Materiały źródłowe

• #1 Metabolic Syndrome: Updates on Pathophysiology and Management in 2021

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8775991/

  Metabolic syndrome (MetS) forms a cluster of metabolic dysregulations including insulin resistance, atherogenic dyslipidemia, central obesity, and hypertension. The pathogenesis of MetS encompasses multiple genetic and acquired entities that fall under the umbrella of insulin resistance and chronic low-grade inflammation. […] Among the proposed mechanisms, insulin resistance, chronic inflammation, and neurohormonal activation seem to be essential players in the progression of MetS and its subsequent transition to CVDs and T2DM. […] Insulin resistance develops in fat tissues, insulin-mediated inhibition of lipolysis is impaired. The resulting increase in circulating free fatty acids (FFAs) in turn worsens insulin resistance by causing alterations in the insulin signaling cascade in different organs, thus creating a vicious cycle.

• #2 Metabolic Syndrome: Updates on Pathophysiology and Management in 2021

  https://www.mdpi.com/1422-0067/23/2/786

  Metabolic syndrome (MetS) forms a cluster of metabolic dysregulations including insulin resistance, atherogenic dyslipidemia, central obesity, and hypertension. The pathogenesis of MetS encompasses multiple genetic and acquired entities that fall under the umbrella of insulin resistance and chronic low-grade inflammation. […] If left untreated, MetS is significantly associated with an increased risk of developing diabetes and cardiovascular diseases (CVDs). […] The pathophysiology of the MetS encompasses several complex mechanisms that are yet to be fully elucidated. It is still debated as to whether the different elements of MetS form by themselves distinct pathologies or fall under a common, broader pathogenic process. In addition to genetic and epigenetic factors, some lifestyle and environmental such as overeating and lack of physical activity have been identified as major contributors to the development of MetS. A causative role can be given to high caloric intake since visceral adiposity has been shown to be an important trigger that activates most of the pathways of MetS.

• #3 Metabolic syndrome: definitions and controversies | BMC Medicine | Full Text

  https://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-9-48

  Despite advances in pathophysiology and delineation of risk factors that predispose to MetS, there are many key aspects that remain unclear. The great variation in susceptibility and age of onset in individuals with a very similar risk profile, suggests a major interaction between genetic and environmental factors. […] Although obesity and IR remain at the core of the pathophysiology of MetS, a number of other factors such as chronic stress and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS), increases in cellular oxidative stress, renin-angiotensin-aldosterone system activity, and intrinsic tissue glucocorticoid actions, as well as currently discovered molecules such as micro RNAs can also be involved in its pathogenesis. […] Central obesity is thought to be an early step, as visceral adipose tissue secretes a variety of bioactive substances termed adipocytokines, such as leptin, resistin, tumor necrosis factor (TNF), interleukin-6 (IL-6), and angiotensin II which induce IR, along with plasminogen activator inhibitor 1 (PAI-1), which is related to thrombogenic vascular diseases.

• #4 Metabolic syndrome: definitions and controversies | BMC Medicine | Full Text

  https://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-9-48

  Metabolic syndrome (MetS) is a complex disorder defined by a cluster of interconnected factors that increase the risk of cardiovascular atherosclerotic diseases and diabetes mellitus type 2. […] Its main components are dyslipidemia (elevated triglycerides and apolipoprotein B (apoB)-containing lipoproteins, and low high-density lipoproteins (HDL)), elevation of arterial blood pressure (BP) and dysregulated glucose homeostasis, while abdominal obesity and/or insulin resistance (IR) have gained increasing attention as the core manifestations of the syndrome. […] Besides the many components and clinical implications of MetS, there is still no universally accepted pathogenic mechanism or clearly defined diagnostic criteria. […] A main evolving aspect of MetS is its increasing prevalence in both childhood and young adulthood and the future implications to the global health burden this may confer.

• #5 Metabolic Syndrome: Updates on Pathophysiology and Management in 2021

  https://www.mdpi.com/1422-0067/23/2/786

  Among the proposed mechanisms, insulin resistance, chronic inflammation, and neurohormonal activation seem to be essential players in the progression of MetS and its subsequent transition to CVDs and T2DM. […] Insulin resistance develops in fat tissues, insulin-mediated inhibition of lipolysis is impaired. The resulting increase in circulating free fatty acids (FFAs) in turn worsens insulin resistance by causing alterations in the insulin signaling cascade in different organs, thus creating a vicious cycle. […] Another contribution of insulin resistance to MetS is the development of hypertension caused partly by loss of insulin’s vasodilatory effect and by FFA-induced vasoconstriction due to reactive oxygen species production and subsequent scavenging of nitric oxide. […] The various pathogenic pathways contributing to the development of MetS culminate in a pro-inflammatory state that explains the elevation in various inflammatory markers such as IL-6, C-reactive protein (CRP), and TNFα seen in individuals with MetS.

• #6 The Metabolic Syndrome: Pathogenesis, Consequences, and Treatment Strategies

  https://www.hcplive.com/view/2005-01_02

  Several metabolic abnormalities emerge as key players in the pathogenesis of the syndrome, including insulin resistance, obesity, and inflammation. […] Insulin resistance describes impaired insulin-mediated glucose disposal, inhibition of lipolysis, or inhibition of gluconeogenesis, often resulting in hyperinsulinemia as a means of overcoming tissue resistance (eg, in skeletal muscle). […] Among the best documented are glucose intolerance and dyslipidemia (high triglycerides, low HDL-C). […] However, the metabolic syndrome, particularly as defined by ATP III criteria, does not equal insulin resistance. […] Insulin resistance is also closely related to hypertension. […] As a marker of insulin resistance, hyperinsulinemia predicts the development of hypertension in all age-groups. […] Initially, most associations between insulin resistance and metabolic abnormalities were demonstrated in small clinical studies.

• #7 The Metabolic Syndrome: An Overview and Proposed Mechanisms

  https://www.mdpi.com/2673-4168/4/3/20

  Obesity has emerged as a major public health challenge in the 21st century, contributing to the rising prevalence of metabolic syndrome (MetS), a cluster of interrelated health risk factors. These factors include obesity or abdominal obesity, type 2 diabetes mellitus (T2DM), hypertension (HTN), and dyslipidaemia. […] The pathogenetic mechanisms of MetS are complex and not yet fully elucidated; however, chronic low-grade inflammation, also known as systemic inflammation, is widely recognised as a significant contributor to its associated diseases. Additionally, both genetic and environmental factors can contribute to the development of MetS. […] The World Health Organization has identified IR as central to MetS, with obesity also playing a significant role. The complexity of MetS arises from the interplays of multiple interconnected factors that contribute to its associated diseases.

• #8 Metabolic Syndrome: Updates on Pathophysiology and Management in 2021

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8775991/

  Metabolic syndrome (MetS) forms a cluster of metabolic dysregulations including insulin resistance, atherogenic dyslipidemia, central obesity, and hypertension. The pathogenesis of MetS encompasses multiple genetic and acquired entities that fall under the umbrella of insulin resistance and chronic low-grade inflammation. […] Among the proposed mechanisms, insulin resistance, chronic inflammation, and neurohormonal activation seem to be essential players in the progression of MetS and its subsequent transition to CVDs and T2DM. […] Insulin resistance develops in fat tissues, insulin-mediated inhibition of lipolysis is impaired. The resulting increase in circulating free fatty acids (FFAs) in turn worsens insulin resistance by causing alterations in the insulin signaling cascade in different organs, thus creating a vicious cycle.

• #9 Metabolic Syndrome: Updates on Pathophysiology and Management in 2021

  https://www.mdpi.com/1422-0067/23/2/786

  Among the proposed mechanisms, insulin resistance, chronic inflammation, and neurohormonal activation seem to be essential players in the progression of MetS and its subsequent transition to CVDs and T2DM. […] Insulin resistance develops in fat tissues, insulin-mediated inhibition of lipolysis is impaired. The resulting increase in circulating free fatty acids (FFAs) in turn worsens insulin resistance by causing alterations in the insulin signaling cascade in different organs, thus creating a vicious cycle. […] Another contribution of insulin resistance to MetS is the development of hypertension caused partly by loss of insulin’s vasodilatory effect and by FFA-induced vasoconstriction due to reactive oxygen species production and subsequent scavenging of nitric oxide. […] The various pathogenic pathways contributing to the development of MetS culminate in a pro-inflammatory state that explains the elevation in various inflammatory markers such as IL-6, C-reactive protein (CRP), and TNFα seen in individuals with MetS.

• #10 Metabolic Syndrome: Updates on Pathophysiology and Management in 2021

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8775991/

  Another contribution of insulin resistance to MetS is the development of hypertension caused partly by loss of insulin’s vasodilatory effect and by FFA-induced vasoconstriction due to reactive oxygen species production and subsequent scavenging of nitric oxide. […] The various pathogenic pathways contributing to the development of MetS culminate in a pro-inflammatory state that explains the elevation in various inflammatory markers such as IL-6, C-reactive protein (CRP), and TNF seen in individuals with MetS. […] The complex interplay of environmental factors, lifestyle, and genetic/epigenetic factors in the pathophysiology of MetS has led to the emergence of novel studies that evaluate new perspectives in the early diagnosis, classification of new biomarkers, and discovery of potential targets for therapeutic interventions.

• #11 Metabolic Syndrome: Updates on Pathophysiology and Management in 2021

  https://www.mdpi.com/1422-0067/23/2/786

  Among the proposed mechanisms, insulin resistance, chronic inflammation, and neurohormonal activation seem to be essential players in the progression of MetS and its subsequent transition to CVDs and T2DM. […] Insulin resistance develops in fat tissues, insulin-mediated inhibition of lipolysis is impaired. The resulting increase in circulating free fatty acids (FFAs) in turn worsens insulin resistance by causing alterations in the insulin signaling cascade in different organs, thus creating a vicious cycle. […] Another contribution of insulin resistance to MetS is the development of hypertension caused partly by loss of insulin’s vasodilatory effect and by FFA-induced vasoconstriction due to reactive oxygen species production and subsequent scavenging of nitric oxide. […] The various pathogenic pathways contributing to the development of MetS culminate in a pro-inflammatory state that explains the elevation in various inflammatory markers such as IL-6, C-reactive protein (CRP), and TNFα seen in individuals with MetS.

• #12 Metabolic syndrome in children and adolescents – Al-Hamad – Translational Pediatrics

  https://tp.amegroups.org/article/view/16890/html

  Prevalence of metabolic syndrome in children and adolescents is increasing, in parallel with the increasing trends in obesity rates. […] While pathogenesis of metabolic syndrome is not completely understood, insulin resistance and subsequent inflammation are thought to be among its main mechanistic underpinnings. […] Although the pathogenesis of metabolic syndrome is not completely understood, recent data suggest that interaction between obesity, insulin resistance and inflammation play a key-role in its development. […] It is suggested that accumulation of free fatty acids in the liver, adipocytes, skeletal muscles and the pancreas in the setting of obesity leads to impaired insulin signaling and subsequent insulin resistance. […] Insulin resistance in the liver leads to decrease in its effect on suppression of glucose production.

• #13 Metabolic syndrome in children and adolescents – Al-Hamad – Translational Pediatrics

  https://tp.amegroups.org/article/view/16890/html

  Additionally, hyperinsulinemia causes an increase in the transcription of genes for lipogenic enzymes in the liver, which leads to increased production of triglycerides. […] The increase in free fatty acids delivery to the liver is thought to result in hepatic insensitivity to the inhibitory effects of insulin on very low density lipoprotein (VLDL) secretion and overproduction of triglyceride-rich VLDL particles. […] Elevated BP in metabolic syndrome is thought to be secondary to hyperinsulinemia via mechanisms such as sympathetic nervous system activity, renal sodium retention and smooth muscle growth. […] Insulin has a vasodilatory effect on the endothelium secondary to the production of nitric oxide (a potent vasodilator). […] Endothelial dysfunction and disturbed vasodilatory response frequently occur secondary to insulin resistance.

• #14 Metabolic syndrome in children and adolescents – Al-Hamad – Translational Pediatrics

  https://tp.amegroups.org/article/view/16890/html

  Additionally, hyperinsulinemia causes an increase in the transcription of genes for lipogenic enzymes in the liver, which leads to increased production of triglycerides. […] The increase in free fatty acids delivery to the liver is thought to result in hepatic insensitivity to the inhibitory effects of insulin on very low density lipoprotein (VLDL) secretion and overproduction of triglyceride-rich VLDL particles. […] Elevated BP in metabolic syndrome is thought to be secondary to hyperinsulinemia via mechanisms such as sympathetic nervous system activity, renal sodium retention and smooth muscle growth. […] Insulin has a vasodilatory effect on the endothelium secondary to the production of nitric oxide (a potent vasodilator). […] Endothelial dysfunction and disturbed vasodilatory response frequently occur secondary to insulin resistance.

• #15 Mechanisms of the components of the metabolic syndrome that predispose to diabetes and atherosclerotic CVD | Proceedings of the Nutrition Society | Cambridge Core

  https://www.cambridge.org/core/journals/proceedings-of-the-nutrition-society/article/mechanisms-of-the-components-of-the-metabolic-syndrome-that-predispose-to-diabetes-and-atherosclerotic-cvd/5C5506FFE812D0EE5C548B571D599EB0

  Impaired fasting glucose often relates to defects in insulin secretion in addition to insulin resistance, and probably more than any other component of the syndrome predicts the increased incidence of type 2 diabetes. […] Although not included in the diagnostic criteria, increases in pro-inflammatory cytokines and pro-thrombotic factors, in addition to decreases in plasma adiponectin, may also contribute to the increased incidence of atherosclerotic CVD and diabetes. […] The most accepted and unifying hypothesis to describe the pathophysiology of the metabolic syndrome is insulin resistance. […] A major contributor to the development of insulin resistance is circulating fatty acids. […] In muscle excessive fatty acids decrease insulin sensitivity. […] Increased fatty acid availability results in the accumulation of intramyocellular fatty acyl-CoA, which then unfavourably modifies a number of downstream pathways including: insulin signalling; insulin-(in)dependent glucose transport and phosphorylation; insulin-stimulated glycogen synthesis; insulin-stimulated oxidative phosphorylation (ATP synthesis); accumulation of TAG; expression of PPAR coactivator-1 and PPAR coactivator-1-controlled genes involved in mitochondrial biogenesis and oxidative phosphorylation and potentially the initiation of inflammatory processes by activation of protein kinase C and NF-B.

• #16 Metabolic syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Metabolic_syndrome

  The continuous provision of energy via dietary carbohydrate, lipid, and protein fuels, unmatched by physical activity/energy demand, creates a backlog of the products of mitochondrial oxidation, a process associated with progressive mitochondrial dysfunction and insulin resistance. […] Recent research indicates prolonged chronic stress can contribute to metabolic syndrome by disrupting the hormonal balance of the hypothalamic-pituitary-adrenal axis (HPA-axis). […] A dysfunctional HPA-axis causes high cortisol levels to circulate, which results in raising glucose and insulin levels, which in turn cause insulin-mediated effects on adipose tissue, ultimately promoting visceral adiposity, insulin resistance, dyslipidemia and hypertension. […] Central obesity is a key feature of the syndrome, as both a sign and a cause, in that the increasing adiposity often reflected in high waist circumference may both result from and contribute to insulin resistance.

• #17 Mechanisms, pathophysiology and asssessment of metabolic syndrome

  https://www.abcam.cn/content/metabolic-syndrome-mechanisms-pathophysiology-and-laboratory-assessment

  Metabolic syndrome is a common pathological condition characterized by a group of risk factors that raises the risk for type 2 diabetes and cardiovascular disease (CVD). This article summarizes the pathophysiology, molecular mechanisms and animal models of metabolic syndrome discussed during our 3-part webinar series, presented by Prof. Khosrow Adeli. […] Insulin resistance and obesity are thought to be the most important risk factors for metabolic syndrome. […] The main problem in obesity is the visceral fat, which – as opposed to subcutaneous fat – accumulates deep inside the abdomen. Visceral fat releases free fatty acids into the circulation which find their way to other tissues not designed to store fat, such as the liver, heart and skeletal muscle. Visceral fat will also wrap itself around these internal organs leading to insulin resistance.

• #18 Metabolic syndrome: definitions and controversies | BMC Medicine | Full Text

  https://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-9-48

  Despite advances in pathophysiology and delineation of risk factors that predispose to MetS, there are many key aspects that remain unclear. The great variation in susceptibility and age of onset in individuals with a very similar risk profile, suggests a major interaction between genetic and environmental factors. […] Although obesity and IR remain at the core of the pathophysiology of MetS, a number of other factors such as chronic stress and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system (ANS), increases in cellular oxidative stress, renin-angiotensin-aldosterone system activity, and intrinsic tissue glucocorticoid actions, as well as currently discovered molecules such as micro RNAs can also be involved in its pathogenesis. […] Central obesity is thought to be an early step, as visceral adipose tissue secretes a variety of bioactive substances termed adipocytokines, such as leptin, resistin, tumor necrosis factor (TNF), interleukin-6 (IL-6), and angiotensin II which induce IR, along with plasminogen activator inhibitor 1 (PAI-1), which is related to thrombogenic vascular diseases.

• #19

  https://www.alliedacademies.org/articles/understanding-the-molecular-mechanisms-behind-metabolic-syndrome-28400.html

  Dysfunctional adipocytes, especially in visceral fat depots, secrete pro-inflammatory cytokines like TNF- and IL-6, promoting insulin resistance and systemic inflammation, key features of metabolic syndrome. […] Chronic low-grade inflammation is a hallmark of metabolic syndrome, linking obesity, insulin resistance, and cardiovascular disease. Activation of inflammatory pathways, including NF-B and JNK, in adipose tissue, liver, and other organs, disrupts insulin signaling, impairs lipid metabolism, and promotes atherosclerosis. […] Molecular insights have highlighted disturbances in lipid metabolism, including enhanced lipogenesis, impaired fatty acid oxidation, and altered lipoprotein metabolism, driven by factors such as insulin resistance and inflammation. […] Emerging evidence suggests a bidirectional relationship between gut microbiota and metabolic syndrome. Dysbiosis, characterized by alterations in microbial composition and function, contributes to metabolic disturbances by modulating energy harvest from diet, inflammation, gut barrier integrity, and bile acid metabolism, highlighting the intricate molecular crosstalk between the gut microbiome and host metabolism.

• #20 Metabolic syndrome: definitions and controversies | BMC Medicine | Full Text

  https://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-9-48

  Chronic hypersecretion of stress mediators, such as cortisol, in individuals with a genetic predisposition exposed to a permissive environment, may lead to visceral fat accumulation as a result of chronic hypercortisolism, low growth hormone secretion and hypogonadism. […] Moreover, since intracellular GC levels are regulated by 11-hydroxysteroid dehydrogenase type 1 (11-HSD1), which converts inactive cortisone to cortisol, a large number of studies have focused on evaluating tissue specific alterations in 11-HSD1 expression and activity in obesity and IR. […] Emerging evidence suggests that nitric oxide (NO), inflammatory and oxidative stress also play important roles in the pathophysiology of MetS hypertension and DMT2. […] Increased production of reactive oxygen species (ROS) in numerous tissues, including skeletal muscle and cardiovascular tissues, has been linked (amongst others) to activation of the renin-angiotensin-aldosterone system, which is also implicated in the development of IR.

• #21 Metabolic syndrome: definitions and controversies | BMC Medicine | Full Text

  https://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-9-48

  Chronic hypersecretion of stress mediators, such as cortisol, in individuals with a genetic predisposition exposed to a permissive environment, may lead to visceral fat accumulation as a result of chronic hypercortisolism, low growth hormone secretion and hypogonadism. […] Moreover, since intracellular GC levels are regulated by 11-hydroxysteroid dehydrogenase type 1 (11-HSD1), which converts inactive cortisone to cortisol, a large number of studies have focused on evaluating tissue specific alterations in 11-HSD1 expression and activity in obesity and IR. […] Emerging evidence suggests that nitric oxide (NO), inflammatory and oxidative stress also play important roles in the pathophysiology of MetS hypertension and DMT2. […] Increased production of reactive oxygen species (ROS) in numerous tissues, including skeletal muscle and cardiovascular tissues, has been linked (amongst others) to activation of the renin-angiotensin-aldosterone system, which is also implicated in the development of IR.

• #22 Metabolic Syndrome: Updates on Pathophysiology and Management in 2021

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8775991/

  Another contribution of insulin resistance to MetS is the development of hypertension caused partly by loss of insulin’s vasodilatory effect and by FFA-induced vasoconstriction due to reactive oxygen species production and subsequent scavenging of nitric oxide. […] The various pathogenic pathways contributing to the development of MetS culminate in a pro-inflammatory state that explains the elevation in various inflammatory markers such as IL-6, C-reactive protein (CRP), and TNF seen in individuals with MetS. […] The complex interplay of environmental factors, lifestyle, and genetic/epigenetic factors in the pathophysiology of MetS has led to the emergence of novel studies that evaluate new perspectives in the early diagnosis, classification of new biomarkers, and discovery of potential targets for therapeutic interventions.

• #23 Metabolic Syndrome: Updates on Pathophysiology and Management in 2021

  https://www.mdpi.com/1422-0067/23/2/786

  Among the proposed mechanisms, insulin resistance, chronic inflammation, and neurohormonal activation seem to be essential players in the progression of MetS and its subsequent transition to CVDs and T2DM. […] Insulin resistance develops in fat tissues, insulin-mediated inhibition of lipolysis is impaired. The resulting increase in circulating free fatty acids (FFAs) in turn worsens insulin resistance by causing alterations in the insulin signaling cascade in different organs, thus creating a vicious cycle. […] Another contribution of insulin resistance to MetS is the development of hypertension caused partly by loss of insulin’s vasodilatory effect and by FFA-induced vasoconstriction due to reactive oxygen species production and subsequent scavenging of nitric oxide. […] The various pathogenic pathways contributing to the development of MetS culminate in a pro-inflammatory state that explains the elevation in various inflammatory markers such as IL-6, C-reactive protein (CRP), and TNFα seen in individuals with MetS.

• #24 The interplay of factors in metabolic syndrome: understanding its roots and complexity | Molecular Medicine | Full Text

  https://molmed.biomedcentral.com/articles/10.1186/s10020-024-01019-y

  Insulin resistance (IR) plays a pivotal role in the development of both hypertension and MetS. Under normal conditions, insulin promotes vasodilation by stimulating nitric oxide (NO) production in endothelial cells via the PI3K-Akt pathway. However, in insulin-resistant states, this pathway is impaired, leading to reduced NO production and endothelial dysfunction, a key feature of hypertension. Simultaneously, IR activates the MAPK pathway, enhancing the activity of vasoconstrictors such as endothelin-1 (ET-1) and angiotensin II (Ang II), further elevating blood pressure. […] Inflammation is a core element of the pathophysiology of MetS, which includes obesity, insulin resistance (IR), dyslipidemia, and hypertension. Chronic low-grade inflammation serves as a critical link among these metabolic abnormalities, driving the progression of MetS and significantly increasing the risk of cardiovascular diseases and type 2 diabetes. At the molecular level, visceral adipose tissue plays a pivotal role in the inflammatory processes associated with MetS. During obesity, adipocytes expand and become dysfunctional, resulting in hypoxia and tissue stress. This dysfunction recruits immune cells, particularly macrophages, into the adipose tissue, shifting their phenotype from an anti-inflammatory (M2) to a pro-inflammatory (M1) state. These macrophages release pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-), interleukin-6 (IL-6), and interleukin-1 (IL-1), which propagate systemic inflammation and aggravate IR, a hallmark feature of MetS.

• #25 The interplay of factors in metabolic syndrome: understanding its roots and complexity | Molecular Medicine | Full Text

  https://molmed.biomedcentral.com/articles/10.1186/s10020-024-01019-y

  Insulin resistance (IR) plays a pivotal role in the development of both hypertension and MetS. Under normal conditions, insulin promotes vasodilation by stimulating nitric oxide (NO) production in endothelial cells via the PI3K-Akt pathway. However, in insulin-resistant states, this pathway is impaired, leading to reduced NO production and endothelial dysfunction, a key feature of hypertension. Simultaneously, IR activates the MAPK pathway, enhancing the activity of vasoconstrictors such as endothelin-1 (ET-1) and angiotensin II (Ang II), further elevating blood pressure. […] Inflammation is a core element of the pathophysiology of MetS, which includes obesity, insulin resistance (IR), dyslipidemia, and hypertension. Chronic low-grade inflammation serves as a critical link among these metabolic abnormalities, driving the progression of MetS and significantly increasing the risk of cardiovascular diseases and type 2 diabetes. At the molecular level, visceral adipose tissue plays a pivotal role in the inflammatory processes associated with MetS. During obesity, adipocytes expand and become dysfunctional, resulting in hypoxia and tissue stress. This dysfunction recruits immune cells, particularly macrophages, into the adipose tissue, shifting their phenotype from an anti-inflammatory (M2) to a pro-inflammatory (M1) state. These macrophages release pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-), interleukin-6 (IL-6), and interleukin-1 (IL-1), which propagate systemic inflammation and aggravate IR, a hallmark feature of MetS.

• #26 Metabolic syndrome in children and adolescents – Al-Hamad – Translational Pediatrics

  https://tp.amegroups.org/article/view/16890/html

  It is believed that inflammatory cytokines release from dysfunctional adipocytes, such as, monocyte chemoattractant protein-1, and tumor necrosis factor-alpha, promotes macrophages migration to those adipose tissues and further increase cytokine production. […] Additionally, a decrease in adiponectin level seen in obesity can result in more inflammatory process in the adipose tissues.

• #27 The interplay of factors in metabolic syndrome: understanding its roots and complexity | Molecular Medicine | Full Text

  https://molmed.biomedcentral.com/articles/10.1186/s10020-024-01019-y

  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 insulins 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.

• #28 Mechanisms of the components of the metabolic syndrome that predispose to diabetes and atherosclerotic CVD | Proceedings of the Nutrition Society | Cambridge Core

  https://www.cambridge.org/core/journals/proceedings-of-the-nutrition-society/article/mechanisms-of-the-components-of-the-metabolic-syndrome-that-predispose-to-diabetes-and-atherosclerotic-cvd/5C5506FFE812D0EE5C548B571D599EB0

  The metabolic syndrome represents a summation of obesity-driven risk factors for atherosclerotic CVD and type 2 diabetes. […] Insulin resistance appears to explain much of the pathophysiology of the syndrome. […] Both increased fatty acid flux and an excess of circulating pro-inflammatory cytokines are likely mediators. […] With increased waist circumference, increases in fatty acid delivery to the liver result in higher rates of hepatic glucose production and increases in the secretion of apoB-containing lipoproteins. […] Concomitant changes in HDL ensue, including a replacement of the cholesterol content with TAG, an accelerated clearance from the plasma and thus a reduced number of HDL particles. […] Typically also present are increases in small dense LDL. […] Hypertension in part relates to the insulin resistance, but may involve other mechanisms.

• #29 The interplay of factors in metabolic syndrome: understanding its roots and complexity | Molecular Medicine | Full Text

  https://molmed.biomedcentral.com/articles/10.1186/s10020-024-01019-y

  Insulin resistance (IR) plays a pivotal role in the development of both hypertension and MetS. Under normal conditions, insulin promotes vasodilation by stimulating nitric oxide (NO) production in endothelial cells via the PI3K-Akt pathway. However, in insulin-resistant states, this pathway is impaired, leading to reduced NO production and endothelial dysfunction, a key feature of hypertension. Simultaneously, IR activates the MAPK pathway, enhancing the activity of vasoconstrictors such as endothelin-1 (ET-1) and angiotensin II (Ang II), further elevating blood pressure. […] Inflammation is a core element of the pathophysiology of MetS, which includes obesity, insulin resistance (IR), dyslipidemia, and hypertension. Chronic low-grade inflammation serves as a critical link among these metabolic abnormalities, driving the progression of MetS and significantly increasing the risk of cardiovascular diseases and type 2 diabetes. At the molecular level, visceral adipose tissue plays a pivotal role in the inflammatory processes associated with MetS. During obesity, adipocytes expand and become dysfunctional, resulting in hypoxia and tissue stress. This dysfunction recruits immune cells, particularly macrophages, into the adipose tissue, shifting their phenotype from an anti-inflammatory (M2) to a pro-inflammatory (M1) state. These macrophages release pro-inflammatory cytokines, including tumor necrosis factor-alpha (TNF-), interleukin-6 (IL-6), and interleukin-1 (IL-1), which propagate systemic inflammation and aggravate IR, a hallmark feature of MetS.

• #30 Metabolic syndrome in children and adolescents – Al-Hamad – Translational Pediatrics

  https://tp.amegroups.org/article/view/16890/html

  Additionally, hyperinsulinemia causes an increase in the transcription of genes for lipogenic enzymes in the liver, which leads to increased production of triglycerides. […] The increase in free fatty acids delivery to the liver is thought to result in hepatic insensitivity to the inhibitory effects of insulin on very low density lipoprotein (VLDL) secretion and overproduction of triglyceride-rich VLDL particles. […] Elevated BP in metabolic syndrome is thought to be secondary to hyperinsulinemia via mechanisms such as sympathetic nervous system activity, renal sodium retention and smooth muscle growth. […] Insulin has a vasodilatory effect on the endothelium secondary to the production of nitric oxide (a potent vasodilator). […] Endothelial dysfunction and disturbed vasodilatory response frequently occur secondary to insulin resistance.

• #31

  https://www.jci.org/articles/view/129190

  The central hallmark of the metabolic syndrome is insulin resistance, and, other than obesity itself, compelling arguments exist linking almost all the features of the metabolic syndrome to underlying insulin resistance. […] The severity of insulin resistance is broadly proportional to the extent of fat loss or dysfunction. […] Collectively, the two points above indicate that lack and/or dysfunction of white fat is consistently associated with insulin resistance and the metabolic syndrome, particularly when the defect in white fat is compounded by hyperphagia due to relative leptin deficiency. […] NAFLD is a very consistent feature in insulin-resistant lipodystrophies, and is typically associated with metabolic dyslipidemia (high triglycerides and low HDL cholesterol). […] Insulin receptoropathies, a term used to describe insulin-resistant states caused by a mutation or acquired defect in one of the proximal insulin signaling components (most commonly the insulin receptor [INSR] itself), represent another cluster of monogenic disorders associated with severe insulin resistance.

• #32 Inflammation and Metabolic Syndrome- An Overview

  http://www.foodandnutritionjournal.org/volume3number3/inflammation-and-metabolic-syndrome-an-overview/

  Chronic levels of free fatty acids and glucose induces inflammation, results in increased apoptosis and impaired insulin secretion of cells, which prompts the progression from obesity and insulin resistance to overt T2DM. […] The pathogenesis of atherosclerosis is a process that requires a complex and orchestrated interaction between endothelial cells, smooth muscle cells and macrophages. […] The main cause of liver pathology in societies is NAFLD. Its prevalence reaches 30% in the population and up to 75100% in obesity. […] Inflammation is a critical component of metabolic syndrome. Great progress has been made in the understanding of how pro-inflammatory cytokines and specific immune cell populations promote metabolic disease progression.

• #33 Autophagy in metabolic syndrome: breaking the wheel by targeting the renin–angiotensin system | Cell Death & Disease

  https://www.nature.com/articles/s41419-020-2275-9

  The role of autophagy in the liver is surprisingly different from adipose tissue in MetS. During obesity, autophagy is significantly reduced in hepatocytes and impaired metabolism along with deformed mitochondria are observed in the liver. […] The relationship of autophagy with insulin resistance is possibly mediated via mTOR. […] The link between autophagy and insulin signaling warrants further investigation to find specific therapeutic targets against MetS-associated metabolic deviations. […] The interrelationship of RAS and autophagy, specifically in the adipose tissue, is not well studied. […] Therefore, more studies are required to properly understand the molecular mechanisms by which RAS interacts with autophagy in disease development and progression. […] Thus, unraveling the RAS pathway and how it controls autophagy using pharmacological or immune selective therapy may help break the vicious cycle that contributes to MetS burden and establishment.

• #34

  https://www.alliedacademies.org/articles/understanding-the-molecular-mechanisms-behind-metabolic-syndrome-28400.html

  Genetic factors play a significant role in predisposing individuals to metabolic syndrome. Genome-wide association studies have identified numerous genetic loci associated with metabolic traits, including adiposity, insulin resistance, and lipid metabolism. These genetic variants influence molecular pathways involved in energy balance, adipocyte differentiation, insulin signaling, and lipid metabolism, contributing to metabolic syndrome susceptibility. […] Impaired mitochondrial function is increasingly recognized as a contributing factor to metabolic syndrome pathogenesis. Mitochondrial dysfunction in adipose tissue, liver, and skeletal muscle compromises cellular energy production, promotes oxidative stress, and disrupts metabolic homeostasis, exacerbating insulin resistance and lipid dysregulation.

• #35 Mechanisms of the components of the metabolic syndrome that predispose to diabetes and atherosclerotic CVD | Proceedings of the Nutrition Society | Cambridge Core

  https://www.cambridge.org/core/journals/proceedings-of-the-nutrition-society/article/mechanisms-of-the-components-of-the-metabolic-syndrome-that-predispose-to-diabetes-and-atherosclerotic-cvd/5C5506FFE812D0EE5C548B571D599EB0

  In the liver of high-fat-fed rats insulin resistance can be attributed to a defect in insulin-stimulated insulin receptor substrate-1 and insulin receptor substrate-2 tyrosine phosphorylation. […] More detailed studies in human subjects have examined the cellular and molecular basis of insulin resistance in more detail, and in insulin-resistant subjects with obesity and/or type 2 diabetes and in the elderly a defect in mitochondrial oxidative phosphorylation has been identified. […] Oxidative stress has also been viewed as a cellular mechanism for insulin resistance. […] Thus, with time more basic mechanisms of insulin resistance are being discovered. […] Nearly all the criteria included in the metabolic syndrome relate to or are a cause of insulin resistance and confer increased risk for atherosclerotic CVD and diabetes.

• #36 Mechanisms of the components of the metabolic syndrome that predispose to diabetes and atherosclerotic CVD | Proceedings of the Nutrition Society | Cambridge Core

  https://www.cambridge.org/core/journals/proceedings-of-the-nutrition-society/article/mechanisms-of-the-components-of-the-metabolic-syndrome-that-predispose-to-diabetes-and-atherosclerotic-cvd/5C5506FFE812D0EE5C548B571D599EB0

  In the liver of high-fat-fed rats insulin resistance can be attributed to a defect in insulin-stimulated insulin receptor substrate-1 and insulin receptor substrate-2 tyrosine phosphorylation. […] More detailed studies in human subjects have examined the cellular and molecular basis of insulin resistance in more detail, and in insulin-resistant subjects with obesity and/or type 2 diabetes and in the elderly a defect in mitochondrial oxidative phosphorylation has been identified. […] Oxidative stress has also been viewed as a cellular mechanism for insulin resistance. […] Thus, with time more basic mechanisms of insulin resistance are being discovered. […] Nearly all the criteria included in the metabolic syndrome relate to or are a cause of insulin resistance and confer increased risk for atherosclerotic CVD and diabetes.

• #37 Metabolic syndrome: definitions and controversies | BMC Medicine | Full Text

  https://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-9-48

  Chronic hypersecretion of stress mediators, such as cortisol, in individuals with a genetic predisposition exposed to a permissive environment, may lead to visceral fat accumulation as a result of chronic hypercortisolism, low growth hormone secretion and hypogonadism. […] Moreover, since intracellular GC levels are regulated by 11-hydroxysteroid dehydrogenase type 1 (11-HSD1), which converts inactive cortisone to cortisol, a large number of studies have focused on evaluating tissue specific alterations in 11-HSD1 expression and activity in obesity and IR. […] Emerging evidence suggests that nitric oxide (NO), inflammatory and oxidative stress also play important roles in the pathophysiology of MetS hypertension and DMT2. […] Increased production of reactive oxygen species (ROS) in numerous tissues, including skeletal muscle and cardiovascular tissues, has been linked (amongst others) to activation of the renin-angiotensin-aldosterone system, which is also implicated in the development of IR.

• #38 Pathophysiology of the Metabolic Syndrome | Encyclopedia MDPI

  https://encyclopedia.pub/entry/21942

  The production of reactive oxygen species (ROS) is many associated with dysfunctional homeostasis, though some of these, called bioradicals, originate from the physiological process. The excess accumulation of free radicals leads to chronic inflammation and an imbalance in cellular apoptosis and proliferation via the altered hyper- or hypo-activation of some cellular signaling pathways. […] The cardiovascular system is also subject to alterations related to MetS. Essential roles in hemodynamic pathophysiology are played by the activation of the renin–angiotensin–aldosterone system; differing levels of adipocytokine secretion—i.e., leptin, tumor necrosis factor (TNF-α), and interleukin 6 (IL-6); and the hyperactivity of the sympathetic nervous system.

• #39 Autophagy in metabolic syndrome: breaking the wheel by targeting the renin–angiotensin system | Cell Death & Disease

  https://www.nature.com/articles/s41419-020-2275-9

  Moreover, our review will focus on the molecular mechanisms by which autophagy orchestrates MetS and the ways future treatments could target RAS in order to achieve metabolic homeostasis. […] Although autophagy is considered as a housekeeping cell process, abnormalities of autophagy have increasingly been associated with metabolic disorders such as obesity, insulin resistance, T2D onset, nonalcoholic steatohepatitis, atherosclerosis, and heart disease, which are pathologically linked to autophagy dysfunction and may influence the onset of MetS. […] Autophagy plays a pivotal role in adipocyte differentiation and maturation whereas during metabolic syndrome obesity further triggers autophagic activity. […] Autophagy is crucial for proper functioning and differentiation of adipocytes, defective regulation during obesity causes metabolic abnormalities, leading to MetS.

• #40 Autophagy in metabolic syndrome: breaking the wheel by targeting the renin–angiotensin system | Cell Death & Disease

  https://www.nature.com/articles/s41419-020-2275-9

  Moreover, our review will focus on the molecular mechanisms by which autophagy orchestrates MetS and the ways future treatments could target RAS in order to achieve metabolic homeostasis. […] Although autophagy is considered as a housekeeping cell process, abnormalities of autophagy have increasingly been associated with metabolic disorders such as obesity, insulin resistance, T2D onset, nonalcoholic steatohepatitis, atherosclerosis, and heart disease, which are pathologically linked to autophagy dysfunction and may influence the onset of MetS. […] Autophagy plays a pivotal role in adipocyte differentiation and maturation whereas during metabolic syndrome obesity further triggers autophagic activity. […] Autophagy is crucial for proper functioning and differentiation of adipocytes, defective regulation during obesity causes metabolic abnormalities, leading to MetS.

• #41 Metabolic syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Metabolic_syndrome

  The continuous provision of energy via dietary carbohydrate, lipid, and protein fuels, unmatched by physical activity/energy demand, creates a backlog of the products of mitochondrial oxidation, a process associated with progressive mitochondrial dysfunction and insulin resistance. […] Recent research indicates prolonged chronic stress can contribute to metabolic syndrome by disrupting the hormonal balance of the hypothalamic-pituitary-adrenal axis (HPA-axis). […] A dysfunctional HPA-axis causes high cortisol levels to circulate, which results in raising glucose and insulin levels, which in turn cause insulin-mediated effects on adipose tissue, ultimately promoting visceral adiposity, insulin resistance, dyslipidemia and hypertension. […] Central obesity is a key feature of the syndrome, as both a sign and a cause, in that the increasing adiposity often reflected in high waist circumference may both result from and contribute to insulin resistance.

• #42

  https://www.xiahepublishing.com/1555-3884/GE-2023-00202

  A key element in the pathogenesis of metabolic syndrome (MetS) is the reprogramming of hypothalamic cells at the genetic level (in the prenatal phase), which leads to neuroinflammation. […] We hypothesize that alterations in the structure of hypothalamic neurons mediated by (epi)genetic alterations are directly related to impaired expression/production of neurotrophins and neurotransmitters that control the metabolism of substances in the brain and periphery, including brain-derived neurotrophic factor (BDNF). […] A key element in the pathogenesis of MetS might be the reprogramming of hypothalamic cells at the genetic level (in the prenatal phase), which leads to neuroinflammation. At the same time, neuroinflammation of the hypothalamus, which occurs in those who consume a Western diet, leads to the development of peripheral inflammation and creates a vicious cycle of neuro-/meta-inflammation.

• #43 Pathogenesis of the Metabolic Syndrome | SpringerLink

  https://link.springer.com/chapter/10.1007/978-1-84628-911-8_3

  A powerful genetic basis for insulin resistance is supported by its high prevalence in certain populations, especially the Nauru Islanders of the Pacific, the Pima Indians in Arizona, and the urban Wanigela people in Papua New Guinea. […] Environmental and genetic factors lead to obesity and insulin resistance, which contribute to metabolic abnormalities. The final outcome is cardiovascular disease. […] The environmental contribution of insulin resistance to the metabolic syndrome is estimated to be approximately 50%. […] Mechanisms of insulin resistance in humans and possible links with inflammation. […] Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. […] Endoplasmic reticulum stress links obesity, insulin action and type 2 diabetes. […] Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. […] Mechanism of hepatic VLDL overproduction in insulin resistance. […] Cellular mechanism of insulin resistance.

• #44 Pathogenesis of the Metabolic Syndrome | SpringerLink

  https://link.springer.com/chapter/10.1007/978-1-84628-911-8_3

  A powerful genetic basis for insulin resistance is supported by its high prevalence in certain populations, especially the Nauru Islanders of the Pacific, the Pima Indians in Arizona, and the urban Wanigela people in Papua New Guinea. […] Environmental and genetic factors lead to obesity and insulin resistance, which contribute to metabolic abnormalities. The final outcome is cardiovascular disease. […] The environmental contribution of insulin resistance to the metabolic syndrome is estimated to be approximately 50%. […] Mechanisms of insulin resistance in humans and possible links with inflammation. […] Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. […] Endoplasmic reticulum stress links obesity, insulin action and type 2 diabetes. […] Mechanism of hepatic insulin resistance in non-alcoholic fatty liver disease. […] Mechanism of hepatic VLDL overproduction in insulin resistance. […] Cellular mechanism of insulin resistance.

• #45

  https://www.alliedacademies.org/articles/understanding-the-molecular-mechanisms-behind-metabolic-syndrome-28400.html

  Genetic factors play a significant role in predisposing individuals to metabolic syndrome. Genome-wide association studies have identified numerous genetic loci associated with metabolic traits, including adiposity, insulin resistance, and lipid metabolism. These genetic variants influence molecular pathways involved in energy balance, adipocyte differentiation, insulin signaling, and lipid metabolism, contributing to metabolic syndrome susceptibility. […] Impaired mitochondrial function is increasingly recognized as a contributing factor to metabolic syndrome pathogenesis. Mitochondrial dysfunction in adipose tissue, liver, and skeletal muscle compromises cellular energy production, promotes oxidative stress, and disrupts metabolic homeostasis, exacerbating insulin resistance and lipid dysregulation.

• #46

  https://www.xiahepublishing.com/1555-3884/GE-2023-00202

  The concept of transgenerational epigenetic inheritance is related to the theory of developmental origins of health and disease, which emphasizes the role of the environment during intrauterine life in predisposition to disease in adulthood by altering the number of copies of mtDNA. […] The important role of transgenerational inheritance in the development of MetS has been confirmed by studies showing a high risk of developing MetS components in the offspring against a background of the same pathologies in the parents. […] The precursor of pre-proBDNF is formed in the endoplasmic reticulum and then transported to the Golgi apparatus, where it is cleaved by endoproteolytic proteases. […] BDNF exerts a postsynaptic effect on neurons by interacting with the tropomyosin B kinase receptor (TrkB, encoded by the NTRK2 gene) and a receptor from the tumor necrosis factor family p75 neurotrophin receptor (p75NTR).

• #47

  https://xiahepublishing.com/1555-3884/GE-2023-00202

  New areas of science that have developed rapidly over the last decade (e.g., epigenetics and transgenerational inheritance) point to another fundamental reason for the development of MetS, linking the internal and external aspects of pathogenesis and allowing us to look at deeper connections when studying this disease. […] At the same time, transient changes in the genome (e.g., methylation and acetylation), which can be inherited among generations and stabilized due to environmental factors, may play a key role in MetS. […] A key element in the pathogenesis of MetS might be the reprogramming of hypothalamic cells at the genetic level (in the prenatal phase), which leads to neuroinflammation. […] The hypothalamus also regulates the body’s endocrine functions and cholesterol metabolism, which are impaired in MetS.

• #48

  https://www.xiahepublishing.com/1555-3884/GE-2023-00202

  Studies in humans and animals have shown an unclear relationship between the expression of BDNF in the brain and in the periphery. […] The important role of BDNF in glucose homeostasis and cholesterol biosynthesis has been demonstrated. […] The structure of the BDNF gene is complex and is regulated by nine functional promoters, which control the formation of different transcripts, depending on the stress signal. […] Genetic changes in BDNF, therefore, have a direct effect on the function of brain neurons and the body’s metabolism via signaling cascades that are involved in the development of MetS. […] Epigenetic modulations such as DNA methylation, histone modifications, and the regulation of noncoding RNAs play an important role in BDNF expression. […] Prenatal stress-induced methylation of the BDNF gene (in rats) is associated with a decrease in BDNF protein expression in the brain of male offspring.

• #49

  https://www.xiahepublishing.com/1555-3884/GE-2023-00202

  Molecular genetic studies on animal models and meta-studies conducted on large cohorts of MetS patients have identified many aspects and signaling pathways involved in the development of the disease, but an effective drug that can prevent and stop the global spread of MetS has not yet been proposed, even after a series of clinical trials. […] New areas of science that have developed rapidly over the last decade (e.g., epigenetics and transgenerational inheritance) point to another fundamental reason for the development of MetS, linking the internal and external aspects of pathogenesis and allowing us to look at deeper connections when studying this disease. […] Studies on BDNF point to its role in metabolic processes, including glucose, insulin, and cholesterol homeostasis. […] Evidence-based studies show that multiple genes in close proximity to BDNF are involved in the development of MetS.

• #50

  https://www.xiahepublishing.com/1555-3884/GE-2023-00202

  The concept of transgenerational epigenetic inheritance is related to the theory of developmental origins of health and disease, which emphasizes the role of the environment during intrauterine life in predisposition to disease in adulthood by altering the number of copies of mtDNA. […] The important role of transgenerational inheritance in the development of MetS has been confirmed by studies showing a high risk of developing MetS components in the offspring against a background of the same pathologies in the parents. […] The precursor of pre-proBDNF is formed in the endoplasmic reticulum and then transported to the Golgi apparatus, where it is cleaved by endoproteolytic proteases. […] BDNF exerts a postsynaptic effect on neurons by interacting with the tropomyosin B kinase receptor (TrkB, encoded by the NTRK2 gene) and a receptor from the tumor necrosis factor family p75 neurotrophin receptor (p75NTR).

• #51

  https://www.xiahepublishing.com/1555-3884/GE-2023-00202

  Studies in humans and animals have shown an unclear relationship between the expression of BDNF in the brain and in the periphery. […] The important role of BDNF in glucose homeostasis and cholesterol biosynthesis has been demonstrated. […] The structure of the BDNF gene is complex and is regulated by nine functional promoters, which control the formation of different transcripts, depending on the stress signal. […] Genetic changes in BDNF, therefore, have a direct effect on the function of brain neurons and the body’s metabolism via signaling cascades that are involved in the development of MetS. […] Epigenetic modulations such as DNA methylation, histone modifications, and the regulation of noncoding RNAs play an important role in BDNF expression. […] Prenatal stress-induced methylation of the BDNF gene (in rats) is associated with a decrease in BDNF protein expression in the brain of male offspring.

• #52

  https://www.xiahepublishing.com/1555-3884/GE-2023-00202

  A HFD contributes to oxidative stress and a reduction in BDNF expression that mediates damage to neurogenesis and synaptic plasticity, alterations in the formation of projections of melanocortin neurons in the hypothalamus, and the maintenance of disorders in subsequent generations in the postnatal period. […] The key role of BDNF in growth, development, central/peripheral nervous system nutrition, follicle formation, implantation/placentation, and maternal and fetal health has been established.

• #53 Metabolic Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK459248/

  Metabolic syndrome, characterized by a constellation of metabolic abnormalities, including central obesity, insulin resistance, hypertension, and dyslipidemia, poses a significant risk for the development of atherosclerotic cardiovascular diseases and type II diabetes mellitus. […] The underlying etiology of metabolic syndrome is multifactorial. The proposed causes include genetic predisposition and multiple environmental or lifestyle factors, including obesity, lack of physical activity, and unhealthy dietary habits. […] The crux of the syndrome is a buildup of fatty tissue, especially in the abdomen, leading to insulin resistance. […] Visceral obesity has been identified as the main trigger of all pathways involved in the pathogenesis of metabolic syndrome, and high-calorie intake is the primary cause of visceral fat accumulation.

• #54 Metabolic syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Metabolic_syndrome

  Metabolic syndrome can be induced by overfeeding with sucrose or fructose, particularly concomitantly with high-fat diet. […] The resulting oversupply of omega-6 fatty acids, particularly arachidonic acid (AA), is an important factor in the pathogenesis of metabolic syndrome. […] The involvement of the endocannabinoid system in the development of metabolic syndrome is indisputable.

• #55 Metabolic syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Metabolic_syndrome

  The continuous provision of energy via dietary carbohydrate, lipid, and protein fuels, unmatched by physical activity/energy demand, creates a backlog of the products of mitochondrial oxidation, a process associated with progressive mitochondrial dysfunction and insulin resistance. […] Recent research indicates prolonged chronic stress can contribute to metabolic syndrome by disrupting the hormonal balance of the hypothalamic-pituitary-adrenal axis (HPA-axis). […] A dysfunctional HPA-axis causes high cortisol levels to circulate, which results in raising glucose and insulin levels, which in turn cause insulin-mediated effects on adipose tissue, ultimately promoting visceral adiposity, insulin resistance, dyslipidemia and hypertension. […] Central obesity is a key feature of the syndrome, as both a sign and a cause, in that the increasing adiposity often reflected in high waist circumference may both result from and contribute to insulin resistance.

• #56 Stem Cell Therapy – Boulder, Colorado | Boulder Biologics | Jason Glowney, MD |Lauren Rudolph, MD | Stem Cells – Denver, Colorado | PRP | Regenerative Medicine | EPAT | Dr. Jason Glowney | Boulder Biologics

  https://www.boulderbiologics.com/metabolic-syndrome

  Metabolic syndrome is a complex condition characterized by a cluster of interconnected factors, including abdominal obesity, elevated blood pressure, high fasting blood glucose, elevated triglycerides, and reduced high-density lipoprotein cholesterol, which collectively increase the risk of cardiovascular disease, type 2 diabetes, and other chronic illnesses (Varanasi, 2011) (Phillips, 2013) (Groop, 2000) (Brown Walker, 2016). […] Genetic factors play a significant role in predisposing individuals to this syndrome, with variations in genes related to insulin signaling, lipid metabolism, and inflammation influencing susceptibility (Varanasi, 2011) (Brown Walker, 2016) (Groop, 2000). […] Environmental and lifestyle factors are critical drivers of metabolic syndrome, with a sedentary lifestyle, poor dietary habits, and excessive calorie intake contributing significantly to its development (Varanasi, 2011).

• #57 Metabolic Syndrome – StatPearls – NCBI Bookshelf

  https://www.ncbi.nlm.nih.gov/books/NBK459248/

  Metabolic syndrome, characterized by a constellation of metabolic abnormalities, including central obesity, insulin resistance, hypertension, and dyslipidemia, poses a significant risk for the development of atherosclerotic cardiovascular diseases and type II diabetes mellitus. […] The underlying etiology of metabolic syndrome is multifactorial. The proposed causes include genetic predisposition and multiple environmental or lifestyle factors, including obesity, lack of physical activity, and unhealthy dietary habits. […] The crux of the syndrome is a buildup of fatty tissue, especially in the abdomen, leading to insulin resistance. […] Visceral obesity has been identified as the main trigger of all pathways involved in the pathogenesis of metabolic syndrome, and high-calorie intake is the primary cause of visceral fat accumulation.

• #58

  https://www.alliedacademies.org/articles/understanding-the-molecular-mechanisms-behind-metabolic-syndrome-28400.html

  Dysfunctional adipocytes, especially in visceral fat depots, secrete pro-inflammatory cytokines like TNF- and IL-6, promoting insulin resistance and systemic inflammation, key features of metabolic syndrome. […] Chronic low-grade inflammation is a hallmark of metabolic syndrome, linking obesity, insulin resistance, and cardiovascular disease. Activation of inflammatory pathways, including NF-B and JNK, in adipose tissue, liver, and other organs, disrupts insulin signaling, impairs lipid metabolism, and promotes atherosclerosis. […] Molecular insights have highlighted disturbances in lipid metabolism, including enhanced lipogenesis, impaired fatty acid oxidation, and altered lipoprotein metabolism, driven by factors such as insulin resistance and inflammation. […] Emerging evidence suggests a bidirectional relationship between gut microbiota and metabolic syndrome. Dysbiosis, characterized by alterations in microbial composition and function, contributes to metabolic disturbances by modulating energy harvest from diet, inflammation, gut barrier integrity, and bile acid metabolism, highlighting the intricate molecular crosstalk between the gut microbiome and host metabolism.

• #59 Mechanisms, pathophysiology and asssessment of metabolic syndrome

  https://www.abcam.cn/content/metabolic-syndrome-mechanisms-pathophysiology-and-laboratory-assessment

  Liver, muscle, intestinal and fat cells can become resistant to insulin in metabolic syndrome. In the liver, the condition results in an increase in glucose production and secretion, while in muscle and fat cells, reduced glucose uptake results in hyperglycemia. The pancreas then releases even more insulin, leading to a transient hyperinsulinemia. […] There is growing evidence that the small intestine plays a critical role in the development of insulin resistance, metabolic syndrome and type 2 diabetes. […] Insulin and leptin are hormones involved in key metabolic signaling pathways. […] Downstream mediators of the insulin receptor cascade can regulate carbohydrate and lipid metabolism, which become dysregulated in obesity and diabetes. […] Protein tyrosine phosphatase 1B (PTP1B) is referred to as a Master Switch since it can block insulin action through dephosphorylation of the receptor.

• #60 Metabolic syndrome – Wikipedia

  https://en.wikipedia.org/wiki/Metabolic_syndrome

  Metabolic syndrome can be induced by overfeeding with sucrose or fructose, particularly concomitantly with high-fat diet. […] The resulting oversupply of omega-6 fatty acids, particularly arachidonic acid (AA), is an important factor in the pathogenesis of metabolic syndrome. […] The involvement of the endocannabinoid system in the development of metabolic syndrome is indisputable.

• #61

  https://www.alliedacademies.org/articles/understanding-the-molecular-mechanisms-behind-metabolic-syndrome-28400.html

  The central nervous system plays a pivotal role in regulating energy balance and metabolic homeostasis through complex neuroendocrine pathways. Dysregulation of these pathways, involving hormones like leptin, ghrelin, and corticotropin-releasing hormone, disrupts appetite regulation, energy expenditure, and glucose metabolism, contributing to the development of obesity and metabolic syndrome. […] Understanding the molecular mechanisms underlying metabolic syndrome holds promise for developing targeted therapeutic interventions. Strategies aimed at improving insulin sensitivity, reducing inflammation, restoring lipid homeostasis, modulating the gut microbiota, and promoting healthy lifestyle habits offer potential avenues for preventing and managing metabolic syndrome, emphasizing the importance of personalized approaches tailored to individual molecular profiles and environmental influences.

• #62 Inflammatory cause of metabolic syndrome via brain stress and NF-κB | Aging

  https://www.aging-us.com/article/100431/text

  Importantly, the CNS and the comprised hypothalamus are known to govern various metabolic activities of the body including appetite control, energy expenditure, carbohydrate and lipid metabolism, and blood pressure homeostasis. […] The role of brain oxidative stress in the development of metabolic diseases represents a new and highly interesting research topic. Overall, intracellular oxidative stress in the brain is potentially widely implicated in the pathogenesis of metabolic syndrome and related diseases, and defining the molecular and cellular pathways upstream and downstream of brain oxidative stress will significantly advance the mechanistic understandings of these diseases. […] ER stress can activate cellular inflammatory pathways which impairs cellular functions and leads to metabolic disorders.

• #63 Metabolic syndrome: definitions and controversies | BMC Medicine | Full Text

  https://bmcmedicine.biomedcentral.com/articles/10.1186/1741-7015-9-48

  The concept of fetal/developmental origin of MetS, since the first study linking intrauterine undernutrition with later obesity, continues to raise interest. […] Although the role of all these components as integral parts of MetS has not been evaluated in epidemiological and interventional studies, they may represent the missing link that provides full susceptibility to CVD besides the traditionally accepted components of MetS.

• #64 (Epi)genetic aspects of metabolic syndrome pathogenesis in relation to brain-derived neurotrophic factor expression | EurekAlert!

  https://www.eurekalert.org/news-releases/1052866

  Inflammation and alterations in hypothalamic function can precipitate MetS. […] The blood-brain barrier (BBB) integrity is compromised, allowing inflammatory mediators and fatty acids to affect fetal hypothalamus development. […] These changes are sex-specific, with female offspring exhibiting greater susceptibility to metabolic disorders. […] The maternal hypercaloric diet affects lipid metabolism and the endogenous cannabinoid system in the hypothalamus of adult offspring, leading to sex-specific metabolic responses. […] Developmental programming plays a crucial role in determining the susceptibility to metabolic disorders. […] Epigenetic mechanisms, including DNA methylation and histone modifications, mediate these long-lasting effects. […] The Notch signaling pathway, for instance, is involved in hypothalamic neurogenesis and is disrupted in the offspring of obese mothers, leading to altered neuronal development and metabolic dysfunction.

• #65 Metabolic Syndrome: Updates on Pathophysiology and Management in 2021

  https://pmc.ncbi.nlm.nih.gov/articles/PMC8775991/

  Another contribution of insulin resistance to MetS is the development of hypertension caused partly by loss of insulin’s vasodilatory effect and by FFA-induced vasoconstriction due to reactive oxygen species production and subsequent scavenging of nitric oxide. […] The various pathogenic pathways contributing to the development of MetS culminate in a pro-inflammatory state that explains the elevation in various inflammatory markers such as IL-6, C-reactive protein (CRP), and TNF seen in individuals with MetS. […] The complex interplay of environmental factors, lifestyle, and genetic/epigenetic factors in the pathophysiology of MetS has led to the emergence of novel studies that evaluate new perspectives in the early diagnosis, classification of new biomarkers, and discovery of potential targets for therapeutic interventions.

• #66 Metabolic Syndrome: Updates on Pathophysiology and Management in 2021

  https://www.mdpi.com/1422-0067/23/2/786

  The complex interplay of environmental factors, lifestyle, and genetic/epigenetic factors in the pathophysiology of MetS has led to the emergence of novel studies that evaluate new perspectives in the early diagnosis, classification of new biomarkers, and discovery of potential targets for therapeutic interventions.

• #67 Metabolic Syndrome: What It Is, Causes, Symptoms & Treatment

  https://my.clevelandclinic.org/health/diseases/10783-metabolic-syndrome

  The following can all contribute to insulin resistance: Excess weight around your abdomen or having obesity, Lack of physical activity, Certain medications, Genetics. […] The main goals of treating metabolic syndrome are to lower your risk of heart disease and Type 2 diabetes if you dont already have them. Treatment can involve medications and/or lifestyle changes. […] Yes, its possible to reverse metabolic syndrome. Lifestyle changes can do a lot to improve your health. Medications can help as well. Your healthcare provider will work with you to find the best plan for you. […] Metabolic syndrome can lead to a wide range of complications, including: Heart disease, Aortic stenosis, Atrial fibrillation (Afib), Thromboembolic disease, Stroke, Organ damage, Certain cancers, Type 2 diabetes, Long-term inflammation and problems with your immune system, Erectile dysfunction, Pregnancy complications, Issues with thinking and memory. […] The good news is that its possible to reverse metabolic syndrome with lifestyle changes and medications. The sooner you can make changes to protect your health, the better.

• #68

  https://www.alliedacademies.org/articles/understanding-the-molecular-mechanisms-behind-metabolic-syndrome-28400.html

  The central nervous system plays a pivotal role in regulating energy balance and metabolic homeostasis through complex neuroendocrine pathways. Dysregulation of these pathways, involving hormones like leptin, ghrelin, and corticotropin-releasing hormone, disrupts appetite regulation, energy expenditure, and glucose metabolism, contributing to the development of obesity and metabolic syndrome. […] Understanding the molecular mechanisms underlying metabolic syndrome holds promise for developing targeted therapeutic interventions. Strategies aimed at improving insulin sensitivity, reducing inflammation, restoring lipid homeostasis, modulating the gut microbiota, and promoting healthy lifestyle habits offer potential avenues for preventing and managing metabolic syndrome, emphasizing the importance of personalized approaches tailored to individual molecular profiles and environmental influences.

• #69 Metabolic Syndrome: Updates on Pathophysiology and Management in 2021

  https://www.mdpi.com/1422-0067/23/2/786

  Metabolic syndrome (MetS) forms a cluster of metabolic dysregulations including insulin resistance, atherogenic dyslipidemia, central obesity, and hypertension. The pathogenesis of MetS encompasses multiple genetic and acquired entities that fall under the umbrella of insulin resistance and chronic low-grade inflammation. […] If left untreated, MetS is significantly associated with an increased risk of developing diabetes and cardiovascular diseases (CVDs). […] The pathophysiology of the MetS encompasses several complex mechanisms that are yet to be fully elucidated. It is still debated as to whether the different elements of MetS form by themselves distinct pathologies or fall under a common, broader pathogenic process. In addition to genetic and epigenetic factors, some lifestyle and environmental such as overeating and lack of physical activity have been identified as major contributors to the development of MetS. A causative role can be given to high caloric intake since visceral adiposity has been shown to be an important trigger that activates most of the pathways of MetS.

• #70 Metabolic Syndrome: Updates on Pathophysiology and Management in 2021

  https://www.mdpi.com/1422-0067/23/2/786

  Among the proposed mechanisms, insulin resistance, chronic inflammation, and neurohormonal activation seem to be essential players in the progression of MetS and its subsequent transition to CVDs and T2DM. […] Insulin resistance develops in fat tissues, insulin-mediated inhibition of lipolysis is impaired. The resulting increase in circulating free fatty acids (FFAs) in turn worsens insulin resistance by causing alterations in the insulin signaling cascade in different organs, thus creating a vicious cycle. […] Another contribution of insulin resistance to MetS is the development of hypertension caused partly by loss of insulin’s vasodilatory effect and by FFA-induced vasoconstriction due to reactive oxygen species production and subsequent scavenging of nitric oxide. […] The various pathogenic pathways contributing to the development of MetS culminate in a pro-inflammatory state that explains the elevation in various inflammatory markers such as IL-6, C-reactive protein (CRP), and TNFα seen in individuals with MetS.

• #71 The interplay of factors in metabolic syndrome: understanding its roots and complexity | Molecular Medicine | Full Text

  https://molmed.biomedcentral.com/articles/10.1186/s10020-024-01019-y

  The pathogenesis of MetS is thought to involve several complex pathways that have not been fully characterized. Medical and scientific experts became concerned about whether the various MetSs are linked by a single pathogenic pathway or fall under a mutual pathogenic process. The complicated interactions between different genetic and environmental factors, including overeating, smoking, stress, and physical activity, can influence the development of MetS. Visceral adiposity is the crucial trigger that is correlated with most of the pathways involved in the development of MetS. Chronic inflammation, IR, and neurohormonal activation play key roles in the complex syndrome known as MetS as it progresses. Numerous other factors, including genetic susceptibility, dyslipidemia, hypertension, and CVD, can have an impact on MetS.

• #72

  https://www.alliedacademies.org/articles/understanding-the-molecular-mechanisms-behind-metabolic-syndrome-28400.html

  The central nervous system plays a pivotal role in regulating energy balance and metabolic homeostasis through complex neuroendocrine pathways. Dysregulation of these pathways, involving hormones like leptin, ghrelin, and corticotropin-releasing hormone, disrupts appetite regulation, energy expenditure, and glucose metabolism, contributing to the development of obesity and metabolic syndrome. […] Understanding the molecular mechanisms underlying metabolic syndrome holds promise for developing targeted therapeutic interventions. Strategies aimed at improving insulin sensitivity, reducing inflammation, restoring lipid homeostasis, modulating the gut microbiota, and promoting healthy lifestyle habits offer potential avenues for preventing and managing metabolic syndrome, emphasizing the importance of personalized approaches tailored to individual molecular profiles and environmental influences.

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