Early life stress alters hypothalamic–peripheral metabolic signaling linking psychiatric and metabolic vulnerability

Background

Early life stress (ELS), particularly prenatal stress (PNS), is a major risk factor for both psychiatric disorders and metabolic dysfunction, suggesting shared neurobiological mechanisms linking central nervous system function and peripheral metabolic regulation. Converging evidence indicates that stress exposure during critical developmental windows may induce long-lasting alterations in neuroendocrine and metabolic systems, yet the mechanisms mediating vulnerability across brain and peripheral tissues remain poorly understood. In particular, the hypothalamus plays a central role in integrating hormonal and metabolic signals, but how its interaction with peripheral organs contributes to stress-related phenotypes is still unclear.

Aims

In this context, we investigated whether prenatal stress induces long-term alterations in brain–periphery metabolic communication, focusing on glucose homeostasis and insulin signaling as potential convergent mechanisms underlying affective and metabolic vulnerability.

Methods

Using a validated prenatal restraint stress paradigm in rats (gestational day 14 until delivery), adult male offspring were assessed through a comprehensive phenotyping approach. Behavioral analyses focused on social interaction to identify stress-related phenotypes, enabling stratification into vulnerable and resilient subgroups. Metabolic assessments included longitudinal body weight monitoring, glucose tolerance test (GTT), and insulin tolerance test (ITT). Circulating metabolic hormones were quantified to evaluate systemic metabolic status. In parallel, molecular analyses were performed to assess gene expression changes in the hypothalamus and liver, targeting pathways involved in insulin signaling, glucose and lipid metabolism, and cellular energy regulation.

Results

PNS offspring exhibited increased body weight across development (postnatal days 55, 72 and 84), impaired glucose tolerance (p = 0.0327), and altered insulin responsiveness during ITT (p = 0.0334), consistent with systemic metabolic dysregulation. This phenotype was accompanied by significant alterations in circulating metabolic hormones, including increased levels of insulin (p = 0.035), amylin (p = 0.002), GLP-1 (p = 0.045), and C-peptide (p = 0.030), alongside elevated leptin (p = 0.003) and reduced adiponectin (p = 0.008), indicative of an insulin-resistant profile. At the central level, prenatal stress induced a significant upregulation of hypothalamic insulin signaling components, including INSR (p = 0.015), IRS (p = 0.043), and IGF1R (p = 0.028), with more pronounced effects in vulnerable animals. In addition, increased expression of adiponectin receptors AdipoR1(p=0.0014) and AdipoR2 (p=0.0061) was observed in the hypothalamus of vulnerable offspring, supporting a broader dysregulation of insulin- and adipokine-related signaling pathways. In parallel, liver gene expression analyses are investigating pathways related to glucose and lipid metabolism, while mitochondrial-related processes are being examined in both hypothalamus and liver to assess potential alterations in cellular energy homeostasis across hypothalamus and periphery.

Conclusions

These findings demonstrate that prenatal stress programs long-lasting dysregulation of brain–periphery metabolic signaling, characterized by altered hypothalamic insulin pathway activity and systemic metabolic impairment. These results further support the hypothesis that the hypothalamus acts as a critical integrative hub linking environmental stress exposure to coordinated metabolic and behavioral outcomes. Importantly, hypothalamic insulin signaling emerges as a potential mechanistic node underlying the comorbidity between psychiatric and metabolic disorders, highlighting its relevance as a target for future translational interventions.

References

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