Anorexia-Induced Hypoleptinemia Drives Adaptations in the JAK2/STAT3 Pathway in the Ventral and Dorsal Hippocampus of Female Rats

Abstract

Leptin is an appetite-regulating adipokine that is reduced in patients with anorexia nervosa (AN), a psychiatric disorder characterized by self-imposed starvation, and has been linked to hyperactivity, a hallmark of AN. However, it remains unknown how leptin receptor (LepR) and its JAK2-STAT3 downstream pathway in extrahypothalamic brain areas, such as the dorsal (dHip) and ventral (vHip) hippocampus, crucial for spatial memory and emotion regulation, may contribute to the maintenance of AN behaviors. Taking advantage of the activity-based anorexia (ABA) model (i.e., the combination of food restriction and physical activity), we observed reduced leptin plasma levels in adolescent female ABA rats at the acute phase of the disorder [post-natal day (PND) 42], while the levels increased over control levels following a 7-day recovery period (PND49). The analysis of the intracellular leptin pathway revealed that ABA rats showed an overall decrease of the LepR/JAK2/STAT3 signaling in dHip at both time points, while in vHip we observed a transition from hypo- (PND42) to hyperactivation (PND49) of the pathway. These changes might add knowledge on starvation-induced fluctuations in leptin levels and in hippocampal leptin signaling as initial drivers of the transition from adaptative mechanisms to starvation toward the maintenance of aberrant behaviors typical of AN patients, such as perpetuating restraint over eating.