LEAP2 is associated with impulsivity and reward sensitivity depending on the nutritional status and decreases with protein intake in humans

Abstract Aim Liver‐expressed antimicrobial peptide 2 (LEAP2) dynamics in human plasma and its association with feeding behaviour remain poorly understood. Therefore, this study aims: (a) to investigate fasting LEAP2 in participants with normal weight or with overweight or mild obesity (OW/OB); (b) to study the association between fasting LEAP2 and anthropometric and metabolic traits, feeding behaviour, LEAP2 genetic variants and blood cell DNA methylation status; and (c) to ascertain postprandial changes in LEAP2 after high protein intake and the association with feeding behaviour and food intake. Methods Anthropometric and behavioural measures, genotyping, methylation profiling, plasma glucose and LEAP2 concentrations were assessed in 327 females and males. A subgroup of 123 participants received an ad libitum high‐protein meal, and postprandial LEAP2 concentration and behavioural measures were assessed. Results LEAP2 concentration was higher in participants with OW/OB ( p  < 0.001) and in females ( p  < 0.001), and was associated with LEAP2 single nucleotide polymorphisms rs765760 ( p  = 0.012) and rs803223 ( p  = 0.019), but not with LEAP2 methylation status. LEAP2 concentration was directly related to glycaemia ( p  = 0.001) and fullness ( p  = 0.003) in participants with normal weight, whereas it was associated with body mass index ( p  = 0.018), waist circumference ( p  = 0.014) and motor impulsivity in participants with OW/OB ( p  = 0.005). A negative association with reward responsiveness was observed in participants with OW/OB ( p  = 0.023). LEAP2 concentration was inversely associated with food intake ( p  = 0.034) and decreased after a high‐protein meal ( p  < 0.001), particularly in women ( p  = 0.002). Conclusion Increased LEAP2 in participants with OW/OB is associated with behavioural characteristics of obesity. Our results show sexual dimorphism in LEAP2 concentration before and after food intake and highlight the role of LEAP2 in feeding regulation.