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Liver-expressed antimicrobial peptide-2 (LEAP2) is an endogenous ghrelin receptor antagonist, which is upregulated in the fed state and downregulated during fasting. We hypothesized that the ketone body, beta-hydroxybutyrate (BHB), is involved in the downregulation of LEAP2 during conditions with high circulating levels of BHB. Methods Hepatic and intestinal Leap2 expression were determined in three groups of mice with increasing circulating levels of BHB: prolonged fasting, prolonged ketogenic diet and oral BHB treatment. LEAP2 levels were measured in lean and obese individuals, in human subjects following endurance exercise and in mice after BHB treatment. Lastly, we investigated Leap2 expression in isolated murine hepatocytes challenged with BHB. Results We confirmed increased circulating LEAP2 levels in individuals with obesity compared to lean individuals. The recovery period after endurance exercise was associated increased plasma levels of BHB levels and decreased LEAP2 in humans. Leap2 expression was selectively decreased in the liver after fasting and after exposure to a ketogenic diet for three weeks. Importantly, we found that oral administration of BHB increased circulating levels of BHB in mice and decreased expression of Leap2 and systemic LEAP2 plasma levels, as did Leap2 expression after direct exposure to BHB in isolated murine hepatocytes. Conclusion From our data, we suggest that LEAP2 is downregulated during different states of energy deprivation in both humans and rodents. Furthermore, we here provide evidence that the highly upregulated ketone body during fasting metabolism, BHB, directly downregulates LEAP2 levels. This may be relevant in ghrelin receptor-induced hunger signaling during energy deprivation.

Beta-Hydroxybutyrate Suppresses Hepatic Production of the Ghrelin Receptor Antagonist LEAP2