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Polyphenols and ω-3 PUFAs: Beneficial Outcomes to Obesity and Its Related Metabolic Diseases

Obesity is associated with the leading causes of death in the worldwide. On the other hand, the intake of vegetables, fruits and fish is related to the reduction of obesity and other metabolic syndromes. This review aims to highlight the role of ingestion of polyphenols and omega-3 polyunsaturated fatty acids (ω-3 PUFAs) in reducing obesity and related metabolic diseases (RMDs). The consumption of vegetables, fish and by-products rich in polyphenols and α-linolenic acid (ALA), as well as oils rich in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) are associated with a decrease in obesity and its RMDs in consumers. Furthermore, we discussed the adequate amount of extracts, powder, polyphenols, ω-3 PUFAs administrated in animal models and human subjects, and the relevant outcomes obtained. Thus, we appeal to the research institutions and departments of the Ministries of Health in each country to develop a food education joint project to help schools, businesses and families with the aim of reducing obesity and other metabolic diseases.


INTRODUCTION
Obesity is an abnormal accumulation of fat in cells that interferes with the maintenance of an individual's health. It is a chronic disease characterized by lower amounts of energy expenditure than ingestion, leading to body weight gain over time due to excessive increase in adipose tissue mass (1), triggering pro-inflammatory agents (2). Furthermore, obesity is linked with several diseases such as insulin resistance, systematic inflammation, diabetes mellitus (DM), hypertension, coronary heart diseases (CHD), adipocyte hypertrophy, non-alcoholic fatty liver disease (NAFLD), and others (3,4). Weight can be calculated from the mathematical formula of the body mass index (BMI = mass/height × height), being considered overweight that can progress to obesity when BMI ≥ 25 and ≥ 30 kg/m 2 (1,2). In the adult population, the occurrence of obesity and overweight is 39 and 50%, and it is mainly explained by the easy access to high-calorie foods (fast food) and sedentary lifestyle (5).
Systemic complications in obese patients are associated with increased abdominal fat, severe organ and tissue failure due to an increased pro-inflammatory cytokine storm, lipopolysaccharide and oxidative stress conditions (6). In addition, several studies have reported a decrease in obesity and its RMDs due to consumption of vegetables (leaves, seeds, nuts, fruits, vegetable oils, by-products) and fish (mainly marine fish, oils, byproducts) rich in polyphenols and ω-3 PUFAs: ALA, EPA, and DHA (7)(8)(9)(10)(11)(12)(13). Furthermore, obesity and its RMDs lowering can be explained by consequence of synergistic actions of polyphenols and ω-3 PUFAs improving several metabolic health pathways (14,15). Due to the synergistic actions of the polyphenols and ω-3 PUFAs, some products that are found, like fish and vegetables, and their by-products can potentially improve and control obesity and its RMDs as anti-glucose tolerance, anti-oxidative, anti-atherosclerosis, antiinflammation, anti-weight gain, hepato-protective, vascularprotective, cardiovascular-protective, anti-hypertension, antidiabetic effects, thus improving the human health (13,(16)(17)(18)(19)(20)(21). The beneficial effects of foods that contain polyphenols, ALA, EPA and DHA in their composition are summarized in Figure 1.
However, despite the reported benefit of polyphenols and ω-3 PUFAs reported, obesity and its RMDs high incidence can be correlated with inadequate food intake FIGURE 1 | Overview of polyphenols, α-linolenic (ALA), eicosapentaenoic (EPA), and docosahexaenoic acids (DHA) natural sources. The polyphenol compounds obtained from vegetables are active natural antioxidants, which slow up or reduce the high speed of degradation of ALA, EPA, and DHA, quenching singlet oxygen and reacting or eliminating the free radicals, prolong the half-life of these acids during their storing and confection of food. The ingestion of polyphenols, ALA, EPA, and DHA in natural conditions prevent obesity and its related metabolic diseases, including these presented in the scheme. However, the benefit does not occur when polyphenols, ALA, EPA, and DHA are denaturated during the extraction process, storage, and food confection. Through the biosynthesis processes with the actions of enzymes, ALA is converted to EPA and DHA. The synergistic effects of polyphenols, EPA and DHA in the body promote health with preventing and reducing obesity and its related diseases for the consumers. ↓, significant decrease; DM, diabetes mellitus; CHD, cardiovascular heart diseases. (22), the lower cost of unhealthy food acquisition (23) and cultural behaviors barriers (24) allied to unfavorable educational programs impact negatively on healthy food acquisition (25).
In this review, we aimed to emphasize the benefit of polyphenols and ω-3 PUFAs regular intake and their sources and to propose joint actions allied to consumer's behavior change for reducing obesity and its RMDs (systematic inflammation, cardiovascular diseases, hypertension, diabetes mellitus, high insulin level, metabolic syndrome, and others).

THE MAIN POLYPHENOLS SOURCES
Vegetables, fruits, seeds, almonds, and cereals are widely known in diets and supplementations for their enormous benefits on health improving, preventing, and reducing obesity and its RMDs (9,13). Health benefits are associated with the effect of bioactive substances, mainly represented by compounds with antioxidant action that are responsible for functions such as the half-life of products and their by-products (residue products as peel, pulp and seed) (12,16,(26)(27)(28)(29)(30). The main polyphenol substances occurs in leaves, flowers, roots, bulbs, and rhizomes of several wild edible plants (31,32). In addition, polyphenol is present in fruits as apple, grapes, pear, cherries, berries, coffee, cereals and chocolate (33), citrus, mangoes, garlic, onions (34), tomatoes, potatoes, carrots, leaves (tea), and vegetables (broccoli, cabbages, pumpkin, spinach, and lettuce). In addition, these plants (35) (37), ellagitannins, and others (38). The effects of vegetables, fruits and polyphenols on obesity and its RMDs in animal models are summarized in Table 1.
Several studies have been reported on obesity and its RMDs lowering using different extracts from leaves, flowers, fruits, seeds, rhizome, powder, and EVOO obtained from wild and cultivated plants regularly administrated at 3 mg/kg/day to 23 g/kg/day for 3-24 weeks to animal models ( Table 1). Controversially, other studies using dairy dose administrated from the green tea polyphenols (10-29 mg/kg), catechin (200 and 400 mg/kg) (54), caffeic acid, quercetin (2 or 4%) (55), and proanthocyanin grape seed extract (4 g/kg/2 weeks) (56), reported liver, kidney and gastrointestinal toxicity, which can evolve to inflammation or death, due to high reactive oxygen species and oxidative stress formation. In addition, some studies with humans administered polyphenols showed the same results that can be explained by genetic effects, ethnicity, gender, eating habits, length of time, lifestyle, and others (57). Therefore, the reported high health benefits of regular consumption of polyphenol-rich plants and vegetables are widely recommended to prevent, control and reduce obesity and RMDs in humans and animals (57). Likewise, the health benefit for humans with obesity, that administered vegetables, fruits and polyphenols for 4-12 weeks are summarized in Table 2.
The ω-3 PUFAs and ω-6 PUFAs are essential fatty acids (cannot be biosynthesized by the mammalian body, including humans) are required from the diet (78,79). In the human body, through to physiology mechanism reactions, which ALA is converted to long chain PUFAs (LC-PUFAs, fatty acids ≤ C20) and very-long-chain fatty acids (VLCFAs, fatty acids ≥ C22) (78,79), which the ALA converted rate to EPA and DHA is 5-8% (80). The biosynthetic process of VLCFAs production, starting by ALA from the diet to the bloodstream is illustrated in Figure 2.
When consumed and going through several physiological reactions in the body, EPA and DHA present positive effects such as anti-inflammation, vasodilation, bronchodilation and antiplatelet aggregation (78). Beyond, both acids are correlated with cyclooxygenase, prostacyclin, thromboxane, leukotrienes, lipoxins, and resolvins, which play a crucial role in several beneficial physiologic actions (78,79,81). The consumption of an ω-3 PUFAs-rich balanced diet, including ALA, EPA, and DHA is correlated with health-improving and decreasing and or preventing obesity and its RMDs, such as adipose tissue fat accumulation, insulin resistance, inflammation, hypertension, atherosclerosis, CVD, CHD, and DM (4,78,79).
However, due to the presence of double bond in carbon-3 of methyl end (ω-3), including ALA, EPA, and DHA, ω-3 PUFAs family is susceptible to oxidation by light, temperature, metal ions and microorganism degradation during oil extraction and storage by autoxidation reactions (photochemical and photosensitized oxidation) with 4-Hydroxy-2-hexenal production (82,83). These reactions result in enzymatic oxidation with increase the production of Eseries resolvins from EPA, and D-series Resolvins (DHA), prostaglandins, thromboxanes, leukotrienes, epoxy products (84,85). Besides, the ω-3 PUFAs decrease in amount during food confections by thermal processing, while in inversely proportion occurs the increasing of degradation and hazard oxidized substances that damage cell membranes (86,87). The oxidation products are higher in fried, followed by roasted, and boiled foods, which present the same proportion of oxidative products when compared to raw food (88,89). The frying and roasting food confections release the most oxidative products (4(RS)-4-F4t-NeuroP, 4-Hydroxy-2hexenal production, and others), which are correlated with obesity, CVD, inflammation, hypertension, and others diseases (82,83). Therefore, the application of natural antioxidant compounds such as carotenoids, tocopherols, tocotrienols, phytostanols, phytosterols, and ascorbic acid are recommended due to their symbiotic and synergistic interactions decrease oxidation and thermal degradation, prolonging the shelf life of ω-3 PUFAs during the period of storage (90)(91)(92).

DIETARY EPA AND DHA DIETS BENEFITS ON OBESITY AND ITS RMDs
Diets consumption rich in vegetables and fish and their byproducts are correlated with reducing obesity and its RDMs effects for presenting ALA, EPA, and DHA in their composition (4,78,79), and for animal models are summarizing in Table 4.

POLYPHENOLS AND ω-3 PUFAs MECHANISMS ON OBESITY AND ITS RMDs
Increasing of obesity and its RMDs are already observed from childhood to elderly individuals and have become a public health problem in modern society (120,121). A practical alternative against obesity and its RDMs in humans can be associated with diet-rich in polyphenols and ω-3 PUFAs in composition, including their by-products (112). In the body, polyphenols and ω-3 PUFAs (DHA and EPA) physiologically act protecting and inhibiting cascade inflammatory reaction processes that can evolve into obesity, diabetes, CVD, hypercholesterolemia, and others metabolic diseases (122,123). Thus, mechanisms that polyphenols and ω-3 PUFAs are involved in the body, which are crucial to prevent several metabolic diseases, which can be used as adjuvant therapy, are summarized in Figure 3.
In the liver, PUFAs are metabolized and converted into prostaglandins (PGE2) and leukotrienes, which reach the inflammation site being converted into lipoxins, resolvins, protectins, and maresins, which will stimulate type 2 macrophages more so than the type 1 kind, leading to the production of anti-inflammatory interleukins (124,125). Likewise, polyphenols are absorbed in the intestine after being hydrolyzed by intestine enzymes and the host's microbiota (126). Then, the resulting molecules can interact with free radicals and inhibit enzymes involved in the AA pathway, modulating the inflammatory response and blocking the AA pathway (14). Besides that, endothelial cells are also being stimulated by both products from polyphenols and ω-3 PUFAs metabolization to produce NO and H 2 S in the first case, which will aid the resolution of the inflammatory situation and the tissue regeneration, or trigger signaling cascades by interacting with cell membrane receptors such as vascular endothelial growth factor (VEGF) or blocking p-AKT, NF-κB, and MMP-9 activities (122,127).
The mechanisms involved in balancing the inflammatory process are the change of the phospholipid fatty acid composition of the cell membrane, inhibition of the NF-κβ activation, thus reducing the expression of pro-inflammatory genes and production of resolving mediators by macrophages (122).

CONSUMER BEHAVIOR CHANGES ON OBESITY AND ITS RMDs
Choosing daily healthy food type intake is the chief component and managed by humans to improve their own and all family healthy lifestyle (128). Among the several factors of healthy lifestyle or prevalence of obesity and its RMDs can be associated with regular or irregularly and healthy or unhealthy daily food consumed in each meal (22,129). In addition, it may also be associated with the lower purchase price of unhealthy foods on the market compared with healthy ones, whose edible parts (leaves, peel, flesh, seeds, and others) are wasted in homes, restaurants and other food enterprises due to their lack of nutritional knowledge (130,131). In addition, also it is known that refined sugar is often always added to edible vegetables, fruits, natural juices and other by-products and other beverages, which can be associated with obesity, overweight, CVD, and other metabolic diseases prevalence (132). Thereby, Figure 4 summarizes food types that improve healthy life (green line), which oil rich in ω-3 PUFAs, oleic acid and short-chain fatty acid are widely recommended (4). Daily at least 400 mg of natural and/or native fruits and vegetables (133), while weekly 3 × 150 g of fish are recommended (134). Furthermore, fruits, vegetables and fishes are natural sources of macro-and microelements, vitamins, resistant nutrients, free sugars and fibers, which play a crucial role in microbiota balance, satiety, gut health and act as antioxidants in the body, improving and/or impeding obesity and others prevalent metabolic diseases (135)(136)(137).
Paradoxically, nowadays, meals rich in vegetables and fruits are associated with poor and traditional peoples, while meat and sweetened ones are associated with rich and modern life (24,138,139). The consumption of foods marked by the red line (Figure 4) must be reduced, because they are sweetened and fatted, including long-chain saturated fatty acids (mainly myristic and palmitic acids), ω-6 PUFAs and industrialized transfatty acids present high amounts of calories in their composition, which are primarily associated with obesity and its prevalent RDMs (134).
Hence, for human behavior changes, joint activities between Universities, Research Centers, Health Ministries, and others will be legally necessary constitution of Departments that could be responsible by outline joint projects and approaches for health promotion through seminars, and lectures to implement in schools (Primary and Secondary), enterprises and families to promote healthy food cooking, sale, and intake to pave the way to reduce obesity and its RMDs prevalence (140)(141)(142)(143)(144). FIGURE 3 | Mechanism involved in an inflammatory condition and its resolution using ω-3 PUFAs and polyphenols dietary. The action of products from PUFAs metabolization (hepatic biosynthesis or tissue under inflammation), lipoxins, resolvins, protectins, and maresins on macrophage profile change and the endothelial cells. As a result, there are anti-inflammatory interleukins, nitric oxide (NO) and hydrogen sulfite (H 2 S) being produced, which will provide the resolution and tissue regeneration. Products from polyphenols metabolization are also connected with this anti-inflammatory pathway to several organs in the body. M1, type 1 macrophages; M2, type 2 macrophages; IL, interleukin; TNF-α, tumor necrosis factor-alpha. Green lines mean resolution of the inflammatory process and red lines mean the uncontrolled inflammatory process leading to an inflammatory cascade.

CONCLUSION
The consumption of vegetables, fruits, seed and fish and/or supplements rich in polyphenols and ω-3 PUFAs is widely correlated with reducing of obesity and its related metabolic diseases prevalence. Thus, for behavior change, it is necessary to draw out a joint projects of research institutions and the Health Ministries to schools, enterprises and families to promote healthy food intake to reduce obesity and its related metabolic diseases.

AUTHOR CONTRIBUTIONS
TS, DM, VZ-P, DB, AP, and RG conceptualized the topic, researched and analyzed the literature, wrote the manuscript, and including interpretation. PF, GM, PH, MV, RF, EC, and VN contributed with draft and interpretation and revised the manuscript critically for intellectual content. All authors have read and approved the final version of the manuscript, ensure the accuracy and integrity of the work, and agree to be accountable for all appearance. Personnel Improvement (CAPES)-Portaria 2016/2018. This study was financed in part by the CAPES-finance code 001. The study was also supported by research grants from the National Council for Scientific and Technological Development (Conselho Nacional de Desenvolvimento Científico e Tecnológico-CNPq).