The interplay of factors in metabolic syndrome: understanding its roots and complexity

Abstract

Metabolic syndrome (MetS) is an indicator and diverse endocrine syndrome that combines different metabolic defects with clinical, physiological, biochemical, and metabolic factors. Obesity, visceral adiposity and abdominal obesity, dyslipidemia, insulin resistance (IR), elevated blood pressure, endothelial dysfunction, and acute or chronic inflammation are the risk factors associated with MetS. Abdominal obesity, a hallmark of MetS, highlights dysfunctional fat tissue and increased risk for cardiovascular disease and diabetes. Insulin, a vital peptide hormone, regulates glucose metabolism throughout the body. When cells become resistant to insulin's effects, it disrupts various molecular pathways, leading to IR. This condition is linked to a range of disorders, including obesity, diabetes, fatty liver disease, cardiovascular disease, and polycystic ovary syndrome. Atherogenic dyslipidemia is characterized by three key factors: high levels of small, low-dense lipoprotein (LDL) particles and triglycerides, alongside low levels of high-density lipoprotein (HDL), the "good" cholesterol. Such a combination is a major player in MetS, where IR is a driving force. Atherogenic dyslipidemia contributes significantly to the development of atherosclerosis, which can lead to cardiovascular disease. On top of that, genetic alteration and lifestyle factors such as diet and exercise influence the complexity and progression of MetS. To enhance our understanding and consciousness, it is essential to understand the fundamental pathogenesis of MetS. This review highlights current advancements in MetS research including the involvement of gut microbiome, epigenetic regulation, and metabolomic profiling for early detection of Mets. In addition, this review emphasized the epidemiology and fundamental pathogenesis of MetS, various risk factors, and their preventive measures. The goal of this effort is to deepen understanding of MetS and encourage further research to develop effective strategies for preventing and managing complex metabolic diseases.

Keywords: Dyslipidemia; Epidemiology; Insulin resistance; Metabolic syndrome; Obesity; Pathogenesis.

Fig. 1

Schematic presentation of MetS. Multiple factors (genetics, age, lifestyle, overeating, inactivity, and smoking) lead to visceral adiposity, central to MetS. This adiposity triggers altered free fatty acid metabolism, promoting insulin resistance, dyslipidemia, and increased inflammation through markers like TNF, and IL-6. Additionally, adipokines (leptin, aldosterone) and the RAAS exacerbate chronic inflammation. These interconnected processes raise the risk of cardiovascular diseases like sudden cardiac death and hypertension, all key features of MetS. FFA: Free Fatty Acid, ATII: Angiotensin II, CRP: C-reactive protein, TNF: Tumor Necrosis Factor, IL-6: Interleukin 6, LOX: Lectin-like Oxidized, LDL: Low-Density Lipoprotein, ROS: Reactive Oxygen Species, RAAS; Renin Angiotensin Aldosterone System

Fig. 2

Pathophysiology of visceral obesity. Factors like inactivity, poor diet, and smoking cause positive energy balance, leading to visceral obesity and dysfunctional adipose tissue. These triggers altered fat metabolism and adipokine release, resulting in ectopic fat accumulation in organs like the heart, liver, and muscles, which ultimately drives MetS

Fig. 3

Schematic diagram of the mechanism action of insulin on an intracellular pathway. Insulin binds to the insulin receptor on the cell membrane, it triggers the phosphorylation (activation) of IRS (insulin receptor substrate) proteins. This, in turn, activates PI3-kinase, which converts PIP2 to PIP3, leading to the activation of AKT. Activated AKT promotes several downstream effects: it inhibits glycogen synthase kinase-3 (GSK3), which prevents glycogen breakdown and supports glycogen synthesis. AKT also facilitates the translocation of GLUT4 (a glucose transporter) to the cell membrane, enabling glucose uptake into the cell. Additionally, protein kinase A (PKA) is involved in the regulation of lipolysis, with insulin suppressing this process to reduce fat breakdown. The overall pathway enhances glucose uptake, glycogen storage, and reduces lipolysis, promoting energy storage and utilization. GLUT4: glucose transporter 4, PI-3: phosphoinositide-3, PIP2: phosphatidylinositol-4,5-bisphosphate, PIP3: phosphatidylinositol-3,4,5-triphosphate, PKA: protein kinase A

Fig. 4

Domination of INSR on MetS. The median expression of INSR in normal samples (bodymap) (a), Gene Gene interaction and their function (Physical Interaction, Genetic Interaction) (b, c). Overall Survival with high and low INSR units as transcript per million in Pancreatic adenocarcinoma (d), Overall Survival with high and low INSR units as transcript per million in Liver hepatocellular carcinoma (e), Overall Survival with high and low INSR unit as transcript per million in Lung adenocarcinoma (f). The INSR network is highly interconnected with various signaling pathways and that its expression can significantly influence survival outcomes in diseases like cancer or metabolic disorders. The survival carbs and bodymap were made by GEPIA (http://gepia.cancer-pku.cn/index.html). Gene–gene interaction was made from GeneMANIA (https://genemania.org/)