**4. Pathophysiological Background of Metabolic Syndrome**

As is the case with other chronic non-communicable diseases, MetS also results from a complex interplay between genetic and environmental factors. Currently, central obesity/visceral adipose tissue (VAT) is considered to play one of the main roles in initiating the deadly quartet of MetS. VAT exerts its influence on glucose and lipid metabolism via multiple mechanisms. Firstly, VAT is a major source of free fatty acids (FFA), which are directly connected to the liver via splanchnic circulation [4]. In the liver, FFAs lead to increased gluconeogenesis, as well as increased triglycerides and very low-density lipoprotein (VLDL) production [6]. The increase in liver FFA oxidation induces a decrease in xylulose 5-phosphate, which results in the activation of gluconeogenesis (by inhibiting phosphofructokinase 1 and activating fructose-1,6-bisphosphatase) [47]. Furthermore, the ectopic accumulation of lipid metabolites (ceramides, diacylglycerol, acetyl-CoA and fatty acids) decreases insulin sensitivity [48]. These lipid metabolites, in turn, activate serine/threonine kinases (protein kinase C (PKC), nuclear factor-kB (NFkB), inhibitory kB kinase b (IKKb)), which then phosphorylate insulin receptor substrate (IRS) and protein kinase B/Akt, and therefore inhibit insulin signaling [47,48].

Moreover, adipose tissue is a source of many cytokines and hormones, called adipokines. Studies have shown that central obesity/VAT is related to dysregulated adipokine secretion, with increased levels of plasminogen activator inhibitor (PAI-1), tumor necrosis factoralpha (TNF-α), monocyte chemotactic protein-1 (MCP-1), angiotensinogen, and interleukin 6 (IL-6). In addition, leptin, a hormone that regulates satiety, energy expenditure, and appropriate glucose homeostasis, is directly correlated to the amount of white adipose tissue. Even though, in physiological conditions, leptin promotes satiety and signals the amount of fat storage to the hypothalamus, it seems that in MetS, there is a leptin resistance or a certain ceiling on the possible effect of leptin, beyond which new leptin stimulates little effect [49].

On the other hand, in central obesity, there are decreased levels of adiponectin, which is considered the "good" adipokine. The primary action of adiponectin is phosphorylation and the activation of key intermediates in the insulin signaling pathway, increasing insulin sensitivity [50]. Therefore, a lack of adiponectin in MetS promotes insulin resistance and disrupts glucose homeostasis.

The aforementioned TNF-α, IL-6, and MCP-1 are pro-inflammatory cytokines, which contribute to the systemic low-grade inflammation found in MetS. At the same time, PAI-1 increases the risk of thrombosis and accelerates the development of atherosclerosis [4,51]. This low-grade inflammation leads to further insulin resistance in muscles, as well as to disruption of o β-cells [52,53].

As recently reviewed, there is also essential gut–adipose tissue crosstalk, which is disrupted in the setting of MetS. Postprandial incretins, glucagon-like peptide 1 (GLP-1), and glucose-dependent insulinotropic peptide (GIP), which regulate glucose homeostasis and exert anorexigenic effects, are significantly decreased in obese or T2DM patients [54]. Furthermore, in patients with obesity and MetS, the levels of appetite-inducing hormone ghrelin fail to progressively decline after meal ingestion [54]. This disruption in anorexigenic/orexigenic hormone homeostasis induces a positive loop that ultimately ends in obesity/MetS.

Finally, the pathogenesis of hypertension in MetS is multifactorial as well. Hyperinsulinemia exerts an anabolic effect on the heart muscle and the media of the blood

vessel wall. It also promotes sympathetic nervous system (SNS) and renin-angiotensinaldosterone system (RAAS) activity, leading to vasoconstriction, sodium retention, and endothelial dysfunction [55]. Interestingly, recent studies have also elucidated leptin's role in obesity-related hypertension. Acting on its receptors in the hypothalamus, leptin initiates a downstream signal transduction that ends in the preganglionic autonomic neurons of the spinal cord, leading to increased sympathetic activity in the kidneys and, therefore, increased blood pressure [56]. Nevertheless, each presented mechanism's relative contribution to hypertension development remains elusive.

Moreover, the presence of obstructive sleep apnea and baroreflex dysfunction in MetS further increase SNS activity [57–59].

While the current understanding of MetS pathophysiology is discussed above, it is a continuously improving subject with new research that will help us better understand the puzzle of MetS.
