*2.2.2 Oxidized low-density lipoproteins (LDLox)*

The increase in vascular production of EROS not only causes a decrease in the synthesis and bioavailability of endothelial NO but also can react and oxidize small, dense low-density lipoproteins (sdLDL) that infiltrate and easily adhere to proteoglycans in the basal vascular lamina [33].

The presence of LDLox constitutes a crucial factor in the development of proinflammatory processes in the arterial vascular wall. Once these molecules are captured by membrane receptors of endothelial cells, they promote a series of proapoptotic and remodeling processes that favor the development of atherosclerosis and endothelial dysfunction. The increase in LDLox concentrations has also been associated with an increase in the proteasomal degradation of eNOS, changes in the ratio of eNOS: iNOS expression and with protein oxidation [34].

Similarly, LDLox are recognized and phagocytosed by macrophages that during the process undergo changes in their conformation and become foam cells. These cells adhere to the smooth muscle cells of the endothelium and continue to accumulate lipids, which favors the formation of lipid striae that progress to form atheromas [35].

It was shown that the incubation of cell cultures with (−)-epicatechin had a protective effect against the oxidative damage generated by the presence of LDLox. This reduces the activation of endothelial cells that promote inflammatory responses (release of cytokines, chemokines, and angiogenic factors) and the production of cell adhesion molecules that facilitate the migration of macrophages to the vascular intima to phagocytose LDLox [36].

### *2.2.3 Effects of flavanols on hyperglycemia and insulin resistance*

In addition to the anti-inflammatory effects that cocoa flavanols have shown, there are recent publications indicating that these also have beneficial effects on hyperglycemia and insulin resistance. These alterations are closely related to dyslipidemia and the presence of abdominal obesity and, consequently, to the pathogenesis of the metabolic syndrome [37, 38].

In a study with hypertensive patients, a vasodilator effect was observed, as well as a decrease in blood pressure and an improvement in blood glucose and fasting and postprandial insulin response, after the daily consumption of dark chocolate rich in flavanols [40, 41].

In another study in mice with type 2 diabetes (DT2) and obesity, it was observed that the administration of cocoa liquor rich in procyanidins (CLPr) decreased the hyperglycemia in a dose-dependent manner. The proposed mechanisms involve an increase in the translocation of GLUT-4 toward the cell membrane, an increase in phosphorylation of AMPK, and the induction of gene expression of UCP-2 in skeletal muscle [39, 40]. Another phenolic compound, ellagic acid, increases the expression of the type 4 glucose transporter (GLUT4) and the peroxisome proliferator-activated gamma receptor (PPAR-γ). Activation of the latter by pioglitazone upregulates adiponectin, but when combined with pure ellagic acid, this positive regulation is achieved at lower drug concentrations, i.e., ellagic acid is responsible for antidiabetic activity [41].

These results are consistent with those obtained in two studies in which it shows that the administration of a flavanol-rich cocoa extract in an animal model with DT2 has hypoglycemic and lipid-lowering effects [39, 42]. In a similar study, it was evaluated whether supplementation of a high-fat diet with CLPr could attenuate the development of obesity, insulin resistance, and hyperglycemia induced by a high-fat diet and that glucose levels were obtained at different doses of CLPr. Plasma fasting decreases, compared to the group fed with a high-fat diet without supplementation. Also, when performing the oral glucose tolerance test, it was observed that supplementation with 2% of CLPr manages to reduce hyperglycemia and postprandial hyperinsulinemia [43].

Phosphatidylinositol-3-kinase (PI3K) and AMPK are the two main molecules involved in the regulation of GLUT4 translocation. Thus, the increase in the activation of AMPK by the administration of CLPr was related to an increase in the expression and translocation of GLUT4 and, therefore, with a higher glucose uptake.

Finally, the effect of the administration of CLPr on the protein expression of UCP1 (brown adipose tissue) and UCP2 (white adipose tissue and liver), involved in the regulation of thermogenesis and energy metabolism, was studied. The results showed that both concentrations of CLPr increase energy expenditure, through an increase in protein expression of UCP1 and UCP2 [44].

### *2.2.4 Effects of flavanols on alterations in lipid metabolism*

Atherogenic dyslipidemia (increased levels of TG, c-LDL, and c-VLDL, accompanied by decreased HDL) not only constitutes one of the central criteria of the

#### *Flavonoids: A Promising Therapy for Obesity Due to the High-Fat Diet DOI: http://dx.doi.org/10.5772/intechopen.84665*

metabolic syndrome but has also been shown to be directly related to the development of CVD. In addition to its beneficial effects on oxidation, inflammation, and endothelial function, cocoa flavanols have also been shown to have lipid-lowering effects that attenuate the development of NCDs associated with alterations in lipid metabolism. There are meta-analyses of clinical trials that have shown that the consumption of products derived from cocoa (cocoa and dark chocolate) has beneficial effects on the lipid profile of patients with some type of CVD or with metabolic risk factors. Most studies are consistent in showing a decrease in plasma levels of CT and c-LDL; however, in relation to the increase in HDL-c levels, the results are heterogeneous [45–47].

Other studies in animals and humans (healthy or with CV risk) have also reported a significant decrease in plasma levels of TG, CT, and c-LDL and an increase in c-HDL levels, after a period of chocolate consumption dark or cocoa [48, 49].

In an animal study, the hypocholesterolemic effects of a mixture of epicatechin and catechin and another mixture of oligomeric procyanidins of cocoa were evaluated, after the ingestion of a high cholesterol diet for 4 weeks. The results showed that only the procyanidin mixture significantly reduced the plasma concentrations of TG and increased the fecal excretion of bile salts and cholesterol, compared to the control group. Through an in vitro study with procyanidin B2, B5, C1, and A2, it was determined that a possible mechanism to explain the previous results is a decrease in the solubility of cholesterol in the micelles that allow intestinal absorption [50, 51].

In a recent in vitro study by Gu et al., the inhibitory effects of cocoa extracts and monomeric, oligomeric, and polymeric flavanols on the activity of pancreatic lipase and phospholipase A2 were evaluated. The results showed that the different extracts had inhibitory effects on the activity of both enzymes and that said effects are proportional to the total polyphenol content and the degree of polymerization of the flavanols [52].

In the liver, alterations in lipid metabolism promote an increase in its fatty infiltration and lipotoxicity that culminate in the development of nonalcoholic steatohepatitis (NASH), one of the most severe comorbidities of the metabolic syndrome [40, 54]. In an experimental study with rats, the preventive or palliative effects that cocoa supplementation could have on the development of NASH induced by a diet high in fat and deficient in choline were evaluated. The results showed that the supplementation with cocoa reduces the degree of steatosis, liver fibrosis, and portal inflammation. In this same study, it was observed that the supplementation with cocoa reduced the accumulation of fat in the liver, due to an increase in the levels of gene and protein expression of the fatty acid-binding protein (LFABP) in the hepatocytes of rats with NASH.

Another flavonoid that has positive effects in obesity is morin, suppressing lipogenesis, gluconeogenesis, inflammation, and oxidative stress, tending to modify the concentration of triacylglycerides in the liver.

A preclinical study showed that morin acts as an inhibitor of fatty acid synthase (FAS) by regulating the SREBP1-c protein binding element, in addition to regulating the liver increase of carnitine palmitoyl transferase 1a (CPT1a) [51, 52].

It is important to mention that morin could interact with various receptors involved in metabolic diseases as well as ligand of altered genes in obesity and therefore in the present inflammation. However, the mechanism of action of the flavonoid is still unknown since there are no major reports of research related to the mechanism and effect of it.

### *2.2.4.1 Effect of flavonoids of marine algae on obesity*

The content of flavonoids in *Undaria pinnatifida* is equivalent to 42% of the total phenols, and several studies have shown that the main phenolic compounds and flavonoids contained in this alga are rutin, caffeic acid, catechol, quercetin, and morin with approximately 3.1 mg/g of sample. Although there are not many reports regarding the content of flavonoids in Undaria, in other brown algae, the content varies from 0.9 to 6.3 mg/g of sample [53].

### *2.2.4.2 Effects of flavonoids on body fat*

The content of epididymal adipose tissue (ATe), retroperitoneal (ATr), mesenteric (ATm), and total (%) is modified by the intake of phenols from marine algae, such that in the standard group with 5.10% adipose tissue, and the group that was given a high-fat diet, 11.33% was reached, in contrast to the group that consumed free phenols, the content was reduced to 8.9%.

The effect of the phenols was the reduction of the concentrations of triacylglycerols in 57% with respect to the group fed with a high-fat diet; only 10% above the group was fed a normal diet. In relation to changes in total cholesterol levels, phenols decreased it by 75% with respect to the group with a high-fat diet, remaining only above the group with a normal diet by 20% [58].

### *2.2.4.3 Clinical studies on the effect of flavonoids*

Recent studies have shown the importance of the intake of flavonoids and their relation to the risk of chronic diseases, where the intake of flavonoids and obesity were inversely associated in both men and women using multivariate models in a study in the USA. Adults in the highest quartile of flavonoid intake had a significantly lower body mass index and waist circumference than those in the lowest quartile of flavonoid intake (P < 0.03 and P < 0.04, respectively); and the ingestion of flavonoids was inversely related to the levels of C-reactive protein in women (trend p, 0.01). These findings support a growing evidence that the consumption of flavonoids may be beneficial for the prevention of diseases [57].

Scientific evidence has been found in clinical studies of the effect of flavonoids present in fruits that can be consumed regularly and be part of the diet, suggesting a beneficial effect for health, as is the case of anthocyanins, punicalagin, and ellagic acid, present in the pomegranate fruit.

The effect of flavonoids present in pomegranate juice on the function of adipocytes has been studied. Using increasing doses of juice and by radiometric methods, the activity of the amino oxidase was determined, and with colorimetric methods the influence of the juice on the lipogenic and lipolytic activities of the human adipose tissue was evaluated. The results showed a dose-dependent response of juice to inhibit the monoamine oxidase and the activity of the amino oxidases present in the human adipose tissue sensitive to semicarbazide. The juice also inhibits lipogenesis and lipolysis in human and mouse adipose cells [58].

Oral supplementation with pomegranate extract on biomarkers of inflammation and oxidative stress in plasma, as well as serum metabolic profiles in overweight and obese people, for 30 days, resulted in a significant decrease in serum glucose, insulin, and blood levels, total cholesterol, concentration of low density lipoproteins LDL-c, MDA and IL-6. It is concluded that the consumption of pomegranate extract can reduce complications related to obesity [59].

The functionality of flavonoids in various diseases has been demonstrated, and these have been part of our diet all the time, since they are found abundantly in fruits, vegetables, and grains that we consume, such as apples, grapes, blueberries, pomegranates, oranges, broccoli, spinach, thyme, cocoa, nuts, and soybeans, to name a few.

However, the concern that the benefits of these compounds have aroused in the food industry is wide, since, from these natural sources, products containing *Flavonoids: A Promising Therapy for Obesity Due to the High-Fat Diet DOI: http://dx.doi.org/10.5772/intechopen.84665*

flavonoids are manufactured, enriching, fortifying, or increasing the concentration of flavonoids present in various products to have a positive effect on health. In the market there are various products rich in flavonoids such as fruit and vegetable juices, wines, cereals, milk formulas, soy milk, almond milk, confectionery, rice drinks, relaxing drinks, food supplements, and capsules containing extracts of flavonoids. The development of new functional products is increased due to the need to contribute to the health welfare.
