Central liver-expressed antimicrobial peptide 2 induces anxiety- and depression-related behaviors and activates the hypothalamic-pituitary-adrenal axis in male mice

The ghrelinergic system is a key regulator of feeding and metabolism. Beyond this, the ghrelinergic system has been implicated for reward, anxiety and depression. In this regard, the effects of the endogenous ghrelin receptor inverse agonist liver-expressed antimicrobial peptide (LEAP) 2 on mental health parameters are unknown. In the present study, the aim was to delineate LEAP2's central effects on anxiety- and depressive-like behaviors in mice, as well as downstream central monoaminergic signaling and HPA-axis activation. Acute intracerebroventricular administration was used to evaluate the effect of central LEAP2. The anxiogenic and depressive-like effects were measured through open-field test, elevated plus maze and forced swim test. Corticosterone and monoamine levels were measured in ex vivo blood and brain tissues, respectively. Acute central administration of LEAP2 increased anxiety-like behavior in both open-field test and elevated plus maze, and increased immobility time in forced swim test, compared to vehicle. Further, LEAP2 administration was associated with a marked increase in blood corticosterone, elevated dopamine in the bed nucleus of the stria terminalis and a trend to increased serotonin in the nucleus accumbens, ventral tegmental area and hypothalamus. These results highlight the influence of the ghrelinergic system on central signaling and mental health, in particular where LEAP2 is elevated or dysregulated, for example in obesity and anorexia nervosa which are often associated with anxiety and depression. Here, LEAP2 emerges as a potential target to treat depression and anxiety in eating disorders.