Effect of desacyl-ghrelin on food anticipatory activity in a mouse model of chronic food restriction

Abstract

Background The physiological mechanisms involved in the adaptation to chronic food restriction are largely unknown. Anorexia nervosa (AN) is characterized by elevated plasma concentrations of ghrelin, a gut orexigenic hormone. AN patients maintain a restricted feeding behavior, usually associated with elevated physical activity in meal anticipation called food anticipatory activity (FAA). Ghrelin exists in two forms: acylghrelin (AG), carrying an octanoyl group, and des-acylghrelin (DAG) which predominates in plasma and having an opposite action on energy homeostasis. The respective role of AG and DAG in the initiation of FAA remains unknown. Objectives We used a mouse model, which combined chronic food restriction and voluntary activity mimicking most of the alterations of AN1. We evaluated: – the change in plasma AG and/or DAG concentrations in relation with FAA; – determine whether injections of AG and/or DAG elicit FAA and interact on hypothalamic (ARC: energy homeostasis) and mesolimbic (VTA: reward/motivation) neurons. Methods Eight-week old female mice were placed in a cage containing a running wheel in free access for 20 days. Mice were exposed to a progressive food restriction (FRW, n = 24) compared to ad libitum fed condition (ALW, n = 24). On D10, blood samples were collected before the onset of FAA (9 a.m.) and during FAA (5 p.m). AG and DAG were measured with selective immunoassays. On D20, AG (10 nmol/10 g BW), DAG (10 nmol/10 g BW), AG + DAG (respectively 10 and 20 nmol/10 g BW), or saline solution were injected subcutaneously both in ALW and FRW mice (n = 6/group); followed by 2 h of the evaluation of physical activity. Immunocytochemical detection of c-Fos protein, a marker of neuronal activation, was obtained in the ARC and VTA. Data were analyzed with a One-Way ANOVA test (Statview software, P  Results FRW mice displayed a stable FAA from D6 of restriction. Plasma concentrations of AG and DAG significantly increased between 9 a.m and 5 p.m in FRW mice compared to ALW mice. AG and DAG concentrations were the highest in mice displaying the highest FAA. Interestingly, only the injection of DAG was able to elicit: – an increase in physical activity (P = 0.06) associated with significant neuronal activation in the VTA (P  – to decrease glycemia (P = 0.06) and low neuronal activation in the ARC contrary to AG (P  Conclusion These results suggest that DAG might have an unexpected function in the induction of physical activity in meal anticipation.