The induction phase of Activity-Based Anorexia (ABA) model is associated with the activation of IL-6 classical signaling

Anorexia nervosa (AN) is a psychiatric condition characterized by the reiteration of disturbed eating behavior and excessive exercise. The underlying molecular mechanisms are unclear, although preclinical and clinical evidence suggest the involvement of neuroinflammatory alterations. Employing Activity-Based Anorexia (ABA) model, we previously observed a downregulation of pro-inflammatory cytokine levels, possibly representing an adaptive response to ABA induction. Interestingly, only IL-6 showed an opposite trend and being aware of IL-6 dual role, our aim was to explore its downstream pathways to assess whether it acted as either pro- or anti-inflammatory. Adolescent Sprague-Dawley female rats were divided in four experimental groups and exposed for 6 days to (1) food restriction and wheel activity, (2) wheel activity, (3) food restriction, (4) normal maintenance procedure, respectively. Animals were then euthanized and the dorsal hippocampus dissected. Subsequent protein analyses through Western blot included microglial markers and IL-6 downstream targets. Following ABA induction, we observed an increase in IL-6 and TGF-b expression, paralleled by a tendency to increase of M2 marker ARG1 and a downregulation of M1 marker IBA1. Moreover, SOCS3 was decreased, while STAT3 activated form (pSTAT3) was upregulated. Our results show that IL-6 might participate in reducing inflammation by shifting microglial activation to the M2 phenotype via “classical signaling”, leading to STAT3 activation. Interestingly, TGF-b as well is involved in this downstream cascade modulation, as it seems to account for the reduction of SOCS3 through a complex post-transcriptional mechanism. A deeper understanding of IL-6 downstream pathways might allow us to find new interesting molecular targets involved in the initial phases of AN.