Role of Tea Polyphenols in Metabolic Syndrome

Metabolic syndrome (MetS) increases the risk of type 2 diabetes and cardiovascular diseases (CVD). Tea (Camellia sinensis), one of the most consumed beverages in the world, is rich in polyphenols, mainly catechins. Tea polyphenols may ameliorate obesity by reducing body weight, increasing energy expenditure and fat oxidation, stimulating lipolysis, and improving thermogenesis. Tea polyphenols also reduce the risks of type 2 diabetes (T2D), hypertension, hyperlipidemia, and inflammation. Results of clinical trials on the effects of the consumption of tea beverage, tea extracts, or isolated tea polyphenols on biomarkers of metabolic syndrome will be reviewed in this study. The effects of tea polyphenols on antioxidant status and low-grade chronic inflammation and the molecular mechanisms involved will also be discussed.


Introduction
Metabolic syndrome (MetS) is a cluster of interrelated prejudicial conditions that leads to type 2 diabetes (T2D) and cardiovascular disease (CVD). These conditions include elevated fasting plasma glucose level (hyperglycemia), abdominal/ visceral obesity, dyslipidemia, and hypertension [1,2]. The International Diabetes Federation (IDF) estimates that around 20-25% of the global adult population suffer from MetS and are more likely to die from a heart attack or stroke compared with people without MetS [1].
Since there is no specific treatment for MetS, individual characteristics must be taken into consideration. There is a need for long-term studies to determine whether existing and new therapeutic agents benefit patients with MetS, reducing the effects of MetS and preventing the appearance of associated diseases and to evaluate the potential of novel candidates as effective treatment options [3]. Several clinical studies demonstrate that lifestyle modification, especially dietary changes, is an effective strategy to reduce several factors responsible for the development of MetS. Introducing foods rich in dietary phytochemicals, such as polyphenols, into the diet of an individual is an effective lifestyle modification for the prevention of several diseases, including MetS [4,5].
Polyphenols (phenolic compounds), one of the most relevant families of phytochemicals with health benefits, are biomolecules found in natural products. Several preclinical studies report that some polyphenols exert protective effects in

Tea, obesity, and inflammation
Obesity is a major health concern in the developed and developing world. Obesity leads to an inflammatory condition that is directly involved in the etiology of CVD, T2D, and certain types of cancer. Furthermore, the accumulation of adipose tissue in the abdominal region is a significant risk factor for the development of MetS and associated morbidities. It should be noted that inflammation is  inhibits the in vitro activation of the transcription factor NF-κB and attenuates the IκB-α degradation induced by tumor necrosis factor-alpha (TNF-α) activation. The anti-inflammatory mechanism of EGCG seems to be associated with a decrease in the activity of the IKK-β protein, involved in the phosphorylation of IκB-α. Because of this effect on the NF-κB signaling pathway, catechins can reduce the gene expression of COX-2. In addition, EGCG demonstrates anti-inflammatory activities in the MAPK pathway by inhibiting the phosphorylation of p38. Catechins also reduce the gene expression of c-Jun N-terminal kinase (JNK) protein and the transcription factor AP-1 [25,26]. It should be noted that only a limited number of studies on humans provided strong evidence related to the anti-inflammatory activity of green tea. One example is a double-blind, placebo-controlled trial, in which 56 obese, hypertensive subjects received green tea extract or placebo for 3 months [22]. Green tea extract reduced diabetes and inflammation risk, increased total antioxidant status, and improved the lipid profile.

Tea and lipid profile
Hyperlipidemia, characterized by increased levels of total cholesterol (TC) and low-density lipoprotein (LDL-C), is a major risk factor for CVD. Several clinical trials demonstrated that the ingestion of polyphenols such as flavonoids and phenolic acids can improve the concentrations of TC, LDL-C, and high-density lipoprotein (HDL-C) [8].
Green tea beverage consumption and green tea extract supplementation can also improve lipid profile, reducing blood TC and LDL-C concentrations, especially when used for a long time. These changes are due to the presence of major tea polyphenols, namely, the catechins [27,28]. A study conducted on rats fed with atherogenic diet demonstrated that the supplementation with green tea preparation consisting of 66.5% EGCG and other catechins could decrease plasma TC and LDL-C levels and increase plasma HDL-C levels [29]. Another study on rats and atherogenic diet indicated that EGCG can significantly reduce TC, LDL-C, very low-density lipoprotein cholesterol (VLDL-C), triacylglycerols (TG), and cardiac risk ratio values while increasing the concentration of HDL-C [30].
Studies on humans also reported that EGCG can improve lipid profile. Its mechanisms may be associated with decreasing the absorption of lipids, inhibiting the lipogenesis pathway, and attenuating inflammation [23,24,31] (Table 1).
Other green tea catechins may have a beneficial effect on plasma TC and LDL-C levels in humans. Kim et al. [32] reviewed 20 trials and verified that the intake of green tea catechins, at doses of 145 to 3.000 mg per day, reduced TC by 5.5 mg/dL and LDL-C by 5.3 mg/dL, while there were no changes in plasma HDL-C levels.
More importantly, green tea can decrease plasma TC and LDL-C levels in overweight or obese people with no side effects, especially with long-term consumption [23].
Consumption of green tea extract catechin complex (843 mg of EGCG, 202 mg of ECG, 107 mg of EGC, and 107 mg of EC), for 12 months, significantly reduced (compared with the placebo group) plasma TC, LDL-C, and non-HDL-C levels in postmenopausal women. In hypercholesterolemic participants, green tea extract supplementation resulted in a reduction of 8.5% in TC and 12.4% in LDL-C concentrations. This study suggests that green tea extract, with high concentrations of catechins, may be recommended for lowering cholesterol, especially in those with high cholesterol concentrations [33].

Tea and blood pressure
Hypertension is a multifactorial clinical condition characterized by constant elevation of systolic blood pressure (SBP) levels ≥140 and/or diastolic blood pressure (DBP) ≥ 90 mmHg. It is often associated with metabolic disorders and functional and/or structural changes in target organs, aggravated by the presence of other risk factors, such as dyslipidemia, abdominal obesity, glucose intolerance, and T2D [34]. Hypertension is one of the leading risk factors for CVD, and it is a major cause of premature death worldwide; it affects about 1 billion people worldwide [34].
Tea flavonoids can reduce the risk of hypertension and consequently the risk of CVD [9,35]. Catechins act as antioxidants and vasodilators and inhibit endothelial dysfunction and thrombogenesis [9,36]. Catechins might reduce blood pressure by enhancing nitric oxide signaling [9]. The health benefits of tea for blood pressure were demonstrated in healthy subjects, diabetic subjects, and obese and/or hypertensive subjects [37]. Clinical trials showing the effect of tea on blood pressure are summarized in Table 2. It should be noted that several factors may influence the effect of tea consumption on blood pressure such as the duration and frequency of consumption, dosage, tea bioactive compounds, the evaluated population, and the degree of hypertension [37].

Molecular mechanisms of tea regulating blood pressure
Evidence indicates that vascular superoxide anion inactivates nitric oxide (NO) and plays a critical role in the development of hypertension. NO reacts with superoxide anion to form peroxynitrite. Peroxynitrite can cause protein tyrosine nitration, which modifies protein structure and function and affects cell homeostasis, oxidizes LDL-C, and leads to reduced activity of endothelial nitric oxide synthase (eNOS) [44,45]. Angiotensin II generates vascular superoxide anion by activating nicotinamide adenine dinucleotide phosphate (NADPH) oxidase. Superoxide anion contributes to increased blood pressure, endothelial dysfunction, vascular remodeling, and sodium retention, consequently contributing to the development of hypertension (Figure 2). Possibly, green tea extract reduces the risk of hypertension by reducing vascular reactive oxygen species (ROS) formation and NADPH oxidase activity [37]. In rats, decaffeinated green tea extract stimulated the activation of the eNOS via the phosphatidylinositol 3-kinase (PI3-kinase)/Akt pathway [46].
Caveolin-1, the major negative regulator of eNOS activity, has its gene expression attenuated by green tea polyphenols via the activation of extracellular signal-regulated kinase 1/extracellular signal-regulated kinase 2 (ERK1/ERK2) and inhibition of p38 mitogen-activated protein kinase (MAPK) signaling pathways [47].
Another mechanism by which tea consumption can reduce the risk of hypertension is by inhibiting renin activity. The study conducted by Li et al. [48] showed that oolong and black tea extracts inhibited renin activity. The beneficial effect was attributed to thearubigins. However, monomeric catechins did not contribute to the inhibitory effect promoted by the tea extracts.
Endothelin-1 may contribute to hypertension by enhancing vascular superoxide anion production via ETA/NADPH oxidase. Evidence indicates that epigallocatechin gallate reduces endothelin-1 expression and secretion from endothelial cells, partly via Akt-and AMPK-stimulated forkhead box transcription factor class O1 (FOXO1) regulation of the endothelin-1 promoter [37].

Tea and insulin resistance/diabetes
Insulin resistance is a key feature of MetS and an important risk factor for CVD and T2D. Diabetes is a global health issue with high morbidity and mortality. The global prevalence of diabetes was 8.5% in 2014. In 2016, about 3.7 million deaths were caused by high blood glucose levels and diabetes. Almost half of the deaths caused by high blood glucose levels occur before the age of 70. T2D is linked to insulin resistance, altered lipid profile, hypertension, and endothelial dysfunction [49].
Recent evidence indicates that tea consumption improves insulin sensitivity and reduces the risk of T2D [9,50]. Possibly, tea polyphenols act on gut microbiota, increase the probiotic species in the intestine, and attenuate the gene expression of enzymes involved in gluconeogenesis (phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase) and glucose production in the liver, mediated by AMPK activation [9].

Molecular mechanisms of tea regulating insulin resistance/T2D
Green tea enhances glucose-stimulated insulin secretion through the cyclic adenosine monophosphate (cAMP)/Akt pathway. Moreover, EGCG could activate   AMPK to improve the shutdown of the insulin stress signal pathway caused by serine phosphorylation of insulin receptor substrate-1 (IRS-1), improving insulin resistance [50]. High plasma glucose level increases ROS production, while EGCG improved insulin resistance by scavenging ROS. ROS plays a key role in increasing JNK and IRS-1 serine phosphorylation and reducing the transduction of insulin signal [62]. Green tea catechin increases insulin sensitivity by directly activating peroxisome proliferator-activated receptor (PPAR) γ [50]. In addition to insulin sensitivity, EGCG can also inhibit glucose absorption by competitively binding with the sodium-glucose transporter-1 (SGLT-1) in intestinal epithelial cells and enhance glucose uptake in muscles and adipocytes via enhancement of the GLUT4 expression [44,53].

In hypertension, there is excessive ROS generation in endothelial cells induced by angiotensin II. ROS excess can stimulate the NF-kB pathway and increase endothelial inflammation. ROS excess may also increase LDL-C oxidation and inhibit prostacyclin; superoxide anion reacts with NO to form peroxynitrite, which is cytotoxic. The NO loss may reduce vasorelaxation and contribute to endothelial dysfunction and hypertension. Green tea extract may inhibit the ROS production as well as Oolong tea and black tea may inhibit renin, and
Most studies showing the beneficial effects of EGCG on glucose homeostasis were performed in vitro. EGCG showed an insulin-like activity through the reduction of gluconeogenic enzymes (glucose-6-phosphatase and PEPCK) in hepatocytes by suppressing their gene expression [51,52]. In myocytes, green tea or EGCG stimulates GLUT4 translocation and glucose uptake via the PI3-kinase/ Akt signaling pathway; alternatively, muscle glucose uptake occurs via AMPK [52]. In laboratory animals, EGCG improved insulin sensitivity in peripheral organs and inhibited gluconeogenesis [51]. In humans, EGCG can protect pancreatic β cell from cytokines, inhibiting the NF-kB activation [63]. Tea also reduces carbohydrate absorption by inhibiting α-amylase, β-glucosidase, and sodium-glucose transporters [51,56].
Black tea rich in theaflavins decreases the risk of T2D by inhibiting obesity through AMPK phosphorylation and promoting the browning of white adipose tissue [50]. The pro-inflammatory cytokines TNF-α and interleukin (IL)-1 are involved in obesity-associated insulin resistance and T2D. Black tea consumption has a potential role in downregulating serum TNF-α and IL-1 levels and upregulating IL-10, an anti-inflammatory cytokine [63].

Conclusion
Tea contains polyphenols that may provide an important source of dietary antioxidants in humans. Moderate consumption of tea seems to reduce the risk of MetS and/or MetS-related diseases. EGCG, the main catechin in tea, presents major health benefits. Green tea seems to have the best potential antioxidant effects when compared to other teas. It is worth mentioning that most of the studies have not demonstrated toxicity due to tea consumption or supplementation; however, further research, especially in humans, should be conducted to confirm this property and evaluate the underlying mechanisms of action.  Studies that showed the effect of tea on insulin resistance and diabetes.