Chronic food restriction in mice and increased systemic ghrelin induce preference for running wheel activity

Abstract

Objectives: In eating disorders, particularly anorexia nervosa (AN), patients exhibit intense physical activity which is inappropriate regarding food restriction and chronic undernutrition, and exacerbates weight loss and energy deprivation. Rodent models of food restriction exhibit increased running wheel activity in the food anticipation period, also known as Food Anticipatory Activity (FAA). FAA probably has various physiological and/or neurobiological origins. Plasma concentrations of the orexigenic hormone ghrelin are, for example, increased during FAA. We hypothesize that the drive for physical activity in chronic food restriction is triggered by metabolic factors but also relies on motivational aspects that we aim to decipher in this study.

Methods: Young female C57Bl6/J mice were exposed to a paradigm based on a progressive 50% quantitative food restriction alone (FR) or associated with running wheel activity (Food Restriction Wheel: FRW) in their home-cage during 15 days. We measured preference for running wheel in a three-chamber apparatus in which animals could choose to explore either a known running wheel or a novel object. Testing took place either during resting or during FAA. We calculated the time spent in each compartment and the activity in running wheels. After progressive refeeding over 10 days, mice were tested again when refed. Plasma levels of both ghrelin isoforms were measured with selective immunoassays.

Results: When tested during FAA period, food restricted mice displayed increased preference for the running wheel compared to ad libitum fed controls. Both FR and FRW mice exhibited increased running time and distance in the wheel and running distance was correlated with ghrelin levels. Similar preference and behavior were found when testing took place during the resting period. Animals housed without an active wheel also exhibited active running. Progressive refeeding resulted in body weight restoration, a decrease in FAA and completely abolished preference for the running wheel. Refed animals displayed similar behavior as ad libitum fed controls.

Conclusions: These data provide evidence that food restriction-induced physical activity is closely correlated with metabolic adaptations to nutritional status implicating ghrelin in the quantity of physical activity.

Keywords: Animal models; Anorexia nervosa; Chronic food restriction; Metabolism; Physical activity; Preference.