Altered circadian pattern of activity in a chronic activity-based anorexia nervosa-like female mouse model deficient for GHSR

Abstract

Anorexia Nervosa (AN) is a psychiatric disorder characterized by voluntary food restriction, resulting in severe undernutrition that has been associated with circadian rhythms alterations. Yet, mechanisms that link circadian rhythm shifts to abnormal eating regulation in AN are poorly understood. Plasma ghrelin concentrations, an orexigenic hormone secreted by the stomach and acting through the GHSR (Growth Hormone Secretagogue Receptor), is elevated in restrictive-type AN. We aimed to test the hypothesis that GHSR signaling contributes to altered circadian pattern observed in AN. For this purpose, we first assessed whether chronotypes (morning, intermediate or evening) were different in patients with AN, bulimia nervosa and healthy controls. We next recorded the pattern of physical activity in young female GHSR deleted (Ghsr-/-) and wild-type (Ghsr+/+) mice housed in cages equipped with running wheels and exposed to quantitative food restriction, mimicking AN metabolic status. We demonstrated that chronotypes were different in the three groups of subjects, a difference mainly driven by an excess of morning chronotype in patients with AN. In mice, the shift toward higher daytime and pre-prandial physical activity and lower night-time and post-prandial physical activity, induced by food restriction, was impaired in Ghsr-/- mice, suggesting a lack of capacity to adapt patterns of circadian activity to chronic food restriction. These data suggest an interaction between altered circadian pattern and AN and indicate that GHSR signaling deficiency may play a critical role in adapting circadian patterns of activity to the undernutrition state in this disorder.