.2174/13816121179542888521443485
  141. S.F. NabaviG.L. RussoM. DagliaS.M. NabaviRole of quercetin as an alternative for obesity treatment: You are what you eat!Food Chem.201517930531010.1016/j.foodchem.2015.02.00625722169
  142. R. VinayagamB. XuAntidiabetic properties of dietary flavonoids: A cellular mechanism reviewNutr. Metab.2015126010.1186/s12986-015-0057-726705405
  143. T. ShibataF. NakashimaK. HondaY.J. LuT. KondoY. UshidaK. AizawaH. SuganumaS. OeH. TanakaToll-like receptors as a target of food-derived anti-inflammatory compoundsJ. Biol. Chem.2014289327573277210.1074/jbc.M114.58590125294874
  144. J. AhnH. LeeS. KimJ. ParkT. HaThe anti-obesity effect of quercetin is mediated by the AMPK and MAPK signaling pathwaysBiochem. Biophys. Res. Commun.200837354554910.1016/j.bbrc.2008.06.07718586010
  145. X.K. FangJ. GaoD.N. ZhuKaempferol and quercetin isolated from Euonymus alatus improve glucose uptake of 3T3-L1 cells without adipogenesis activityLife Sci.20088261562210.1016/j.lfs.2007.12.02118262572
  146. J.L. ClarkP. ZahradkaC.G. TaylorEfficacy of flavonoids in the management of high blood pressureNutr. Rev.20157379982210.1093/nutrit/nuv04826491142
  147. G. D’AndreaQuercetin: A flavonol with multifaceted therapeutic applications?Fitoterapia201510625627110.1016/j.fitote.2015.09.01826393898
  148. A. LarsonM.A. WitmanY. GuoS. IvesR.S. RichardsonR.S. BrunoT. JaliliJ.D. SymonsAcute, quercetin-induced reductions in blood pressure in hypertensive individuals are not secondary to lower plasma angiotensin-converting enzyme activity or endothelin-1: Nitric oxideNutr. Res.20123255756410.1016/j.nutres.2012.06.01822935338
  149. J. Tome-CarneiroM. GonzalvezM. LarrosaM.J. Yanez-GasconF.J. Garcia-AlmagroJ.A. Ruiz-RosF.A. Tomas-BarberanM.T. Garcia-ConesaJ.C. EspinResveratrol in primary and secondary prevention of cardiovascular disease: A dietary and clinical perspectiveAnn. N. Y. Acad. Sci.20131290375110.1111/nyas.1215023855464
  150. S.S. LeonardC. XiaB.H. JiangB. StinefeltH. KlandorfG.K. HarrisX. ShiResveratrol scavenges reactive oxygen species and effects radical-induced cellular responsesBiochem. Biophys. Res. Commun.20033091017102610.1016/j.bbrc.2003.08.10513679076
  151. Z. RenL. WangJ. CuiZ. HuocJ. XueH. CuiQ. MaoR. YangResveratrol inhibits NF-κB signaling through suppression of p65 and IκB kinase activitiesDie Pharm.201368689694
  152. N. LatruffeA. LanconR. FrazziV. AiresD. DelmasJ.J. MichailleF. DjouadiJ. BastinM. Cherkaoui-MalkiExploring new ways of regulation by resveratrol involving miRNAs, with emphasis on inflammationAnn. N. Y. Acad. Sci.201513489710610.1111/nyas.1281926190093
  153. H.A. HausenblasJ.A. SchouldaJ.M. SmoligaResveratrol treatment as an adjunct to pharmacological management in type 2 diabetes mellitus—Systematic review and meta-analysisMol. Nutr. Food Res.20155914715910.1002/mnfr.20140017325138371
  154. K. LiuR. ZhouB. WangM.T. MiEffect of resveratrol on glucose control and insulin sensitivity: A meta-analysis of 11 randomized controlled trialsAm. J. Clin. Nutr.2014991510151910.3945/ajcn.113.08202424695890
  155. J.L. BittermanJ.H. ChungMetabolic effects of resveratrol: Addressing the controversiesCell. Mol. Life Sci.2015721473148810.1007/s00018-014-1808-825548801
  156. S. HanJ.S. ParkS. LeeA.L. JeongK.S. OhH.I. KaH.J. ChoiW.C. SonW.Y. LeeS.J. OhCTRP1 protects against diet-induced hyperglycemia by enhancing glycolysis and fatty acid oxidationJ. Nutr. Biochem.201627435210.1016/j.jnutbio.2015.08.01826456564
  157. J. GambiniM. InglesG. OlasoR. Lopez-GruesoV. Bonet-CostaL. Gimeno-MallenchC. Mas-BarguesK.M. AbdelazizM.C. Gomez-CabreraJ. VinaProperties of Resveratrol: In Vitro and In Vivo Studies about Metabolism, Bioavailability, and Biological Effects in Animal Models and HumansOxid. Med. Cell. Longev.2015201583704210.1155/2015/83704226221416
  158. C.S. YangN. SuhCancer prevention by different forms of tocopherolsTop. Curr. Chem.2013329213322836899
  159. Q. JiangNatural forms of vitamin E: Metabolism, antioxidant, and anti-inflammatory activities and their role in disease prevention and therapyFree Radic. Biol. Med.201472769010.1016/j.freeradbiomed.2014.03.03524704972
  160. P.K. WittingJ.M. UpstonR. StockerThe molecular action of alpha-tocopherol in lipoprotein lipid peroxidation. Pro- and antioxidant activity of vitamin E in complex heterogeneous lipid emulsionsFat-Soluble VitaminsP.J. QuinnV.E. KaganSpringerNew York, NY, USA345390
  161. S. SabooriS. Shab-BidarJ.R. SpeakmanE. Yousefi RadK. DjafarianEffect of vitamin E supplementation on serum C-reactive protein level: A meta-analysis of randomized controlled trialsEur. J. Clin. Nutr.20156986787310.1038/ejcn.2014.29625669317
  162. A. AzziS.N. MeydaniM. MeydaniJ.M. ZinggThe rise, the fall and the renaissance of vitamin EArch. Biochem. Biophys.201659510010810.1016/
  163. D. RaederstorffA. WyssP.C. CalderP. WeberM. EggersdorferVitamin E function and requirements in relation to PUFABr. J. Nutr.20151141113112210.1017/S000711451500272X26291567
  164. L. LoffredoL. PerriA. Di CastelnuovoL. IacovielloG. De GaetanoF. VioliSupplementation with vitamin E alone is associated with reduced myocardial infarction: A meta-analysisNutr. Metab. Cardiovasc. Dis.20152535436310.1016/j.numecd.2015.01.00825779938
  165. F. GiampieriS. TulipaniJ.M. Alvarez-SuarezJ.L. QuilesB. MezzettiM. BattinoThe strawberry: Composition, nutritional quality, and impact on human healthNutrition20122891910.1016/j.nut.2011.08.00922153122
  166. M.J. AmiotC. RivaA. VinetEffects of dietary polyphenols on metabolic syndrome features in humans: A systematic reviewObes. Rev.20161757358610.1111/obr.1240927079631
  167. A. SmeriglioD. BarrecaE. BelloccoD. TrombettaChemistry, Pharmacology and Health Benefits of AnthocyaninsPhytother. Res.2016301265128610.1002/ptr.564227221033
  168. M.A. LilaAnthocyanins and Human Health: An In Vitro Investigative ApproachJ. Biomed. Biotechnol.2004200430631310.1155/S111072430440401X15577194
  169. A.J. StullK.C. CashW.D. JohnsonC.M. ChampagneW.T. CefaluBioactives in blueberries improve insulin sensitivity in obese, insulin-resistant men and womenJ. Nutr.20101401764176810.3945/jn.110.12533620724487
  170. Y. ZhuM. XiaY. YangF. LiuZ. LiY. HaoM. MiT. JinW. LingPurified anthocyanin supplementation improves endothelial function via NO-cGMP activation in hypercholesterolemic individualsClin. Chem.2011571524153310.1373/clinchem.2011.16736121926181
  171. Y. QinM. XiaJ. MaY. HaoJ. LiuH. MouL. CaoW. LingAnthocyanin supplementation improves serum LDL- and HDL-cholesterol concentrations associated with the inhibition of cholesteryl ester transfer protein in dyslipidemic subjectsAm. J. Clin. Nutr.20099048549210.3945/ajcn.2009.2781419640950
  172. Y. ZhuW. LingH. GuoF. SongQ. YeT. ZouD. LiY. ZhangG. LiY. XiaoAnti-inflammatory effect of purified dietary anthocyanin in adults with hypercholesterolemia: A randomized controlled trialNutr. Metab. Cardiovasc. Dis.20132384384910.1016/j.numecd.2012.06.00522906565
  173. Y. ZhuX. HuangY. ZhangY. WangY. LiuR. SunM. XiaAnthocyanin supplementation improves HDL-associated paraoxonase 1 activity and enhances cholesterol efflux capacity in subjects with hypercholesterolemiaJ. Clin. Endocrinol. Metab.20149956156910.1210/jc.2013-284524285687
  174. A. KarlsenL. RetterstolP. LaakeI. PaurS.K. BohnL. SandvikR. BlomhoffAnthocyanins inhibit nuclear factor-kappaB activation in monocytes and reduce plasma concentrations of pro-inflammatory mediators in healthy adultsJ. Nutr.20071371951195417634269
  175. M.A. KeskeH.L. NgD. PremilovacS. RattiganJ.A. KimK. MunirP. YangM.J. QuonVascular and metabolic actions of the green tea polyphenol epigallocatechin gallateCurr. Med. Chem.201522596910.2174/092986732166614101217455325312214
  176. R. JohnsonS. BryantA.L. HuntleyGreen tea and green tea catechin extracts: An overview of the clinical evidenceMaturitas20127328028710.1016/j.maturitas.2012.08.00822986087
  177. J. HuangY. WangZ. XieY. ZhouY. ZhangX. WanThe anti-obesity effects of green tea in human intervention and basic molecular studiesEur. J. Clin. Nutr.2014681075108710.1038/ejcn.2014.14325074392
  178. R. HurselM.S. Westerterp-PlantengaCatechin- and caffeine-rich teas for control of body weight in humansAm. J. Clin. Nutr.2013981682S1693S10.3945/ajcn.113.05839624172301
  179. G. Gutierrez-SalmeanP. Ortiz-VilchisC.M. VacaseydelI. Rubio-GayossoE. MeaneyF. VillarrealI. Ramirez-SanchezG. CeballosAcute effects of an oral supplement of (−)-epicatechin on postprandial fat and carbohydrate metabolism in normal and overweight subjectsFood Funct.2014552152710.1039/c3fo60416k24458104
  180. S. KhalesiJ. SunN. BuysA. JamshidiE. Nikbakht-NasrabadiH. Khosravi-BoroujeniGreen tea catechins and blood pressure: A systematic review and meta-analysis of randomised controlled trialsEur. J. Nutr.2014531299131110.1007/s00394-014-0720-124861099
The underlying source XML for this text is taken from The license for the article is Creative Commons Attribution. The main subject has been identified as metabolic syndrome.