Metabolic flexibility (MetFlex) refers to the body's ability to switch between different energy substrates and adapt its metabolism to changing energy demands and nutrient availability. The concept of MetFlex is crucial for maintaining overall health and energy homeostasis. It is regulated by complex interactions between hormones, enzymes, and signalling pathways that control how the body processes and uses nutrients. Both adipose tissue (AT) and liver are regarded as central organs regulating metabolic circuits ensuring proper energetic balance. However, during prolonged metabolic stress resulting from nutrient overload, AT tends to lose its metabolic flexibility, triggering imbalanced fatty acids buffering and trapping machinery, and excessive release of reactive fatty acids, which collectively initiate a systemic maladaptive response to chronic overnutrition. Furthermore, persistent AT metaflammation and stress generate an altered profile of secreted cytokines and extracellular vesicles (EVs), that directly or indirectly contribute to lipid turnover disruption and metabolic inflexibility in the liver, and the development of insulin resistance and NAFLD.
The treatment of metabolic inflexibility typically involves a combination of lifestyle changes, dietary modifications, and, in some cases, medication. However, given the heterogeneity of its underlying causes, such strategies frequently fail to permanently reverse the metabolic gridlock stemming from profound molecular alterations, which represents an ultimate challenge for healthcare professionals.
This Research Topic aims to emphasise and discuss the latest findings describing the various tissular and cellular pathways arousing deleterious molecular changes in both AT and liver creating an unfavourable microenvironment that promotes the excessive production of reactive oxygen species and other derivatives, triggering structural and functional proteins alterations, severe cellular damage, and the development of clinical conditions associated to metabolic inflexibility including obesity, hyperlipidemia, insulin resistance, type 2 diabetes and cardiovascular diseases.
The scope of this Research Topic encompasses a series of original articles, short communications, reviews and meta-analysis aiming at bringing new insights in the understanding of the multiple molecular mechanisms underlying metabolic inflexibility in adipose tissue and liver by addressing the following but not limited to aspects:
● Adipose tissue and liver insulin resistance as a primary hallmark of metabolic inflexibility: describing the molecular events leading to the loss of insulin sensitivity during nutrient surplus in relation to impaired fuel switching and energy metabolism dysregulation.
● Impaired fatty acid oxidation in both AT and liver: exploring the exact mechanisms engendering the pathological reduced ability of cells to switch between utilising glucose and fatty acids for energy.
● Metabolome signature of metabolically inflexible AT and liver: identifying the significant changes in the various metabolites generated under metabolic stress for understanding the pathogenesis of tissues metabolic inflexibility and the discovery of potential biomarkers.
● Adipokines and hepatokines at the crossroad of tissular plasticity: investigating the impact of dysregulated adipokines and hepatokines on the AT and liver metabolic storm, as well as impaired systemic nutrients flux and disposal.
● Mitochondrial dysfunction as a core element in metabolic inflexibility: demonstrating how metabolism stability blunt as mitochondria lose their ability to properly switch between oxidative fuels to meet the cellular demands, and evidencing the role of reactive oxygen species in the pathogenesis of mitochondrion collapse.
● Dysregulated hormone signalling: analysing the changes in hormones like adiponectin, leptin and resistin in the loss of tissue plasticity, and correlating hyperandrogenism and associated polycystic ovary syndrome (PCOS) to a metabolic inflexibility component.
● New therapeutic leads for the management of metabolic inflexibility: screening for new biomolecules and/or molecular targets that may restore MetFlex of AT and liver.
Keywords:
MetFlex, Adipose Tissue, Liver, Insulin Resistance, Mitochondrial Dysfunction, Metabolome, Oxidative Stress, Lipid Turnover, ß-oxidation, Energy Homeostasis, Hepatokines
Important Note:
All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.
Metabolic flexibility (MetFlex) refers to the body's ability to switch between different energy substrates and adapt its metabolism to changing energy demands and nutrient availability. The concept of MetFlex is crucial for maintaining overall health and energy homeostasis. It is regulated by complex interactions between hormones, enzymes, and signalling pathways that control how the body processes and uses nutrients. Both adipose tissue (AT) and liver are regarded as central organs regulating metabolic circuits ensuring proper energetic balance. However, during prolonged metabolic stress resulting from nutrient overload, AT tends to lose its metabolic flexibility, triggering imbalanced fatty acids buffering and trapping machinery, and excessive release of reactive fatty acids, which collectively initiate a systemic maladaptive response to chronic overnutrition. Furthermore, persistent AT metaflammation and stress generate an altered profile of secreted cytokines and extracellular vesicles (EVs), that directly or indirectly contribute to lipid turnover disruption and metabolic inflexibility in the liver, and the development of insulin resistance and NAFLD.
The treatment of metabolic inflexibility typically involves a combination of lifestyle changes, dietary modifications, and, in some cases, medication. However, given the heterogeneity of its underlying causes, such strategies frequently fail to permanently reverse the metabolic gridlock stemming from profound molecular alterations, which represents an ultimate challenge for healthcare professionals.
This Research Topic aims to emphasise and discuss the latest findings describing the various tissular and cellular pathways arousing deleterious molecular changes in both AT and liver creating an unfavourable microenvironment that promotes the excessive production of reactive oxygen species and other derivatives, triggering structural and functional proteins alterations, severe cellular damage, and the development of clinical conditions associated to metabolic inflexibility including obesity, hyperlipidemia, insulin resistance, type 2 diabetes and cardiovascular diseases.
The scope of this Research Topic encompasses a series of original articles, short communications, reviews and meta-analysis aiming at bringing new insights in the understanding of the multiple molecular mechanisms underlying metabolic inflexibility in adipose tissue and liver by addressing the following but not limited to aspects:
● Adipose tissue and liver insulin resistance as a primary hallmark of metabolic inflexibility: describing the molecular events leading to the loss of insulin sensitivity during nutrient surplus in relation to impaired fuel switching and energy metabolism dysregulation.
● Impaired fatty acid oxidation in both AT and liver: exploring the exact mechanisms engendering the pathological reduced ability of cells to switch between utilising glucose and fatty acids for energy.
● Metabolome signature of metabolically inflexible AT and liver: identifying the significant changes in the various metabolites generated under metabolic stress for understanding the pathogenesis of tissues metabolic inflexibility and the discovery of potential biomarkers.
● Adipokines and hepatokines at the crossroad of tissular plasticity: investigating the impact of dysregulated adipokines and hepatokines on the AT and liver metabolic storm, as well as impaired systemic nutrients flux and disposal.
● Mitochondrial dysfunction as a core element in metabolic inflexibility: demonstrating how metabolism stability blunt as mitochondria lose their ability to properly switch between oxidative fuels to meet the cellular demands, and evidencing the role of reactive oxygen species in the pathogenesis of mitochondrion collapse.
● Dysregulated hormone signalling: analysing the changes in hormones like adiponectin, leptin and resistin in the loss of tissue plasticity, and correlating hyperandrogenism and associated polycystic ovary syndrome (PCOS) to a metabolic inflexibility component.
● New therapeutic leads for the management of metabolic inflexibility: screening for new biomolecules and/or molecular targets that may restore MetFlex of AT and liver.
Keywords:
MetFlex, Adipose Tissue, Liver, Insulin Resistance, Mitochondrial Dysfunction, Metabolome, Oxidative Stress, Lipid Turnover, ß-oxidation, Energy Homeostasis, Hepatokines
Important Note:
All contributions to this Research Topic must be within the scope of the section and journal to which they are submitted, as defined in their mission statements. Frontiers reserves the right to guide an out-of-scope manuscript to a more suitable section or journal at any stage of peer review.