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

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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.

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Most cited references 27

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LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity.

A. Krause, S Neitz, H Mägert … (2000)

We report the isolation and characterization of a novel human peptide with antimicrobial activity, termed LEAP-1 (liver-expressed antimicrobial peptide). Using a mass spectrometric assay detecting cysteine-rich peptides, a 25-residue peptide containing four disulfide bonds was identified in human blood ultrafiltrate. LEAP-1 expression was predominantly detected in the liver, and, to a much lower extent, in the heart. In radial diffusion assays, Gram-positive Bacillus megaterium, Bacillus subtilis, Micrococcus luteus, Staphylococcus carnosus, and Gram-negative Neisseria cinerea as well as the yeast Saccharomyces cerevisiae dose-dependently exhibited sensitivity upon treatment with synthetic LEAP-1. The discovery of LEAP-1 extends the known families of mammalian peptides with antimicrobial activity by its novel disulfide motif and distinct expression pattern.

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Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin.

A Asakawa, A. Inui, T Kaga … (2001)

: Ghrelin, an endogenous ligand for growth hormone secretagogue receptor, was recently identified in the rat stomach. We examined the effects of the gastric peptide ghrelin on energy balance in association with leptin and vagal nerve activity. : Food intake, oxygen consumption, gastric emptying, and hypothalamic neuropeptide Y (NPY) messenger RNA expression were measured after intra-third cerebroventricular or intraperitoneal injections of ghrelin in mice. The gastric vagal nerve activity was recorded after intravenous administration in rats. Gastric ghrelin gene expression was assessed by Northern blot analysis. Repeated coadministration of ghrelin and interleukin (IL)-1 beta was continued for 5 days. : Ghrelin exhibited gastroprokinetic activity with structural resemblance to motilin and potent orexigenic activity through action on the hypothalamic neuropeptide Y (NPY) and Y(1) receptor, which was lost after vagotomy. Ghrelin decreased gastric vagal afferent discharge in contrast to other anorexigenic peptides that increased the activity. Ghrelin gene expression in the stomach was increased by fasting and in ob/ob mice, and was decreased by administration of leptin and IL-1 beta. Peripherally administered ghrelin blocked IL-1 beta-induced anorexia and produced positive energy balance by promoting food intake and decreasing energy expenditure. : Ghrelin, which is negatively regulated by leptin and IL-1 beta, is secreted by the stomach and increases arcuate NPY expression, which in turn acts through Y(1) receptors to increase food intake and decrease energy expenditure. Gastric peptide ghrelin may thus function as part of the orexigenic pathway downstream from leptin and is a potential therapeutic target not only for obesity but also for anorexia and cachexia.

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Mice lacking ghrelin receptors resist the development of diet-induced obesity.

Bradford B. Lowell, Roberto Coppari, EL Jones … (2005)

Ghrelin is the endogenous ligand for the growth hormone secretagogue receptor (GHSR; ghrelin receptor). Since its discovery, accumulating evidence has suggested that ghrelin may play a role in signaling and reversing states of energy insufficiency. For example, ghrelin levels rise following food deprivation, and ghrelin administration stimulates feeding and increases body weight and adiposity. However, recent loss-of-function studies have raised questions regarding the physiological significance of ghrelin in regulating these processes. Here, we present results of a study using a novel GHSR-null mouse model, in which ghrelin administration fails to acutely stimulate food intake or activate arcuate nucleus neurons. We show that when fed a high-fat diet, both female and male GHSR-null mice eat less food, store less of their consumed calories, preferentially utilize fat as an energy substrate, and accumulate less body weight and adiposity than control mice. Similar effects on body weight and adiposity were also observed in female, but not male, GHSR-null mice fed standard chow. GHSR deletion also affected locomotor activity and levels of glycemia. These findings support the hypothesis that ghrelin-responsive pathways are an important component of coordinated body weight control. Moreover, our data suggest that ghrelin signaling is required for development of the full phenotype of diet-induced obesity.

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Author and article information

Journal

Journal ID (nlm-ta): J Endocrinol

Journal ID (iso-abbrev): J. Endocrinol

Journal ID (hwp): JOE

Title: The Journal of Endocrinology

Publisher: Bioscientifica Ltd (Bristol )

ISSN (Print): 0022-0795

ISSN (Electronic): 1479-6805

Publication date Collection: January 2020

Publication date (Electronic): 19 September 2019

Volume: 244

Issue: 1

Pages: 13-23

Affiliations

[1 ]Division of Neurology , Respirology, Endocrinology and Metabolism, Department of Internal Medicine, Faculty of Medicine, University of Miyazaki, Miyazaki, Japan

[2 ]Systems Life Sciences Laboratory , Department of Medical Life Systems, Faculty of Life and Medical Sciences, Doshisha University, Kyoto, Japan

[3 ]Department of Sports and Fitness , Faculty of Wellness, Shigakkan University, Aichi, Japan

[4 ]CREST (Japan) Agency for Medical Research and Development (A-MED) 1-7-1 Otemachi , Tokyo, Japan

Author notes

Correspondence should be addressed to M Nakazato: nakazato@ 123456med.miyazaki-u.ac.jp

^*(M N Islam and Y Mita contributed equally to this work)

Article

Publisher ID: JOE-19-0102

DOI: 10.1530/JOE-19-0102

PMC ID: 6839046

PubMed ID: 31539874

SO-VID: 294b472f-5a94-4292-b6af-5a7287832a58

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This work is licensed under a Creative Commons Attribution 4.0 International License.

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

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Most cited references 27

LEAP-1, a novel highly disulfide-bonded human peptide, exhibits antimicrobial activity.

Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin.

Mice lacking ghrelin receptors resist the development of diet-induced obesity.

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