Modulation of glucocorticoid signalling by a ketogenic diet in a prenatal stress model

Background

Exposure to early-life stress is a well-established risk factor for psychiatric disorders, including depression, and is associated with persistent behavioural and neurobiological alterations affecting social behaviour and emotional regulation. Early adverse experiences can lead to long-term dysregulation of stress-response systems, particularly the hypothalamic–pituitary–adrenal (HPA) axis, which plays a central role in maintaining homeostasis under stress. Given the limited efficacy and variability of current pharmacological treatments, alternative strategies such as dietary interventions are being explored. The ketogenic diet (KD), a high-fat, low-carbohydrate and moderate protein regimen that promotes ketone metabolism and shifts energy utilization from glucose to ketone bodies, has gained attention for its potential effects on neuroendocrine regulation, mitochondrial function, and inflammation. Evidence suggests that KD may modulate HPA axis activity and glucocorticoid signalling, potentially influencing stress responsiveness. On these bases, we investigated the effects of prenatal stress (PNS) on HPA axis, related function and evaluated whether post weaning ketogenic diet exposure modulates glucocorticoid signalling in a sex-dependent manner.

Methods

Pregnant Sprague Dawley rats were exposed to repeated restraint stress during the last gestational week to induce PNS. Offspring were weaned at postnatal day 21 (P21) and assigned to either a standard control diet (CD) or KD for four weeks. Behavioural assessments, including the social interaction and splash tests, were conducted during adolescence (P42–P45) to evaluate social behaviour and motivational states. Animals were then euthanized, and hypothalamus, pituitary and liver were collected for molecular analyses focusing on stress-related pathways. Data were analysed using two-way ANOVA followed by Tukey’s post hoc test.

Results

Prenatal stress induced persistent, sex-dependent changes in genes involved in HPA axis regulation across central and peripheral tissues. In the hypothalamus, PNS affected glucocorticoid-related pathways, including FKBP5, NR3C1, NR3C2, and SGK1, with more pronounced effects observed in males. KD partially modulated these alterations, particularly in males, influencing SGK1, NR3C1, and NR3C2 expression. In females, PNS mainly reduced FKBP5 and NR3C1 expression, while KD induced more selective effects on stress-related genes.

In the liver, KD consistently increased SGK1 expression in both sexes, an effect largely independent of PNS exposure. NR3C1 and NR3C2 were not significantly affected by either condition, whereas FKBP5 showed sex-dependent regulation following PNS, with KD exerting a stabilizing effect, particularly in males. These findings suggest tissue-specific and sex-specific responses to both stress and dietary intervention.

Conclusions

These findings indicate that PNS exposure induces long lasting, sex-dependent alterations in HPA axis-related signalling across central and peripheral tissues. KD appears to partially modulate these stress-associated molecular changes, with more pronounced effects in males. Overall, the data suggest that metabolic interventions may influence stress-related neurobiological adaptations and identify the HPA axis as a potential target for dietary modulation following early-life stress exposure, supporting the relevance of nutrition based strategies in neuropsychiatric research.

References

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