Regional heterogeneity of brain insulin resistance: From molecular pathways to neural circuits

Brain insulin resistance (BIR) has emerged as a critical link between metabolic dysfunction and cognitive and behavioral impairment. As the twin epidemics of metabolic and brain disorders accelerate globally, understanding the precise mechanisms of BIR has become a clinical and scientific priority. However, growing evidence indicates that BIR does not manifest uniformly across the central nervous system. Instead, insulin signaling dysfunction exhibit marked regional and circuit-specific heterogeneity across the hippocampus, prefrontal cortex, hypothalamus, amygdala, and mesolimbic reward pathways.In this review, we synthesize molecular, cellular, and neuroimaging evidence to propose a circuit-resolved framework of BIR. While core mechanisms-including impaired IRS-PI3K-Akt signaling, neuroinflammation, oxidative stress, and lipotoxicity-are shared, their functional expression is shaped by region-specific receptor distribution, metabolic demand, and network connectivity. These spatially distinct vulnerabilities translate into dissociable phenotypes, including cognitive decline, emotional dysregulation, hedonic overeating, and impaired metabolic homeostasis.Importantly, BIR extends beyond local signaling failure to disrupt large-scale functional connectivity within default mode, fronto-limbic, and hypothalamic-striatal networks. We argue that conceptualizing BIR as a circuit- and network-level disorder provides a unifying explanation for the co-occurrence of metabolic and neuropsychiatric conditions. Finally, we discuss translational implications, highlighting imaging-guided stratification, liquid biomarkers of central insulin signaling, and circuit-targeted therapeutic strategies. A network-informed approach may enable early intervention before irreversible neurodegenerative and metabolic remodeling occurs.