Irisin/BDNF pathway dysfunction subserves anorexia nervosa pathophysiology.

Patients with Anorexia Nervosa (AN) often exhibit a heightened sense of reward associated with self-imposed starvation and excessive exercise in their pursuit of weight loss, which perpetuates maladaptive behaviors and negative health outcomes. A key feature of AN is compulsive physical activity, which exacerbates malnutrition and worsens clinical outcomes; however, the limited understanding of AN neurobiology has so far hindered the development of effective treatments. In this work, we hypothesized that AN may be sustained by an altered crosstalk between skeletal muscle and the brain induced by hyperactive behaviors via dysfunctional PGC-1α-FNDC5/Irisin-BDNF pathway. While exercise-derived Irisin promotes neuroprotection modulating BDNF expression in the brain of healthy individuals, its dysregulation may contribute to disease persistence. We herein showed that both women with AN and rats exposed to the activity-based anorexia (ABA) paradigm exhibit compulsive hyperactive behaviors, and that their predisposition to engage in exercise is prodromic to the disease progression. We also revealed that an increase in the myokine Irisin is rapidly triggered by exercise in rodents contributing to develop the AN phenotype and that, in humans, Irisin remains persistently elevated only in subjects who did not recover. Moreover, ABA rats showed hippocampal reduction in the BDNF-TrkB signaling that persisted even following body weight recovery, suggesting a long-lasting increased vulnerability. Altogether, our findings indicate that a dysfunctional PGC-1α-FNDC5/Irisin-BDNF pathway, driven by hyperactivity, plays a critical role in a stage-dependent manner in AN pathophysiology in both patients and ABA rats, highlighting its potential as a novel, druggable target to mitigate disease progression.