Irisin/BDNF pathway dysfunction subserves anorexia nervosa pathophysiology.

Area of Science:

• Neurobiology
• Endocrinology
• Behavioral Science

Background:

• Anorexia nervosa (AN) is characterized by compulsive physical activity and altered reward sensitivity, contributing to malnutrition and poor outcomes.
• The neurobiological underpinnings of AN, particularly the role of skeletal muscle-brain communication, remain poorly understood, hindering effective treatment development.

Purpose of the Study:

• To investigate the role of the PGC-1α-FNDC5/Irisin-BDNF pathway in the pathophysiology of anorexia nervosa.
• To explore the link between compulsive hyperactivity, Irisin levels, and brain-derived neurotrophic factor (BDNF) signaling in AN.

Main Methods:

• Comparative analysis of Irisin and BDNF signaling in human patients with AN and in a rat model of activity-based anorexia (ABA).
• Assessment of behavioral phenotypes, including compulsive exercise, and physiological markers in both models.

Main Results:

• Both humans with AN and ABA rats exhibit compulsive hyperactivity, with exercise triggering increased Irisin levels.
• Persistently elevated Irisin was observed in non-recovered human AN patients.
• ABA rats showed lasting reductions in hippocampal BDNF-TrkB signaling, indicating persistent neurobiological changes.

Conclusions:

• A dysfunctional PGC-1α-FNDC5/Irisin-BDNF pathway, driven by hyperactivity, plays a crucial role in AN pathophysiology.
• This pathway is implicated in both the development and persistence of AN, suggesting it as a potential therapeutic target.