Metabolic Syndrome, Brain Dysfunction, and Cognitive Decline: Molecular Mechanisms and Nutritional Modulation

Metabolic Syndrome (MetS) represents a cluster of interrelated metabolic abnormalities—including central obesity, dyslipidemia, insulin resistance, and hypertension—that significantly increase the risk of type 2 diabetes, cardiovascular disease, and neurodegeneration. Over the past decade, converging evidence has reinforced a strong link between MetS and accelerated brain aging, where cognitive deficits, mood disturbances, and neurodegenerative processes coexist with systemic metabolic dysfunction. Regarding the mechanism, MetS drives profound effects on cerebral homeostasis through oxidative stress, chronic inflammation, mitochondrial impairment, brain insulin resistance, and disrupted neurotransmitter signaling. The joint action of these factors compromises synaptic plasticity, neuronal energy metabolism, and cerebral blood flow, establishing a pathophysiological link between peripheral metabolic stress and central cognitive decline.Recent translational studies highlight that metabolic dysregulation impairs neuroenergetic and insulin signalling pathways—particularly PI3K/Akt, MAPK, and mTOR—mirroring molecular hallmarks observed in Alzheimer’s disease and other dementias. Compounding these signaling disruptions, metabolic inflammation and mitochondrial injury converge at the neuronal level to compromise oxidative phosphorylation, amplify redox imbalance, and sustain chronic neuroinflammatory cascades, collectively undermining synaptic integrity, altering the brain electrical activity and accelerating neuronal loss. Beyond direct neuronal effects, the gut–brain axis has gained recognition as a central mediator in this relationship. Microbiota alterations, intestinal permeability, and loss of short-chain fatty acid (SCFA)-producing bacteria contribute to systemic and neuroinflammatory amplification, underscoring the gut´s role in cognitive and metabolic regulation. Collectively, these intersecting mechanisms provide a many-sided perspective on how peripheral metabolic impairment triggers central nervous system dysfunction and neurodegeneration.This Research Topic will be addressed as a link between Metabolic Syndrome and brain alterations leading to cognitive decline, highlighting the underlying molecular mechanisms. Key processes such as oxidative stress, chronic inflammation, mitochondrial dysfunction, alterations in energy metabolism, brain insulin resistance, amyloid deposition, tau phosphorylation, and neurotransmitter imbalances will be explored. It will also examine the role of the gut–brain axis and the influence of the microbiota and derived molecules/metabolites on neuronal function. A central focus will be to evaluate how dietary patterns, bioactive nutrients, and nutritional strategies can modulate these pathways. Finally, it aims to integrate basic and clinical evidence to propose nutritional interventions to prevent or mitigate cognitive decline associated with Metabolic Syndrome.To gather further insights into the molecular and nutritional connections between Metabolic Syndrome and brain function, we welcome contributions addressing, but not limited to, the following themes:o Oxidative stress, chronic inflammation, and mitochondrial dysfunction as molecular links between Metabolic Syndrome and cognitive decline.o Alterations in brain energy metabolism and insulin resistance contributing to neuronal injury and synaptic dysfunction.o Amyloid-β aggregation, tau phosphorylation, and neurodegenerative signaling pathways exacerbated by metabolic stress.o Dysregulation of dopaminergic, serotonergic, and cholinergic neurotransmission in the context of metabolic imbalance.o The gut–brain axis as a mediator of systemic inflammation, gut permeability, and microbiota-derived neuroactive metabolites.o Nutrition and energy-demanding processes in the braino Nutrition/brain excitability relationships and mechanismso Nutritional and dietary strategies—including Mediterranean, MIND, DASH, and ketogenic diets—modulating cognitive pathwayo Neuroprotective effects of dietary bioactive compounds and nutraceuticals (e.g., omega-3 PUFAs, polyphenols, curcumin, resveratrol, flavonoids, bioactive peptides, dietary fiber, B vitamins).o Integrative preclinical, clinical, and epidemiological studies exploring nutrition-based interventions to prevent or mitigate cognitive decline in Metabolic Syndrome. Topic editors: Maria Del Rosario Ferreira, Camila Calfío, Rubem C.A. Guedes Source: https://www.frontiersin.org/research-topics/84945/metabolic-syndrome-brain-dysfunction-and-cognitive-decline-molecular-mechanisms-and-nutritional-modulation