Gut hormone LEAP2 in human metabolism and eating behaviour
File(s)
Author(s)
Bhargava, Raghav
Type
Thesis
Abstract
Introduction: Obesity is a global epidemic with limited therapeutic options. Appetitive gut hormones such as acyl ghrelin (AG) drive weight regain after stopping weight-loss interventions. LEAP2, a novel liver-foregut satiety hormone, act as inverse agonist at growth hormone secretagogue receptor (GHSR) and is reciprocally regulated to AG. Plasma LEAP2 increases post-prandially, after weight gain and decreases after dietary/surgical weight-loss. LEAP2 antagonises orexigenic effects of AG involved in regulating appetite and metabolism. The role of LEAP2 in human eating behaviour and metabolic regulation remains incompletely understood.
Methods: Measurement of plasma LEAP2 from previous human studies examining the effects of: food intake and/or exogenous AG administration in adults without obesity; long-term caloric restriction without or with duodenal-jejunal bypass liner (DJBL) insertion in adults with obesity and T2DM. LEAP2 was correlated with markers of body weight, glucose/fat metabolism, appetite, food intake, food reward and food cue reactivity using fMRI. In pilot studies, safety and metabolic changes were examined during exogenous LEAP2 intravenous infusion in adults without obesity.
Results: Post-prandial increases in plasma LEAP2 correlated with decreases in appetite, high-energy food cue reactivity in brain reward regions and ad libitum food intake. Plasma LEAP2 was unaffected by AG administration; decreased after long-term dietary weight loss without or with DJBL insertion (delayed and attenuated in the latter) and correlated with improvements in weight and glucose/fat metabolism. LEAP2 infusions upto 25pmol/kg/min over 5.7h were safe and dose-dependently reduced plasma glucose and venous beta-hydroxybutyrate independent of serum insulin and GH.
Conclusions: These results support an anorexigenic role for post-prandial LEAP2 in human eating behaviour via GHSR antagonism; independent of AG; suggesting that decreases in plasma LEAP2 contribute to weight regain and acute infusions improve glucose/fat metabolism. This lays the foundation for future studies to examine the therapeutic effects of LEAP2 administration for obesity, weight maintenance, and addiction.
Methods: Measurement of plasma LEAP2 from previous human studies examining the effects of: food intake and/or exogenous AG administration in adults without obesity; long-term caloric restriction without or with duodenal-jejunal bypass liner (DJBL) insertion in adults with obesity and T2DM. LEAP2 was correlated with markers of body weight, glucose/fat metabolism, appetite, food intake, food reward and food cue reactivity using fMRI. In pilot studies, safety and metabolic changes were examined during exogenous LEAP2 intravenous infusion in adults without obesity.
Results: Post-prandial increases in plasma LEAP2 correlated with decreases in appetite, high-energy food cue reactivity in brain reward regions and ad libitum food intake. Plasma LEAP2 was unaffected by AG administration; decreased after long-term dietary weight loss without or with DJBL insertion (delayed and attenuated in the latter) and correlated with improvements in weight and glucose/fat metabolism. LEAP2 infusions upto 25pmol/kg/min over 5.7h were safe and dose-dependently reduced plasma glucose and venous beta-hydroxybutyrate independent of serum insulin and GH.
Conclusions: These results support an anorexigenic role for post-prandial LEAP2 in human eating behaviour via GHSR antagonism; independent of AG; suggesting that decreases in plasma LEAP2 contribute to weight regain and acute infusions improve glucose/fat metabolism. This lays the foundation for future studies to examine the therapeutic effects of LEAP2 administration for obesity, weight maintenance, and addiction.
Version
Open Access
Date Issued
2025-01-31
Date Awarded
2025-05-01
Copyright Statement
Attribution-NonCommercial 4.0 International Licence (CC BY-NC)
License URL
Advisor
Goldstone, Tony
Publisher Department
Department of Brain Sciences
Publisher Institution
Imperial College London
Qualification Level
Doctoral
Qualification Name
Doctor of Philosophy (PhD)