Liver-expressed antimicrobial peptide 2 antagonizes the effect of ghrelin in rodents

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.

Liver Expressed Antimicrobial Peptide 2 is Associated with Steatosis in Mice and Humans

“…A series of experimental results demonstrate that it weakens the binding ability of ghrelin to GHSR1a and reduces ghrelin-induced Ca( 2 + ) release in vitro [7,8,10]. Then, the physiological procedure of the LEAP2-GHSR1a interaction has been revealed in vitro [9,28]. Islam et al [28] found circulating leap2 levels change according to feeding status in rodent, while ghrelin downregulated hepatic leap2 expression via AMPK pathway.…”

“…Then, the physiological procedure of the LEAP2-GHSR1a interaction has been revealed in vitro [9,28]. Islam et al [28] found circulating leap2 levels change according to feeding status in rodent, while ghrelin downregulated hepatic leap2 expression via AMPK pathway. Their results suggest a role of LEAP2 in the link between liver and stomach.…”

Ghrelin-Mediated Regeneration and Plasticity After Nervous System Injury

“…Hence, the endogenous inverse agonist of GHSR1a has drawn attention to development of anti-obesity pharmacological agents. Systemic LEAP2 administration in mice suppresses only ghrelin-stimulated food intake and growth hormone release ( Ge et al, 2018 ), while in rats intraventricularly injected LEAP2 completely abolishes the central ghrelin effects (activation of the hypothalamic neurons, promotion of food intake, increase of blood glucose level, and body temperature reduction) but does not inhibit the central effects of DAG ( Islam et al, 2020 ). However, it is still unclear whether LEAP2 can cross the blood-brain-barrier similarly to ghrelin in order to affect GHSR1a in the central nervous system ( Abizaid and Hougland, 2020 ).…”

Human liver‐expressed antimicrobial peptide 2 elevation in the cerebrospinal fluid in bacterial meningitis

“…A large number of studies have revealed that ghrelin also regulates the immune system by acting on immune cells and endothelial cells to suppress the production of pro‐inflammatory cytokines, suggesting its therapeutic viability in inflammatory conditions (Colldén et al., 2017; Yanagi et al., 2018). Leap2 was found to be highly expressed in the liver and intestine in rodents, and its expression was decreased in the liver of rats under fasting condition (Islam et al., 2020). LEAP2 was also demonstrated to act as an inverse agonist of GHSR1a by blocking its constitutive activity (M’Kadmi et al., 2019).…”

“…Although GHSR1a is widely expressed in the central nervous system (CNS) (Al‐Massadi et al., 2018), it is still unclear whether LEAP2 is involved in human neurological diseases. We demonstrated that the intracerebroventricular administration of LEAP2 to rats antagonized central ghrelin functions, including the promotion of food intake, elevation of blood glucose levels, and reduction of body temperature (Islam et al., 2020). Previous studies have not shown whether LEAP2 is present in human cerebrospinal fluid (CSF), and if so, whether its levels are altered in neurological disorders.…”