Genetic factors contributing to the development of metabolic syndrome

Introduction

One of the leading global public health problems today is metabolic syndrome (MS). The prevalence of MS increases every year. It is known that over the past 40 years, the incidence of MS has doubled, which has led to the fact that today this pathology affects a third of the population. The majority of overweight people live in Mexico - 41%, the United States - 34.7% and Russia - 31%, according to the results of the first national epidemiological cross-sectional study (NATION) [3-5]. Over the past few decades, the prevalence of obesity in Russia has increased 4 times among men and 1.5 times among women [6]. According to a meta-analysis conducted in Asia from 2008 to 2015, the prevalence of MS among the adult population was 24.5% [3]. In 2016, the prevalence of obesity in people aged 5 to 19 years was about 124 million people [4].

MS is a pathological condition that results in decreased sensitivity of peripheral tissues to insulin, resulting in impaired lipid, carbohydrate and purine metabolism. Central obesity (visceral adipose tissue) often contributes to the development of MS with complications [7, 8]. There are many factors that contribute to the development of MS, such as: geographic location, ethnicity, external environmental influences, gender, age, and genetic predisposition (Fig. 1) [9]. The contribution of genetics helps to better understand the true causes of MS and improves the early diagnosis of this pathology [5]. In a genome-wide association study (GWAS), approximately 200 genetic polymorphic variants associated with obesity and more than 4,200 variants associated with an increased body mass index (BMI) were identified. This analysis showed that certain loci with switched-on genes are the main regulatory structures in fat metabolism, the products of which are involved in appetite control, the feeling of satiety, insulin production, adipocyte formation, and energy metabolism [2].

Fig. 1. Risk factors for the development of metabolic syndrome

Genetic aspects of the metabolic syndrome

To date, approximately 50 genes are known to be involved in the development of the main criterion of MS—obesity [9]. Mutations that have arisen in these genes are involved in the leptin-melanocortin signaling pathway and disrupt energy and lipid homeostasis [10, 11].

According to recent studies, severe mutations occur in the leptin receptor (LEPR), leptin, proopiomelanocortin (POMC, corticotropin-like immune peptide), melanocortin receptor 4 (MC4R), and proprotein convertase subtilisin/kexin type 1 (PCSK1) [12].

 Leptin, a peptic hormone, is synthesized by adipose tissue cells and transmits a signal of satiety to the hypothalamus during food intake. A mutation in the coding of the LEP gene contributes to the development of severe early obesity and hyperphagia. Approximately 100 patients worldwide with this pathology have been described [12].

LEPR mutations are inherited in an autosomal recessive manner. Homozygous patients are most often found in consanguineous marriages, and such patients often have severe clinical manifestations. To date, 6 splicing variants of the leptin receptor are known, and all of them differ only in the C-terminal region [5]. LEP-Rb (leptin receptor) is expressed in the hypothalamus and is involved in the regulation of food intake and energy expenditure. When leptin binds to the receptor, it forms a dimer or oligomer with leptin-leptin receptor complexes and induces JAK2 (Janus kinase 2). JAK2 is a tyrosine kinase that activates genes by transcription. Phosphorylated JAK2 phosphorylates IRS, which results in the activation of the PI3K/AKT signaling pathway, AKT kinases phosphorylate FOXO1 (a transcription factor), the outcome of which is the movement of pFOXO1, as a result, food intake is suppressed in the body. The resulting mutation in the leptin receptor (LEPR) leads to the early onset of hunger, as well as infertility, rapid growth of the body and metabolic disorders, namely, the occurrence of increased tissue resistance to the effects of insulin [5, 12].

Quite common is the mutation of MC4R (melanocortin-4 receptor gene). According to the latest data, 0.2% to 8.5% of cases of severe obesity in children are caused by mutations in this gene. The melanocortin-4 receptor gene (MC4R) is expressed in the paraventricular nuclei of the hypothalamus (PVN). The MC4R gene is part of the G protein (GPCR), which binds to α-melanocyte-stimulating hormone (α-MSH). Subsequently, there is activation of adenylate cyclase-3 (ADCY3), which converts adenosine triphosphate (ATP) into cyclic monophosphate (cAMP). The level of cAMP in the cell activates protein kinase A (PKA), which in turn is regulated by extracellular molecules (ERK) and AMP (CREB), thereby playing an important role in the regulation of energy consumption and expenditure [5, 13]. Loss of function of this gene is often associated with obesity and, in combination, with the development of metabolic syndrome. Adiponectin, a hormone of adipose tissue that increases tissue sensitivity to insulin, MC4R deficiency leads to a decrease in the level of this hormone, thereby contributing to the development of metabolic syndrome. There are several polymorphisms of the MC4R gene: rs12970134 and rs17782313. The studies have shown that both variants affect the development of obesity and correlate with increased BMI. It is known that rs17782313 has a greater effect on the development of central obesity because rs12970134 contributes to the development of insulin resistance [10, 14, 15]. 

A mutation in the POMC gene (proopiomelanocortin deficiency) clinically manifests from the first months of life and is a severe pathology. POMC binds to MC4R, suppresses appetite, and participates in the regulation of energy metabolism. This mutation is characterized by a disorder of eating behavior, the development of obesity, with manifestation at an early age, red hair. The pathology is quite rare; to date, about 50 cases have been described in the literature [5, 16]. With a mutation in the PCSK1 gene (prohormone convertase 1), a partial deficiency of the enzyme proprotein convertase type 1 (PC1 / 3) occurs, which is involved in the processing of proinsulin and proglucagon in the pancreas. The defect occurs in the gene region p.Y181H (rs145592525), because of which there is a violation of the synthesis of the enzyme proprotein convertase type 1. Deficiency manifests itself as morbid obesity, diabetes insipidus, and decreased levels of somatotropin and thyroid-stimulating hormone (TSH) [16, 17].

ADCY3 (adenylate cyclase 3) is a gene that is attracting increasing attention from doctors. The ADCY3 gene encodes adenylate cyclase (AC) in the hypothalamus, as a result of which the signal from cAMP is lost and the melanocortin pathway, which is responsible for the regulation of eating behavior and energy metabolism, is disrupted. The loss of ADCY3 function manifests itself as abdominal obesity in children, the development of type 2 diabetes mellitus, and anosmia [16, 18].

MRAP2 is a transmembrane accessory protein of the melanocortin receptor 2. The main function of this enzyme is to influence the localization and signaling of the melanocortin receptor 2 and stimulate cAMP production. Defects in MRAP2 lead to the dysregulation of appetite control and the dysregulation of energy homeostasis, resulting in obesity, hyperglycemia, and hypertension [16, 19].

Primary mechanisms of the metabolic syndrome development

In the pathogenesis of MS, three main mechanisms of development are distinguished: visceral obesity, insulin resistance, and arterial hypertension (Fig. 2). Metabolic syndrome is a pathological condition that includes a group of metabolic disorders, such as excess body weight, arterial hypertension, dyslipoproteinemia, and impaired glucose metabolism (see Fig. 2). MS develops against the background of insulin resistance of body tissues. With the development of metabolic syndrome, activation of the sympathoadrenal system and the renin-angiotensin-aldosterone system occurs [8, 20].

Fig. 2. Metabolic syndrome and its components

Insulin is a peptide hormone of the pancreas that is involved in inhibiting lipolysis and gluconeogenesis in the liver in response to high glucose levels. With the development of insulin resistance in the adipose tissue, lipolysis is disrupted, and the amount of free fatty acid increases. Free fatty acids, in turn, affect the activity of the enzyme phosphoinositide-3-kinase (PI3K signaling pathway), leading to a decrease in insulin-dependent glucose transport protein (GLUT-4), and consequently, glucose absorption decreases. Free fatty acids also increase gluconeogenesis and lipogenesis. As a result, a hyperinsulinemic state occurs [21, 22].

Inflammatory markers and adipokine play an important role in the development of MS. Leptin is a peptide hormone that regulates energy metabolism. With sufficient energy reserves, leptin suppresses hunger and stimulates energy expenditure. When a metabolic imbalance occurs in the body, resistance to leptin occurs, thereby reducing the sensitivity of tissues to the effects of leptin. When an excess of the peptide hormone occurs in patients with genetic disorders, hyperphagia and weight gain occur. For a long time, it was believed that excess leptin in the body also leads to the development of arterial hypertension. Today, there are studies that refute this connection [22, 23]. 

Adiponectin is an anti-inflammatory hormone that is also involved in the development of MS. It affects the B-cell (NF-kB) inflammatory intracellular signaling pathway and is involved in inhibiting the proliferation of vascular smooth muscle cells, increasing insulin sensitivity. Adiponectin enhances glucose metabolism and controls energy homeostasis [22, 23]. Adiponectin also has insulin-like properties; with its help, glucose is captured by muscle and fat cells using the glucose transporter (GLUT-4), inhibiting gluconeogenesis and lipolysis in the human body [24, 25]. Today, most patients with metabolic syndrome have low levels of adiponectin in the blood serum. In healthy people, low levels of adiponectin increase the risk of developing MS by approximately three times compared with patients who have high levels of this hormone [23]. 

An important component of the pathogenesis of MS is chronic inflammation. In overweight or obese individuals, the main criterion of MS is systemic inflammation, with the release of acute phase proteins and inflammatory mediators into the blood (Fig. 3) [26]. Insulin resistance that occurs over time and obesity-induced oxidative stress activate inflammatory cascades, which subsequently lead to tissue fibrosis and vascular damage through the development of atherosclerosis [22]. C-reactive protein (CRP) is a highly sensitive biomarker of tissue damage. In patients with MS, its increase is often noted, determining the concentration of CRP levels can be used as a useful biomarker for determining MS [23].

Fig. 3. Oxidative stress and metabolic syndrome

In metabolic syndrome, macrophages are activated and the synthesis of Th type 1 and Th type 17 increases, resulting in a systemic inflammatory response with the release of cytokines [27]. IL-6 is a proinflammatory cytokine with a hyperglycemic effect. IL-6 is involved in the regulation of lipid and carbohydrate metabolism, triggering an anti-inflammatory cascade of enzymes in the liver [22]. Tissue factor (coagulation factor III), which is synthesized by adipose tissue macrophages, triggers the external pathway of coagulation hemostasis, as a result of which proconvertin (coagulation factor VII) and von Willebrand factor are synthesized in the liver. Tissue factor accelerates the process of converting factor IX and factor X into their active forms, which promotes the formation of fibrin, which increases the risk of thrombosis increases [27]. IL-6 reduces glycogen production in the liver and suppresses the sensitivity of insulin receptors, which subsequently leads to insulin resistance [22].

Metabolic syndrome as a factor in the development of oncogenesis

Metabolic syndrome is not only a factor in the development of cardiovascular diseases, type 2 diabetes, but also increases the risk of developing cancer. Today, it is known that the main and additional criteria of MS increase the risk of developing about 13 types of cancer: cancer of the esophagus, stomach, colon and rectum, liver, prostate, ovaries, kidneys, tumors of the meninges, thyroid gland and multiple myeloma [28-30].

Obesity is a chronic, inflammatory process that contributes to the disruption of preadipocyte differentiation, adipocyte hypertrophy, and the activation of macrophages and leads to the release of cytokines and chemokines. Dysfunction of adipose tissue homeostasis leads to the death of some adipocytes, with the formation of triglyceride breakdown and the release of fatty acids. In such an inflammatory environment, free radicals are released, DNA is damaged, and the risk of mutations increases [29, 30]. In adipose tissue, the inflammatory process is supported by resident macrophages and microRNA. MicroRNA is a small non-coding RNA molecule consisting of 19–23 nucleotides, which participates in the transcriptional and post-transcriptional regulation of gene expression by RNA interference. About a hundred microRNAs can regulate from 30% to 80% of genes. MicroRNA is necessary for the correct regulation of cellular processes, participating in cell proliferation, cellular metabolism and protein synthesis. When dysregulated, the action of microRNA leads to abnormal growth and biosynthesis of pathological cells, which contribute to the development of the oncological process. The activity of microRNA in the adipose tissue of patients with MS plays a decisive role in tumor progression and the formation of metastases [29, 31, 32].

Almost all types of microRNA are associated with proliferation, growth, cell death, and the development of metastatic lesions. Approximately 50% of patients with cervical cancer have more copies of DROSHA (ribonuclease III class 2 enzyme). The microRNA-130 group, including microRNA-130a and microRNA-130b, is associated with the progression of the oncological process. High levels of microRNA-130b are often detected at stages III-IV of the oncological process in patients with colorectal cancer. MicroRNA-21 is involved in the adipogenic differentiation of mesenchymal stem cells. MicroRNA-21 is detected in tumors of the pancreas, colon, breast, glioblastoma, and colorectal cancer with a late stage of metastasis. It is also associated with an anti-apoptotic effect, promoting cell proliferation by influencing the tumor suppressor. MicroRNA-193, on the contrary, has an antitumor effect in breast cancer by reducing cell proliferation and migration [29, 31]. 

In patients with metabolic syndrome, the risk of developing cancer increases several times compared to healthy people. MicroRNAs obtained from adipose tissue play a very important role in adipogenesis and fat and hormonal homeostasis. Today, it is known that the role of microRNA is very large in the development of the oncological process, and it has been proven that it is involved in the progression and invasion of cancer. Through these studies, anticancer therapy will be determined in the future [32].

Conclusion

Metabolic syndrome is a modern disease. Over the past few years, its prevalence has increased several times. MS is a multifactorial disease, and the main components of its development are: obesity, insulin resistance, and developed arterial hypertension. The pathogenesis of this disease has not yet been fully studied, but it is known that the development of this pathology is influenced by the following epigenetic factors: a sedentary lifestyle, poor nutrition, disruption of the daily routine, as well as mutations in the following genes: ADCY3, ADIPOQ, ALMS1, ARL6, BBS1, BBS10, BBS12, BBS2, BBS4, BBS5, BBS6, BBS7, BBS9, BDNF, CEP19, CEP290, FTO, GNAS, GPC3, INSIG2, KSR2, LEP, LEPR, LZTFL1, MC4R, MKKS, MKS1, NEGR1, NTRK2, OFD1, PCSK1, PHF6, POMC, PRKAR1A, RAB23, RAI1, SDCCAG8, SH2B1, SIM1, TBX3, TMEM18, TRIM32, TTC8, VPS13B, WDPCP, WNT10B.

Science does not stand still, and every day more and more studies are being conducted that prove the genetic theory of MS development. Understanding the mechanisms of this syndrome development, the correct treatment tactics and a rehabilitation plan will help reduce mortality from cardiovascular diseases and oncology in the future. These data will be useful to doctors of all specialties for treating patients with MS, in order to reduce metabolic disorders. Knowledge of genetic predictors of MS from a practical point of view provides tools for doctors to prevent the occurrence of pathology, when treating an existing disease, selecting personalized therapy.