Abstract
Ghrelin, a stomach-derived peptide, promotes feeding and growth hormone (GH) secretion. A recent study identified liver-expressed antimicrobial peptide 2 (LEAP2) as an endogenous inhibitor of ghrelin-induced GH secretion, but the effect of LEAP2 in the brain remained unknown. In this study, we showed that intracerebroventricular (i.c.v.) administration of LEAP2 to rats suppressed central ghrelin functions including Fos expression in the hypothalamic nuclei, promotion of food intake, blood glucose elevation, and body temperature reduction. LEAP2 did not inhibit neuropeptide Y (NPY)-induced food intake or des-acyl ghrelin-induced reduction in body temperature, indicating that the inhibitory effects of LEAP2 were specific for GHSR. Plasma LEAP2 levels varied according to feeding status and seemed to be dependent on the hepatic Leap2 expression. Furthermore, ghrelin suppressed the expression of hepatic Leap2 via AMPK activation. Together, these results reveal that LEAP2 inhibits central ghrelin functions and crosstalk between liver and stomach.
Highlights
Ghrelin, a 28-amino acid acylated peptide originally isolated from rat and human stomach, is involved in the regulation of energy homeostasis and growth hormone (GH) secretion (Kojima et al 1999, Nakazato et al 2001)
Feeding behavior is regulated by stomach-derived ghrelin which transfers the hunger signal to the hypothalamic arcuate nucleus via the vagus nerve (Yanagi et al 2018), as well as by adipose tissue-derived protein leptin which acts on the arcuate nucleus to suppress food intake (Friedman & Halaas 1998)
Ghrelin administration to mice reduced the plasma concentration of Liver-expressed antimicrobial peptide 2 (LEAP2) and Leap2 mRNA in the liver. These findings suggest that the concentration of plasma LEAP2 depends on the hepatic Leap2 expression
Summary
A 28-amino acid acylated peptide originally isolated from rat and human stomach, is involved in the regulation of energy homeostasis and growth hormone (GH) secretion (Kojima et al 1999, Nakazato et al 2001). The activities of ghrelin are mediated through binding to the growth hormone secretagogue receptor (GHSR), a G-proteincoupled receptor (GPCR). GHSR is expressed at high levels in the hypothalamic arcuate nucleus (ARC), dorsomedial hypothalamus (DMH), ventromedial hypothalamic nucleus (VMH), and lateral hypothalamic nucleus (LH) (Mitchell et al 2001, Zigman et al 2006). Liver-expressed antimicrobial peptide 2 (LEAP2), a 40 amino acid peptide, was originally isolated by comprehensive chromatographic characterization of human hemofiltrate (Krause et al 2003).
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