COGNITION AT THE CORE: RECONCEPTUALIZING METABOLIC SYNDROME THROUGH NEURO-METABOLIC CASCADES

Metabolic Syndrome (MetS) is traditionally framed by peripheral metabolic abnormalities such as insulin resistance, dyslipidemia and obesity, though its impact on brain physiology and cognition requires further investigation. Reframing cognitive impairment as a core feature of MetS is supported by emerging evidence indicating that cognitive alterations may not only represent sequelae of metabolic dysfunction, but also early, mechanistically relevant features of MetS progression. To this aim, we employed a longitudinal high-fat diet (HFD) rat model over 20 weeks to characterize the temporal evolution of MetS, enabling the identification of neuro-metabolic markers that delineate impaired cognitive dimensions. Rats were subjected to behavioral testing assessing reactivity, anxiety-like behavior, and declarative memory, alongside longitudinal profiling of systemic metabolic and redox markers. Prolonged HFD exposure induced a progressive deterioration of anxiety-related behavior and memory performance that temporally paralleled metabolic impairment, within a progressively increasing MetS phenotype characterized by an early predominance of metabolic alterations followed by convergence with cognitive and affective dysfunctions. Multivariate analyses showed coordinated neurometabolic cascades with covariation of cognitive dysfunction with altered metabolic burden, oxidative stress, leptin signaling, and ketone body levels. Causal modeling also supports that the effects observed were mediated by systemic leptin signaling, supporting a mechanistic link between metabolic load, neuroendocrine dysregulation, and cognitive vulnerability. Collectively, these findings indicate that cognitive impairment is structurally embedded within the progression of MetS, contributing to the organization and expansion of the neuro-metabolic phenotype rather than arising as an epiphenomenon of metabolic dysfunction.