Glucocorticoid signalling dysregulation and immune cell adaptation in Anorexia Nervosa

AI Summary

At first evaluation, women with AN show hyperactivity, hypercortisolemia, reduced immune cell counts and paradoxically increased immune cell activation.
One year later, remission subjects exhibited further cortisol and cytokine increases with enhanced monocyte differentiation and recruitment.
ABA rat model replicated hypercorticosteronemia, innate immune skewing and persistent ventral hippocampal microglial and GR dysfunction; GR blockade reduced hyperactivity and reshaped microglia.

AI Summary

Here we show that women with AN, at the first medical evaluation, exhibit hyperactivity and hypercortisolemia, together with a reduced immune cell count yet paradoxically showing increased levels of cell activation.

Using the activity-based anorexia (ABA) rat model, we reproduced AN core features, including hypercorticosteronemia, and observed innate-skewed immune profiles, as well as persistent microglial and glucocorticoid receptor (GR) dysfunction in the ventral hippocampus.

Our results suggest that cortisol elevation and immune cell adaptation may perpetuate disease vulnerability beyond weight normalization, challenging the notion of weight regain as an indicator of remission.

Basic summary

Mol Psychiatry. 2026 Jul 20. doi: 10.1038/s41380-026-03756-4. Online ahead of print.

ABSTRACT

Anorexia Nervosa (AN) is a neuropsychiatric disorder marked by compulsive weight-loss and hyperactivity, with poorly understood underlying mechanisms and limited treatment outcomes. Here we show that women with AN, at the first medical evaluation, exhibit hyperactivity and hypercortisolemia, together with a reduced immune cell count yet paradoxically showing increased levels of cell activation. One year later, only subjects considered in remission showed greater increases in cortisol and cytokine levels, along with enhanced monocyte differentiation and recruitment. Using the activity-based anorexia (ABA) rat model, we reproduced AN core features, including hypercorticosteronemia, and observed innate-skewed immune profiles, as well as persistent microglial and glucocorticoid receptor (GR) dysfunction in the ventral hippocampus. Pharmacological blockade of GR with RU486 attenuated hyperactivity and reshaped microglial phenotype in the ventral hippocampus. Our results suggest that cortisol elevation and immune cell adaptation may perpetuate disease vulnerability beyond weight normalization, challenging the notion of weight regain as an indicator of remission.

PMID:42477442 | DOI:10.1038/s41380-026-03756-4

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