Brain-Derived Neurotrophic Factor as a Molecular Bridge Between Fasting, Neuroplasticity, and Metabolic Regulation: Clinical and Translational Insights

This narrative review integrates evidence from nutritional, metabolic, and neuroscientific research to examine whether brain-derived neurotrophic factor (BDNF) may represent a metabolically responsive molecular mediator linking fasting-induced metabolic adaptations with neuroplasticity and systemic metabolic regulation, and to discuss potential neurophysiological and clinical implications. Diet-related metabolic states are increasingly recognized as modulators of cognitive function and brain health. Fasting-based nutritional interventions may influence cognitive and metabolic disorders by promoting metabolic flexibility and engaging neuroplastic mechanisms. Among candidate mediators, BDNF has emerged as a key integrative signal at the intersection of metabolism, stress adaptation, and synaptic plasticity, with pleiotropic functions extending across central and peripheral systems; however, its regulation by fasting and interpretation as a biomarker in humans remains incompletely understood. Relevant experimental and clinical literature was synthesized to examine fasting-induced metabolic adaptations, BDNF regulation, and neuroplastic outcomes. Experimental evidence indicates fasting-related metabolic states engage cellular energy-sensing and stress-resistance pathways and are associated with enhanced neuroplasticity, partly mediated by BDNF-dependent mechanisms. In contrast, human findings remain limited and heterogeneous. Intermittent fasting interventions have been associated with inconsistent changes in circulating BDNF concentrations, influenced by baseline metabolic phenotype, inflammatory status, stress regulation, and methodological factors. Changes in circulating BDNF may reflect broader psychometabolic and inflammatory adaptations rather than direct induction of central neurotrophic signaling. Systems-level correlates of fasting-related metabolic adaptation and BDNF dynamics may be detectable using noninvasive neurophysiological approaches, such as electroencephalography, although direct causal links remain insufficiently established. Evidence positions BDNF as a context-dependent, metabolically responsive molecular bridge linking fasting-induced metabolic adaptations with neuroplastic potential, rather than a unidirectional marker of brain plasticity. Human data suggest fasting-related changes should be interpreted within broader metabolic and stress-related contexts. Well-controlled longitudinal studies integrating metabolic and neurobiological outcomes are needed to assess sustained brain health benefits.