Background: The novel liver-gut hormone LEAP2 is a centrally acting inverse agonist, and competitive antagonist of orexigenic acyl ghrelin (AG), at the growth hormone secretagogue receptor, reducing food intake in rodents. In humans, the effects of LEAP2 on eating behaviour and mechanisms behind the post-prandial increase in LEAP2 are unclear, though this is reciprocal to the post-prandial decrease in plasma AG.

Methods: Plasma LEAP2 was measured in a secondary analysis of a previous study. Twenty-two adults without obesity attended after an overnight fast (Fasted-saline), consuming a 730kcal meal without (Fed-saline) or with (Fed-ghrelin) subcutaneous AG administration. Post-prandial changes in plasma LEAP2 were correlated with post-prandial changes in appetite, high-energy (HE) or low-energy (LE) food cue reactivity using functional MRI, ad libitum food intake, and plasma/serum AG, glucose, insulin and triglycerides.

Results: Post-prandial plasma LEAP2 increased by 24.5-52.2% at 70-150 min, but was unchanged by exogenous AG administration. Post-prandial increases in LEAP2 correlated positively with post-prandial decreases in appetite, and cue reactivity to HE/LE and HE food in anterior/posterior cingulate cortex, paracingulate cortex, frontal pole, middle frontal gyrus, with similar trend for food intake. Post-prandial increases in LEAP2 correlated negatively with body mass index, but did not correlate positively with increases in glucose, insulin or triglycerides, nor decreases in AG.

Conclusions: These correlational findings are consistent with a role for post-prandial increases in plasma LEAP2 in suppressing human eating behaviour in adults without obesity. Post-prandial increases in plasma LEAP2 are unrelated to changes in plasma AG and the mediator(s) remain uncertain.