Irisin-BDNF neurometabolic pathway disruption in the Activity-Based Anorexia model

Patients affected by Anorexia Nervosa (AN) experience a strong sense of reward from self-imposed starvation and excessive exercise in their pursuit of weight loss. Despite its high relapse and mortality rates, the neurobiological mechanisms underlying AN pathophysiology remain unclear making treatments challenging and symptomatic. In physiological conditions, physical exercise exerts protective functions on cognitive processes mainly by enhancing BDNF expression in the hippocampus via the peripheral activation of PGC-1α/FNDC5/Irisin pathway from skeletal muscles. Since in AN, physical exercise turns to be pathological, gaining compulsive features, our hypothesis is that AN might be driven, at least partially, by a dysfunctional muscle-to-brain crosstalk, which may drive weight loss seeking thus feeding AN maladaptive behaviour. To test this hypothesis, we took advantage of the activity-based anorexia (ABA) rat model: female rats were exposed to the combination of food restriction and wheel access during adolescence (from postnatal day (P) 38 to P42. Animals were sacrificed at P40, during phenotype induction, at P42, at the acute phase, and at P49, after a 7-day recovery period. We demonstrated that ABA rats exhibit compulsive, hyperactive behaviours. At molecular level, PGC-1α and FNDC5 protein levels in the soleus muscle and the myokine Irisin in the plasma were rapidly triggered in ABA rats. These effects were paralleled by an increase of immediate early genes expression in the hippocampus at P40 and P42, suggestive of a hippocampal hyperactivation. However, ABA rats show reduced expression of Irisin receptor subunits and of BDNF-TrkB signalling at P42, an effect that persisted till P49, suggesting a long-lasting reduced trophic support in the hippocampus of ABA rats. Altogether these data point to the hyperactivity-driven PGC-1α-FNDC5/Irisin-BDNF pathway dysfunctions as critically involved in AN disease pathophysiology in ABA rats and it may represent a signal of altered processing of food reward and of long-term vulnerability to relapse.