Metabolic flexibility (MetFlex) refers to the body’s ability to efficiently switch between energy substrates, adapting its metabolic processes to varying energy demands and nutrient availability. This capacity is central to maintaining systemic energy homeostasis and is tightly regulated by a complex interplay of hormones, enzymes, and signalling pathways governing nutrient utilization. Adipose tissue (AT) and the liver are pivotal in maintaining these metabolic circuits, ensuring a proper energetic balance. However, chronic metabolic stress, particularly from nutrient excess, impairs AT’s metabolic flexibility, disrupting its ability to buffer and trap fatty acids. This leads to the release of excess reactive fatty acids, triggering maladaptive systemic responses associated with chronic overnutrition.Additionally, persistent AT metaflammation and stress result in an altered secretion profile of cytokines and extracellular vesicles (EVs). These factors propagate metabolic inflexibility in the liver, contributing to insulin resistance and the progression of non-alcoholic fatty liver disease (NAFLD). Beyond AT and the liver, other tissues, such as skeletal muscle, the gut, and the cardiovascular system, play integral roles in maintaining or disrupting metabolic flexibility. For example, skeletal muscle is critical for glucose uptake and overall energy expenditure, and its dysfunction exacerbates systemic metabolic rigidity. The gut, through its microbiota composition and barrier integrity, modulates systemic inflammation and nutrient absorption, influencing metabolic regulation. The cardiovascular system, particularly through endothelial dysfunction and altered vascular responses, also contributes to nutrient delivery and systemic metabolic balance.Current therapeutic strategies targeting metabolic flexibility primarily focus on lifestyle interventions, including dietary and exercise modifications, and pharmacological approaches. However, the heterogeneity of metabolic dysfunction at the molecular level poses a challenge to achieving sustained improvements. Profound molecular alterations, such as persistent oxidative stress and chronic inflammation, frequently maintain a state of metabolic gridlock, highlighting a need for more targeted therapeutic approaches.This Research Topic seeks to advance the understanding of tissue-specific and systemic changes contributing to metabolic inflexibility, focusing on the underlying molecular and cellular mechanisms. It aims to elucidate how disruptions in tissue flexibility—particularly in adipose tissue (AT), the liver, and other metabolically relevant tissues—drive metabolic disorders. The issue will examine several key aspects:· How oxidative stress, endoplasmic reticulum (ER) stress, and inflammatory pathways disrupt tissue flexibility and contribute to metabolic dysfunction.· Molecular processes leading to insulin resistance during nutrient excess, specifically focusing on impaired substrate switching and energy metabolism dysregulation.· The role of skeletal muscle, the gut, the cardiovascular system and other tissues in metabolic inflexibility.· The mechanisms driving reduced flexibility in fatty acid and glucose oxidation, particularly in AT and the liver, and its impact on overall energy metabolism.· Key metabolites and signatures associated with inflexible metabolic states to better understand tissue-specific pathogenesis and discover potential biomarkers.· How dysregulated secretion of adipokines and hepatokines drives systemic metabolic disturbances and contributes to disrupted nutrient flux.· Mitochondrial impairments in energy switching and how reactive oxygen species (ROS) contribute to the collapse of mitochondrial function in metabolic inflexibility.· Hormones and their role in maintaining or losing metabolic flexibility.· Potential new molecular targets and therapeutic agents aimed at restoring metabolic flexibility across tissues and organ systems.
Metabolic flexibility (MetFlex) refers to the body’s ability to efficiently switch between energy substrates, adapting its metabolic processes to varying energy demands and nutrient availability. This capacity is central to maintaining systemic energy homeostasis and is tightly regulated by a complex interplay of hormones, enzymes, and signalling pathways governing nutrient utilization. Adipose tissue (AT) and the liver are pivotal in maintaining these metabolic circuits, ensuring a proper energetic balance. However, chronic metabolic stress, particularly from nutrient excess, impairs AT’s metabolic flexibility, disrupting its ability to buffer and trap fatty acids. This leads to the release of excess reactive fatty acids, triggering maladaptive systemic responses associated with chronic overnutrition.Additionally, persistent AT metaflammation and stress result in an altered secretion profile of cytokines and extracellular vesicles (EVs). These factors propagate metabolic inflexibility in the liver, contributing to insulin resistance and the progression of non-alcoholic fatty liver disease (NAFLD). Beyond AT and the liver, other tissues, such as skeletal muscle, the gut, and the cardiovascular system, play integral roles in maintaining or disrupting metabolic flexibility. For example, skeletal muscle is critical for glucose uptake and overall energy expenditure, and its dysfunction exacerbates systemic metabolic rigidity. The gut, through its microbiota composition and barrier integrity, modulates systemic inflammation and nutrient absorption, influencing metabolic regulation. The cardiovascular system, particularly through endothelial dysfunction and altered vascular responses, also contributes to nutrient delivery and systemic metabolic balance.Current therapeutic strategies targeting metabolic flexibility primarily focus on lifestyle interventions, including dietary and exercise modifications, and pharmacological approaches. However, the heterogeneity of metabolic dysfunction at the molecular level poses a challenge to achieving sustained improvements. Profound molecular alterations, such as persistent oxidative stress and chronic inflammation, frequently maintain a state of metabolic gridlock, highlighting a need for more targeted therapeutic approaches.This Research Topic seeks to advance the understanding of tissue-specific and systemic changes contributing to metabolic inflexibility, focusing on the underlying molecular and cellular mechanisms. It aims to elucidate how disruptions in tissue flexibility—particularly in adipose tissue (AT), the liver, and other metabolically relevant tissues—drive metabolic disorders. The issue will examine several key aspects:· How oxidative stress, endoplasmic reticulum (ER) stress, and inflammatory pathways disrupt tissue flexibility and contribute to metabolic dysfunction.· Molecular processes leading to insulin resistance during nutrient excess, specifically focusing on impaired substrate switching and energy metabolism dysregulation.· The role of skeletal muscle, the gut, the cardiovascular system and other tissues in metabolic inflexibility.· The mechanisms driving reduced flexibility in fatty acid and glucose oxidation, particularly in AT and the liver, and its impact on overall energy metabolism.· Key metabolites and signatures associated with inflexible metabolic states to better understand tissue-specific pathogenesis and discover potential biomarkers.· How dysregulated secretion of adipokines and hepatokines drives systemic metabolic disturbances and contributes to disrupted nutrient flux.· Mitochondrial impairments in energy switching and how reactive oxygen species (ROS) contribute to the collapse of mitochondrial function in metabolic inflexibility.· Hormones and their role in maintaining or losing metabolic flexibility.· Potential new molecular targets and therapeutic agents aimed at restoring metabolic flexibility across tissues and organ systems.