Chronic cortisol stimulation enhances hypothalamus-specific enrichment of metabolites in the rainbow trout brain

Abstract

The hypothalamus is a key integrating centre that is involved in the initiation of the corticosteroid stress response, and in regulating nutrient homeostasis. While cortisol, the principal glucocorticoid in humans and teleosts, plays a central role in the feeding regulation, the mechanisms are far from clear. We tested the hypothesis that the metabolic changes to cortisol exposure signal an energy excess in the hypothalamus, leading to feeding suppression during stress in fish. Rainbow trout ( Oncorhynchus mykiss) were administered a slow-release cortisol implant for three days, and the metabolite profiles in the plasma, hypothalamus, and the rest of the brain were assessed. Also, U-13C-glucose was injected into the hypothalamus by intracerebroventricular (ICV) route, and the metabolic fate of this energy substrate was followed in the brain regions by metabolomics. Chronic cortisol treatment reduced feed intake, and this corresponded with a downregulation of the orexigenic gene agrp, and an upregulation of the anorexigenic gene cart in the hypothalamus. The U-13C-glucose-mediated metabolite profiling indicated an enhancement of glycolytic flux and TCA intermediates in the rest of the brain compared to the hypothalamus. There was no effect of cortisol treatment on the phosphorylation status of AMPK or mTOR in the brain, while several endogenous metabolites, including leucine, citrate, and lactate were enriched in the hypothalamus, suggesting a tissue-specific metabolic shift in response to cortisol stimulation. Altogether, our results suggest that the hypothalamus-specific enrichment of leucine and the metabolic fate of this amino acid, including generation of lipid intermediates, contributes to cortisol-mediated feeding suppression in fish.