Cognition at the core of metabolic syndrome: linking metabolic load to behavioural impairment in a longitudinal high-fat diet rat model

Metabolic dysfunction severely affects brain physiology; however, the progression of cognitive and affective alterations and their causal relationship with systemic dysmetabolism driving metabolic syndrome (MetS) have to be fully elucidated. Here, we addressed this hypothesis by combining longitudinal experimental data with a causal statistical modelling framework to explore mechanistic dependencies between cognitive and metabolic processes. To this aim, we used a 20-week high-fat diet (HFD) rat model of MetS, integrating assessment of anxiety-like behaviour, reactivity, and declarative memory with profiling of systemic metabolic, neuroendocrine and redox markers, as candidate neurometabolic mediators. Prolonged HFD exposure induced, together with an early and progressive metabolic dysregulation, a deterioration of anxiety-like behaviour and memory performance with specific temporal dynamics across behavioural domains. Our findings indicate that cognitive impairment is embedded within the progression of MetS, contributing to the organization and expansion of the neuro-metabolic phenotype. Furthermore, our multivariate analyses showed coordinated neurometabolic cascades with covariation of cognitive dysfunction with altered metabolic burden, oxidative stress, leptin signalling, and ketone body regulation. Importantly, causal modelling identified distinct neurometabolic pathways underlying domain-specific vulnerability. In particular, systemic leptin signalling emerged as an integrative signal linking metabolic load and neuroendocrine dysregulation with affective dimension, whereas memory impairment was preferentially linked to redox imbalance. Collectively, this study allows reconceptualization of MetS identifying cognitive–metabolic signatures and their causal architecture that thus provide a translational framework to interpret vulnerability profiles characterized by maladaptive behavioural regulation, with potential implications for early stratification and targeted intervention strategies.