ROLE OF LEAP2 IN REGULATING FEEDING, FOOD ANTICIPATORY ACTIVITY AND REWARD CIRCUITS IN AN ANOREXIA NERVOSA-LIKE MOUSE MODEL

Anorexia nervosa (AN) is a psychiatric disorder characterised by chronic restriction of food intake linked to reward circuits dysfunctions. Recent studies reconceptualised AN as a disorder with both psychiatric and metabolic aetiology. The metabolic hormone ghrelin, an orexigenic signal produced by the stomach, is elevated in undernourished AN patients. Our team demonstrated that the liver peptide Leap2, an endogenous ghrelin antagonist, was also elevated in patients with AN, especially in those who relapsed. We aimed to understand how Leap2 may antagonize ghrelin and contribute to feeding and reward circuits dysfunctions in AN.The effect of s.c. administration of a long-lasting Leap2 analogue was tested on homeostatic feeding, hedonic feeding and running-wheel activity in 8-week-old female mice fed ad libitum (AL) or in mice having access to a running wheel while undergoing 50% food restriction (FR) for three weeks, causing chronically increased ghrelin concentrations, as observed in AN.
In AL conditions, Leap2 did not affect homeostatic night-time feeding. Conversely, it significantly blunted hedonic feeding, reducing the consumption of high-fat high-sucrose (HFHS). In FR conditions, Leap2 treatment reduced running activity associated with the anticipation of food, a behavior typically observed in undernourished animals. The effect of Leap2 analogues on reward circuits activity associated with HFHS and wheel-running was also explored using fiber photometry monitoring of dopamine activity in the nucleus accumbens.
Overall our findings demonstrate a role of Leap2 in regulating hedonic/reward-oriented behaviours in female mice, even upon ghrelin levels elevation, such as observed in AN.