High-fat diet-induced obesity enhances stress vulnerability and promotes a PTSD-like phenotype in rats

The association between post-traumatic stress disorder (PTSD) and subsequent obesity is well-established in humans, however, whether obesity exacerbates vulnerability to PTSD remains underexplored. To investigate this, we employed a rat model fed either a high-fat diet (HFD; 60 % kcal from fat) or a control diet (CD). After confirming significant body mass index differences between HFD and CD groups, rats were exposed to predator scent stress (PSS) or a sham-PSS control. Behavioral phenotyping was conducted using the elevated plus maze (EPM) and acoustic startle response (ASR) to classify stress response profiles, supplemented by the forced swim test to assess depressive-like behavior and the Morris water maze to evaluate spatial learning and memory. Neural cytoarchitecture and molecular mechanisms were examined via Golgi-Cox staining and immunohistochemistry, targeting shared modulators of the orexigenic and anxiolytic systems in the hippocampus and hypothalamus. Our findings reveal that HFD-induced obesity promotes a PTSD-like phenotype, exacerbates depressive-like behavior, and impairs spatial learning and memory acquisition. Morphological alterations in the hippocampus and amygdala of HFD-fed rats resembled those in PSS-exposed CD-fed rats, regardless of stress exposure, suggesting common neurostructural changes. Furthermore, HFD-induced obesity modulated region-specific expression of neuropeptide Y (NPY), NPY-Y1 receptor, and glucocorticoid receptor immunoreactivity in hippocampal and hypothalamic nuclei. These results underscore a bidirectional interplay between diet-induced obesity and stress-related disorders, highlighting the critical role of the orexigenic and anxiolytic systems and their neurobiological underpinnings in mediating these effects.