The role of LEAP2 on cognitive impulsivity after refeeding: evidence from a preclinical study in female mice and from patients with anorexia nervosa

Recents findings suggest that the ghrelin/LEAP2 (Liver Expressed Antimicrobial Peptide 2) ratio impacts the dynamics of reward sensitivity, and that LEAP2 may serve as a biomarker of remission in patients with anorexia nervosa (AN). We hypothesized that the ghrelin/LEAP2 ratio influences impulsive food choices following chronic food restriction and refeeding. Impulse control and plasma ghrelin and LEAP2 concentrations were evaluated in a longitudinal study of 30 female patients with AN after weight restoration and 6-months following discharge to evaluate their weight gain status. Cognitive impulsivity was also assessed in young C57Bl6/J female mice at baseline, after 15 days of 50% quantitative food restriction and after 10 days of refeeding. We collected blood for ghrelin and LEAP2 measurement and brain structures involved in metabolic response, reward and cognitive control. The ghrelin/LEAP2 ratio was negatively correlated with impulse control in patients after weight restoration, but only in those who maintained stable weight gain after discharge. In mice, food restriction increased cognitive impulsivity and refeeding only partially restored this phenotype compared to control conditions. Cognitive impulsivity was also positively correlated with plasma LEAP2 levels but not with the expression of the key hypothalamic neuropeptides or mesocorticolimbic dopamine DRD1/DRD2 receptors. Our results suggest that the interaction between LEAP2 and cognitive impulsivity is affected by changes in nutritional status in patients and female mice. Metabolic and cognitive consequences of food restriction may influence how food choices are modified in patients with AN and may be associated with a greater likelihood of achieving stable weight gain. Schematic representation of the current findings and hypothesis regarding the role of the ghrelin/LEAP2 ratio on the modulation of cognitive impulsivity following refeeding and its effects on weight gain stability in AN.