The dietary regulation of LEAP2 depends on meal composition in mice

Ghrelin represents a key hormone regulating energy balance. Upon activation of the growth hormone secretagogue receptor (GHSR), ghrelin increases blood glucose levels, food intake, and promotes weight gain. The liver‐expressed antimicrobial peptide 2 (LEAP2) acts as an endogenous antagonist of the GHSR. While the regulation of LEAP2 and its effect on the GHSR likely occur in an opposite pattern to that of ghrelin, the dietary regulation of LEAP2 remains to be described. We, therefore, examined the regulation of LEAP2 by different acute meal challenges (glucose, mixed meal, olive, lard, and fish oil) and diets (chow vs. high‐fat) in C57BL/6 male mice. In addition, the effect of specific fatty acids (oleic, docosahexaenoic, and linoleic acid) on LEAP2 was assessed in murine intestinal organoids. While only mixed meal increased liver Leap2 expression, all meal challenges except fish oil increased jejunal Leap2 expression compared to water. Leap2 expression correlated with levels of hepatic glycogen and jejunal lipids. Lipid versus water dosing increased LEAP2 levels in the systemic circulation and portal vein where fish oil was associated with the smallest increase. In line with this, oleic acid, but not docosahexaenoic acid increased Leap2 expression in intestinal organoids. Feeding mice with high‐fat versus chow diet not only increased plasma LEAP2 levels, but also the increment in plasma LEAP2 upon dosing with olive oil versus water. Taken together, these results show that LEAP2 is regulated by meal ingestion in both the small intestine and the liver according to the meal/diet of interest and local energy stores. Oral meal challenge with glucose, mixed meal, or lipid (olive, lard, and fish oil) upregulates LEAP2 in C57BL/6 mice by increasing Leap2 expression levels in the liver and jejunum, and by increasing LEAP2 protein levels in the jejunum and plasma. Olive oil increases Leap2 expression in mice fed chow or high‐fat diet (HFD) for 4 weeks. In addition to higher plasma LEAP2 levels, the increment in plasma LEAP2 upon olive oil dosing is higher in mice fed HFD versus chow.