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

Recent findings suggest an impact of the ghrelin/LEAP2 balance on the dynamics of reward sensitivity and a potential role of LEAP2 as a biomarker of remission in patients with anorexia nervosa. We hypothesized that the ghrelin/LEAP2 balance was involved in impulsive food choices after chronic food restriction and a period of 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 after discharge to evaluate their remission status. Cognitive impulsivity was also assessed in young C57Bl6/J female mice at baseline, after a 15-day 50% quantitative food restriction and following a 10-day refeeding. We collected blood for ghrelin and LEAP2 measurement and brain areas involved in metabolic response or reward and cognitive control. Ghrelin/LEAP2 ratio was negatively correlated with impulse control in patients after weight restoration, more specifically in patients maintaining 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 and negatively correlated with DRD1 gene expression in the prefrontal cortex in the refed state only. Our results provide evidence that the interplay between LEAP2 and cognitive impulsivity is sensitive to changes in the nutritional status in both patients and female mice. Metabolic and cognitive consequences of food restriction could be implicated in how food choices are being modified in patients and might be associated with better chances of stable remission in AN.