Long-lasting Glucocorticoid and Immune Dysregulation sustain Anorexia Nervosa Beyond Weight Recovery

Anorexia Nervosa (AN) is a life-threatening psychiatric disorder primarily affecting girls during adolescence. Individuals with AN experience an intense fear of gaining weight and engage in severe dieting and excessive exercise to lose weight. Despite clear symptoms, what triggers and fuels the disorder remains unknown. Here we demonstrate that women with AN exhibit a compulsive drive toward physical activity despite severe emaciation and are characterized by elevated cortisol, along with reduced, yet activated, immune cells. Of note, after one year follow-up, only individuals who had regained weight, thus clinically considered in remission, showed even higher cortisol and cytokine levels, along with enhanced monocyte differentiation and recruitment, compared to those who had not recovered. Consistently, using the activity-based anorexia (ABA) model of AN, we reproduced AN hallmarks in adolescent female rats, and observed elevated circulating corticosterone levels and altered peripheral immune cell composition skewed toward innate immunity. Moreover, ABA rats showed a microglial pro-phagocyting phenotype, and a dysfunctional genomic activity of the glucocorticoid receptor (GR) which persists despite weight recovery in the ventral hippocampus, a pivotal GR-sensitive hub involved in emotional processing in vulnerable phenotypes. Interestingly, RU486, a non-selective GR antagonist, reduced compulsive hyperactivity in ABA rats, CD3⁺ cell production in the bone marrow, and reshaped microglial phenotype. These findings highlight a periphery-to-brain miscommunication between the glucocorticoid and immune systems in AN, which may contribute to disease maintenance and represent a critical risk factor for relapse, thereby challenging the prevailing reliance on body weight restoration as the primary criterion for remission.