Molecular basis of insulin resistance and its impact on the brain: the role of physical exercise

Insulin resistance (IR) is a pathological condition in which peripheral tissues and the brain fail to respond effectively to circulating insulin, contributing to metabolic disorders and cognitive decline. Adipose distribution, and hormonal regulation modulate IR, resulting in distinct molecular and metabolic profiles between men and women. Physical exercise is a potent intervention for improving insulin sensitivity, impacting both peripheral and central mechanisms. At the molecular level, exercise enhances insulin signaling, glucose uptake, and mitochondrial function in skeletal muscle, liver, and adipose tissue. In the brain, exercise-induced factors such as PGC-1α and irisin mediate neuroplasticity, neuroprotection, and energy metabolism, contributing to improved cognitive function and reduced risk of neurodegenerative disease. Physical exercise modulates lipid intermediates, inflammatory markers, and transcriptional networks that contribute to IR, highlighting its systemic and tissue-specific effects. Understanding these mechanisms is essential for the development of precision exercise prescriptions tailored to individual metabolic and neurological profiles. This review synthesizes current evidence on the molecular mechanisms underlying peripheral and brain IR and examines how aerobic, resistance, and high-intensity interval training influence these pathways. By integrating molecular, physiological, and behavioral perspectives, this work underscores the critical role of physical exercise in mitigating IR and promoting metabolic and cognitive health.