Neuroendocrine-immune perturbations in metabolic disease: pathophysiological mechanisms underlying cognitive...

The escalating global prevalence of obesity and associated metabolic disorders has catalyzed intensive investigation into their multisystemic ramifications. Recent scientific investigations elucidate the sophisticated bidirectional relationship between systemic metabolic aberrations and central nervous system (CNS) dysfunction, orchestrated via complex neuro-immune-endocrine signaling cascades. This integrative analysis consolidates extant literature regarding the mechanisms by which adiposity, metabolic-associated steatotic liver disease (MASLD), and systemic metabolic perturbations disrupt neuro-immune-endocrine communication networks, consequently precipitating neuroinflammatory processes, cognitive dysfunction, and enhanced vulnerability to neurodegenerative disorders. We examine the molecular and cellular mechanisms underlying this pathophysiological cascade, including adipokine dysregulation, systemic inflammatory mediator elevation, hypothalamic inflammation, microglial activation, blood-brain barrier disruption, and subsequent neuronal dysfunction. Furthermore, we analyze the modulatory roles of key endocrine axes-including the hypothalamus, the pituitary and the adrenal glands-, and growth hormone/insulin-like growth factor systems-in metabolic-neural crosstalk. By elucidating these complex pathways, we aim to highlight mechanistically informed therapeutic targets and combinatorial strategies that may attenuate neuroinflammatory processes and cognitive deterioration in metabolically compromised individuals.