Narrative review of metabolic syndrome and its relationships with non-alcoholic fatty liver disease, gonadal dysfunction and obstructive sleep apnea

Abstract

Background: Metabolic syndrome is an emerging health problem, and its prevalence is rapidly increasing. Therefore, we first aimed to investigate its pathophysiology, focusing on the insulin resistance state and the consumption of high-calorie diets. In addition, previous studies have shown an association between metabolic syndrome and non-alcoholic fatty liver disease, gonadal dysfunction and obstructive sleep apnea, but little is known about the nature of the relationship between metabolic syndrome and these conditions. Therefore, second, we aimed to investigate this relationship to better predict the risk of these diseases in MetS patients and vice versa.

Materials and methods: We conducted a comprehensive search in multiple scientific databases to examine the pathophysiology of metabolic syndrome and to investigate the nature of the relationship between metabolic syndrome and these conditions. The selection of the articles included in this review is based on their pertinence to the research issue, methodological rigor, and contribution to the field.

Results: This study revealed that insulin resistance and high fructose consumption are two important contributors to the pathophysiology of metabolic syndrome. Additionally, a bidirectional relationship was detected between metabolic syndrome and both non-alcoholic fatty liver disease and secondary male hypogonadism. Both non-alcoholic fatty liver disease and testosterone deficiency can lead to metabolic dysregulation and insulin resistance, which in turn exacerbate this clinical condition. A mutual relationship between metabolic syndrome and polycystic ovarian syndrome has been demonstrated, with similar risk factors and treatment strategies. Finally, an independent relationship was found between obstructive sleep apnea and the components of metabolic syndrome.

Conclusion: Metabolic syndrome is closely related to non-alcoholic fatty liver disease, gonadal dysfunction and obstructive sleep apnea. It is therefore recommended that further studies be conducted to better understand these relationships to develop a comprehensive treatment strategy for metabolic health and these conditions.

Keywords: Dyslipidemia; High caloric diet; Insulin resistance; Male hypogonadism; Metabolic syndrome; Non-alcoholic fatty liver disease; Obstructive sleep apnea; Polycystic ovarian syndrome.

Fig. 1

The role of insulin resistance and high fructose consumption in the development of metabolic syndrome. In the physiological state, insulin promotes both FoxO1 phosphorylation and SREBP1-c expression, resulting in the inhibition of gluconeogenesis and the promotion of de-novo lipogenesis, respectively. The net result is decreased hepatic glucose output and increased triglyceride production. In insulin resistance, AKT/PKB-dependent phosphorylation of Foxo-1 is blocked, whereas SREBP1-c expression is overstimulated, leading to excessive hepatic production of glucose and triglycerides. Excessive fructose consumption induces SREBP1-c expression and visceral adipose tissue insulin resistance, leading to increased DNL and adipose tissue lipolysis, respectively. The increased lipolysis is associated with the excessive release of free fatty acids from visceral adipose tissue into the bloodstream and then into the liver, which promotes hepatic gluconeogenesis and triglyceride production. FoxO1: forkhead box O1; SREBP1-c: sterol regulatory element-binding protein 1-c; AKT/PKB; protein kinase B; DNL: de novo lipogenesis; TAG: triacylglycerol; FFAs: free fatty acids; IR; insulin resistance; Adipo-IR; adipose tissue resistance

Fig. 2

MAFLD and increasing risk for chronic kidney disease and vascular injury. Excess free fatty acids are transported and esterified in the liver, producing TAG-rich VLDL particles. The increased secretion of VLDL stimulates the CEPT enzyme to transfer TAG from the VLDL particles to both HDL and LDL. This exchange makes TAG-rich HDL susceptible to being easily excreted by the kidneys, increasing the incidence of CDK. Meanwhile, TAG-rich LDL is hydrolyzed by hepatic lipase, producing oxidized LDL particles, which in turn increase the incidence of vascular injury. FFAs, free fatty acids; VLDL, very low-density lipoprotein; CEPT, cholesterol ester transfer protein; HDL, high-density lipoprotein; CDK, chronic kidney disease; LDL, low density lipoprotein; ox -LDL, oxidized low density-lipoprotein

Fig. 3

Viscous cycle of metabolic syndrome, secondary male hypogonadism and obstructive sleep apnea. Besides IR and leptin resistance associated with MetS, the expanded visceral adipose tissue produces inflammatory products. All these factors reduce the expression of kisspeptin and thus the release of GnRH and testosterone. In addition, increased the activity of aromatase enzyme produced from adipose tissue and decreased hepatic production of SHBG contribute to the decrease in testosterone levels. This decrease in testosterone concentration exacerbates the metabolic changes by increasing adipocyte inflammation and fat accumulation. OSA increases the HPA axis and cortisol levels, leading to hyperinsulinemia and IR. On the other hand, it lowers HPG levels, leading to reduced GnRH release and subsequent secondary hypogonadism. GnRH: Gonadotropin releasing hormone; LH: Luteinizing hormone; FSH: follicle stimulation hormone; LPL: lipoprotein lipase enzyme; OSA: obstructive sleep apnea. HPA: hypothalamic-pituitary-adrenal axis; HPG: hypothalamic-pituitary-gonadal axis