Metabolic syndrome (MetS), a risk factor for cardiovascular diseases (CVD) and type 2 diabetes, affects a significant part of the population worldwide, with a prevalence of 10–30%. It is a clustering of interrelated metabolic disorders, which include insulin ^{[1][2][3][4][5][6]}[1,2,3,4,5,6] resistance, central obesity, hypertriglyceridemia, lowered HDL cholesterol concentration, and hypertension ^[1][2][1,2]. MetS has had different criteria over the years, mainly associated with distinguishable definitions of abdominal obesity, with the World Health Organization (WHO), the National Cholesterol Education Program Adult Treatment Panel (NCEP/ATP111), the American Association of Clinical Endocrinologists (AACE), and the European Group for Study of Insulin Resistance (EGSIR) all proposing their own diagnostic criteria ^[3][4][3,4]. Finally, in 2005, the International Diabetes Federation (IDF) provided a standardized consensus. The proposed definition includes waist circumference as a precondition for the identification of MetS and embraces the standard features of the previous definition, such as the assessment of triglyceride (TG) level, high-density lipoprotein cholesterol (HDL), blood pressure, and fasting glucose ^[5][6][5,6].

Metabolic pathways comprising the pathomechanism of MetS have not yet been clearly characterized. However, this is a tedious process due to the wide range of different pathophysiological mechanisms needing to be considered. Evidence suggests that various factors may predispose one to the development of MetS, such as genetics, diet, lifestyle, and gut microbiome ^[7][8][7,8]. A syndrome, which is more of a clinical term than a disease entity, suggests an association with other disorders. The current research shows that MetS predisposes one to cardiovascular dysfunctions via, e.g., atherosclerotic changes ^[9][10][11][9,10,11] and type 2 diabetes [12]. The correlation with other disorders is based on oxidative stress’s role in the pathomechanism. Studies have indicated that there may be an association between MetS and Parkinson’s disease [13], obstructive sleep apnea [14], and the progression and development of different cancers, such as colon cancer or gastric cancer ^[15][16][17][15,16,17]. Treatment is mainly based on lifestyle changes involving increased physical activity and a balanced diet. Researchers are currently looking for new substances that could significantly mitigate the severity and progression of MetS symptoms by affecting the metabolic pathways involved in the MetS pathophysiology. Numerous studies based on animal models have demonstrated the existence of a relationship between the intake of polyphenol-rich products and the mitigation of individual components of MetS. A beneficial effect was obtained via a reduction in body weight, blood pressure, blood glucose levels, and improved lipid metabolism.

Laboratory ZDF rats are derived from the Zucker Fatty strain. A spontaneous mutation that occurred in ZF rats resulted in a diabetic phenotype. The inbreeding of ZF rats carrying the desired mutation led to the development of a new strain called the Zucker Diabetic Fatty strain. The cause of the genetic defect leading to impaired beta-cell function is not clear. However, a number of changes in the expression of pancreatic islet genes have been described, including a reduced expression of the GLUT2 transporter and increased activity of glucokinase and hexokinase. ZDF rats have higher insulin resistance and are less obese compared with the parental strain ^[18][51]. Male ZDF rats develop diabetes at eight weeks of age, which is associated with changes in the morphology of pancreatic islets. Female rats do not develop overt diabetes, despite their significant level of insulin resistance, except when they are fed a high-fat diet ^[19][75]. In male ZDF rats, diabetes-related cataract is observed at 15 weeks of age, first as angiogenesis changes at the periphery of the lens, which progress to the development of a mature cataract at 21 weeks of age ^[20][21][76,77]. Laboratory ZDF rats provide, in particular, a suitable animal model of type 1 and type 2 diabetes and its complications, including retinopathy, cardiomyopathy, and diabetic nephropathy. In addition, due to its specificity (hyperglycemia, hyperinsulinemia, impaired glucose metabolism), the strain can be used in studies on MetS ^[22][49].

The polyphenolic compounds analyzed in studies conducted using this animal model include pomegranate extracts and cocoa flavonols.

The pomegranate (Punica granathum L.) is a long-lived plant that belongs to the Lythraceae family. Its various parts are rich sources of a variety of compounds. Pomegranate seed oil contains punicinic acid (a polyunsaturated fatty acid) and phytoestrogens. The juice and peel are rich in numerous polyphenolic compounds, especially tannins and flavonoids. Pomegranate tannins include ellagitannins, such as punicalagin and punicalin, whereas pomegranate flavonoids include, in particular, anthocyanins and flavonols. Moreover, pomegranate juice and peel contain numerous catechins. In turn, pomegranate bark and roots are sources of alkaloids, including pelletierine and isopelletierine, which are used in folk medicine as anthelmintics. Pomegranate polyphenols have antioxidant properties, as they indirectly inhibit inflammatory markers. They also present anti-carcinogenic effects ^[23][24][78,79]. Pomegranate extracts seem to have a beneficial effect on changes characteristic of MetS, as confirmed by the findings from the available studies. ZDF rats treated with pomegranate flower extract (500 mg/kg, p.o. × six weeks) had milder symptoms of diabetes- and obesity-related hepatic steatosis (lower liver weight, lower triglyceride levels, and lower lipid droplet content) compared with controls. This was due, at least in part, to the enhanced expression of genes associated with the oxidation of fatty acids, including peroxisome proliferator-activated receptors (PPAR-α), acyl-CoA oxidase, and carnitine palmitoyltransferase-1 ^[25][80]. A 6-week treatment with pomegranate extract (500 mg/kg p.o.) was also found to reduce the collagen deposit area in the left ventricle as well as the perivascular collagen deposit areas. The reduction in cardiac fibrosis was mediated by the modulation of the endothelin-1 (ET-1) and nuclear factor kappa B (NF-κB) pathways. The diminished cardiac fibrosis was accompanied by reduced hyperglycemia and hyperlipidemia ^[26][81]. In another study on ZDF rats with insulin resistance and hyperlipidemia, Punica granathum extract reduced cardiac triglyceride accumulation and decreased circulating triglyceride and cholesterol levels. In that study, the improvement in cardiac lipid metabolism was mediated by the activation of, e.g., PPAR-alpha ^[27][82].

The cocoa tree (Theobroma cacao L.) is a tree in the family Malvaceae native to the forests of South and Central America. Its seeds, commonly known as cocoa, are used in many food products. The chemical composition of cocoa includes numerous polyphenolic compounds, including proanthocyanins, catechins, flavan-3-ols, and anthocyanins. It is currently being investigated whether it may play a significant role as a dietary intervention to reduce cardiovascular risk in type 2 diabetes, given that it reduces plasma lipid levels and promotes the production of nitric oxide (NO) ^[28][83]. Recent studies have shown that cocoa polyphenols also have beneficial effects on carbohydrate metabolism. In one study, male ZDF rats fed a cocoa powder-rich diet (10%) for ten weeks showed improved glucose tolerance and insulin resistance. Moreover, the consumption of a diet rich in cocoa products had protective effects against diabetes-induced structural alterations in the kidneys. The antihyperglycemic effects of cocoa, protecting against diabetic nephropathy, were mediated through the inhibition of the synthesis of gluconeogenic enzymes, i.e., phosphoenolpyruvate-carboxykinase (PEPCK) and glucose-6-phosphatase (G-6-Pase), and glucose transporters (i.e., sodium-glucose-co-transporter-2 (SGLT-2) and glucose-transporter-2 (GLUT-2)) in the renal cortex ^[29][84]. In both in vivo (ZDF rats) and in vitro (HepG2 cells) models, cocoa flavonols, especially (−)-epicatechin, improved lipid metabolism by reducing body weight gain and lipid accumulation in liver cells ^[30][85]. Cocoa intake also improves the gut microbiota via interactions that may contribute to its antidiabetic effect. Male ZDF rats fed with 10% cocoa presented more acetate-producing bacteria and had a reduced amount of lactate-producing bacteria compared to the lean group. The modified gut microbiota was associated with an improvement in glucose homeostasis and intestinal integrity and with a reduced expression of pro-inflammatory cytokines, such as tumor necrosis factor-a (TNF-a) or interleukin-6 (IL-6), in the colon of rats ^[31][86].

This entry is adapted from 10.3390/biology11040559