Endocrine Abstracts

Liver-expressed antimicrobial peptide 2 (LEAP-2) has been recently characterized as an endogenous GHSR1a antagonist. LEAP-2 is produced mainly in the liver, and it was described that an acute ghrelin administration blocks food intake, GH release and normalize glucose levels during chronic caloric restriction. For this reason, it could be considered as a key endocrine factor in the regulation of systemic energy metabolism. Nevertheless, the exact mechanism of action is still unknown. Our aim was to investigate the central LEAP-2 effects in energy homeostasis in mice with standard diet and in a ghrelin resistance mice model induced by diet. We used male C57BL/6 mice fed standard or high fat diet (60% fat, 12 weeks). We performance an acute or chronic ICV administration of vehicle, ghrelin, LEAP-2 or ghrelin and LEAP-2. Food intake, body weight and circulating cholesterol and leptin plasma levels were measured. Human HEPG2 hepatocytes treated with oleic acid were used and they were co-treated with LEAP-2. Hepatic fat accumulation was analysed using oil red-O staining. Genes related to glucose and lipid metabolism were studied by qPCR. Statistical analysis conducted through t-student and ANOVA. The results obtained showed that LEAP-2 inhibits food intake, and body weight in all the mice models studied and in an acute and chronic treatment. Moreover, chronic treatment is able to decrease the orexigenic response of ghrelin when they are co-administered. Furthermore, LEAP-2 decreases leptin and cholesterol plasma levels, and decreases the liver lipid content. When we analysed human hepatocytes treated with LEAP-2, they exhibit a lower lipid accumulation with a reduction in the expression of genes of gluconeogenesis and de novo lipogenesis in standard conditions and under oleic acid effect. As a conclusion, chronic central administration of LEAP-2 in mice antagonizes the major effects of ghrelin in vivo and the co-administration with ghrelin attenuates the ghrelin orexigenic and obesogenic effects, in a diet independent manner. Moreover, it decreases fat accumulation directly in human hepatic cells. These novel results place LEAP-2 as a counter-regulatory hormone in the ghrelin system, and as a promising therapeutic target in the treatment of obesity, MAFLD and other metabolic diseases.