Sex-dependent role of orexin deficiency in feeding behavior and affective state of mice following intermittent access to a Western diet - Implications for binge-like eating behavior.

Binge eating disorder is a debilitating disease characterized by recurrent episodes of excessive food consumption and associated with psychiatric comorbidities. Despite a growing body of research investigating the neurobiological underpinnings of eating disorders, specific treatments are lacking. Given its fundamental role in feeding behaviors, we investigated the role of the orexin (hypocretin) neuropeptide system in binge-like eating and associated phenotypes. Specifically, we submitted female and male orexin-deficient mice to a paradigm of intermittent access (once weekly for 24 h) to a Western diet (WD) to induce binge-like eating. Additionally, we measured their anxiety-like behavior and plasma corticosterone levels. All mice showed binge-like eating in response to the intermittent WD access, but females did so to a greater extent than males. While orexin deficiency did not affect binge-like eating in this paradigm, we found that female orexin-deficient mice generally weighed more, and they expressed increased hypophagia and stress levels compared to wild-type mice following binge-like eating episodes. These detrimental effects of orexin deficiency were marginal or absent in males. Moreover, male wild-type mice expressed post-binge anxiety, but orexin-deficient mice did not. In conclusion, these results extend our knowledge of orexin's role in dysregulated eating and associated negative affective states, and contribute to the growing body of evidence indicating a sexual dimorphism of the orexin system. Considering that many human disorders, and especially eating disorders, have a strong sex bias, our findings further emphasize the importance of testing both female and male subjects.