Sex-specific metabolic and inflammatory alterations in adult animals vulnerable to prenatal stress exposure

Early life stress (ELS) is a significant risk factor for the development of mood and metabolic disorders later in life, which are often in comorbidity. Although it is well known that not all the exposed individuals develop these conditions, the mechanisms leading to a vulnerable or a resilient phenotype for mood and metabolic disorders, as consequences of ELS exposure, are still not fully understood. In this study, we used a prenatal stress (PNS) model, mimicking perinatal adversities, to investigate the impact of ELS on metabolic function, stress-related and in- flammatory markers in adult male and female offspring, with a particular focus on vulnerable or resilient phe- notypes. PNS exposure was associated with a dysregulation of stress-related and metabolic markers both in the liver and also in the ventral hippocampus, with vulnerable males exhibiting increased insulin receptor levels and dysregulated expression of adipokine receptors (such as leptin and adiponectin). In contrast, female animals did not exhibit these changes. Additionally, PNS induced a pronounced neuroinflammatory response in the ventral hippocampus of vulnerable male rats, characterized by an upregulation of microglial activation markers. Interestingly, a similar pro-inflammatory status was observed in the liver of PNS-exposed males regardless of the pathologic phenotype; however, anti-inflammatory markers were upregulated only in resilient animals, sug- gesting an active mechanism of resilience. These findings suggest that specific metabolic and inflammatory changes underlie, with a sex-specific effect, the onset of a vulnerable phenotype to PNS and highlight the importance of targeting these pathways in the treatment of mood disorders and metabolic comorbidities.