Not only gut feelings: pancreatic hormone, amylin, controls emotionality and sociability, in a sex divergent manner.

Amylin, a pancreatic peptide hormone, has gained attention for its role in appetite regulation. Its analogues are approved for use in diabetic patients, and it is now under investigation as a potential anti-obesity therapeutic. However, despite its clinical use, its effects on emotionality remain poorly understood. Given that many other food intake-modulating substances influence psychiatric functions, here we determined the role of systemic amylin in modulating key aspects of emotionality and sociability in male and female rats. We further evaluated whether the central amygdala (CeA) is sufficient for mediating amylin's actions on emotionality and sociability. Male and female rats received either systemic or intra-CeA amylin. Anxiety-like behavior was evaluated in the elevated plus maze and the acoustic startle response. Systemic and CeA amylin administration induced sex-specific effects on anxiety-like behavior, with both administration routes consistently eliciting anxiolytic responses in males and anxiogenic responses in females. Intra-CeA amylin increased depression-like behavior, evaluated by the forced swim test, in female rats only. Aggressive behavior, investigated by resident-intruder test, was consistently reduced in both sexes, while only systemic, but not intra-CeA, amylin increased social interaction in the sociability test. These findings suggest that amylin modulates emotional and social behaviors in a sex-dependent manner, with the CeA as a sufficient neural substrate to drive these effects of amylin. Considering previous anti-obesity therapeutics have been withdrawn from the market because of emotionality side effects, our results highlight the importance of understanding these effects in both sexes separately for the development of safe amylin-based obesity treatments that minimize psychiatric risks.