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      Regulation of Gastrointestinal Motility by Motilin and Ghrelin in Vertebrates

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          Abstract

          The energy balance of vertebrates is regulated by the difference in energy input and energy expenditure. Generally, most vertebrates obtain their energy from nutrients of foods through the gastrointestinal (GI) tract. Therefore, food intake and following food digestion, including motility of the GI tract, secretion and absorption, are crucial physiological events for energy homeostasis. GI motility changes depending on feeding, and GI motility is divided into fasting (interdigestive) and postprandial (digestive) contraction patterns. GI motility is controlled by contractility of smooth muscles of the GI tract, extrinsic and intrinsic neurons (motor and sensory) and some hormones. In mammals, ghrelin (GHRL) and motilin (MLN) stimulate appetite and GI motility and contribute to the regulation of energy homeostasis. GHRL and MLN are produced in the mucosal layer of the stomach and upper small intestine, respectively. GHRL is a multifunctional peptide and is involved in glucose metabolism, endocrine/exocrine functions and cardiovascular and reproductive functions, in addition to feeding and GI motility in mammals. On the other hand, the action of MLN is restricted and species such as rodentia, including mice and rats, lack MLN peptide and its receptor. From a phylogenetic point of view, GHRL and its receptor GHS-R1a have been identified in various vertebrates, and their structural features and various physiological functions have been revealed. On the other hand, MLN or MLN-like peptide (MLN-LP) and its receptors have been found only in some fish, birds and mammals. Here, we review the actions of GHRL and MLN with a focus on contractility of the GI tract of species from fish to mammals.

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          Most cited references141

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          A receptor in pituitary and hypothalamus that functions in growth hormone release.

          Small synthetic molecules termed growth hormone secretagogues (GHSs) act on the pituitary gland and the hypothalamus to stimulate and amplify pulsatile growth hormone (GH) release. A heterotrimeric GTP-binding protein (G protein)-coupled receptor (GPC-R) of the pituitary and arcuate ventro-medial and infundibular hypothalamus of swine and humans was cloned and was shown to be the target of the GHSs. On the basis of its pharmacological and molecular characterization, this GPC-R defines a neuroendocrine pathway for the control of pulsatile GH release and supports the notion that the GHSs mimic an undiscovered hormone.
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            The tissue distribution of the mRNA of ghrelin and subtypes of its receptor, GHS-R, in humans.

            Ghrelin is a novel growth hormone-releasing peptide, originally identified in the rat stomach as the endogenous ligand for the growth hormone secretagogue-receptor (GHS-R1a). Ghrelin is involved in the regulation of GH release, but it has recently been suggested that ghrelin may have other actions, including effects on appetite, carbohydrate metabolism, heart, kidney, pancreas, gonads, and cell proliferation. The distribution of ghrelin, its functional receptor (type 1a) and the unspliced, non-functional GHS-R type 1b mRNA expression was investigated in various human tissues using classical and real-time reverse transcription and polymerase chain reaction. GHS-R1a was predominantly expressed in the pituitary and at much lower levels in the thyroid gland, pancreas, spleen, myocardium and adrenal gland. In contrast, ghrelin was found in the stomach, other parts of the gut and, indeed, in all the tissues studied (adrenal gland, atrium, breast, buccal mucosa, esophagus, Fallopian tube, fat tissue, gall bladder, human lymphocytes, ileum, kidney, left colon, liver, lung, lymph node, muscle, muscle, myocardium, ovary, pancreas, pituitary, placenta, prostate, right colon, skin, spleen, testis, thyroid, and vein). GHS-R1b expression was also widespread in all tissues studied. The significance of the widespread tissue distribution of ghrelin remains to be determined. These data suggest that ghrelin might have widespread physiological effects via different, partly unidentified, subtypes of the GHS-R in endocrine and non-endocrine tissues.
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              Ghrelin is an appetite-stimulatory signal from stomach with structural resemblance to motilin.

              : 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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                Author and article information

                Contributors
                Journal
                Front Endocrinol (Lausanne)
                Front Endocrinol (Lausanne)
                Front. Endocrinol.
                Frontiers in Endocrinology
                Frontiers Media S.A.
                1664-2392
                17 May 2019
                2019
                : 10
                : 278
                Affiliations
                [1] 1Comparative Animal Pharmacology, Department of Veterinary Science, Rakuno Gakuen University , Ebetsu, Japan
                [2] 2Department of Biochemistry, National Cerebral and Cardiovascular Center Research Institute , Suita, Japan
                Author notes

                Edited by: María Jesús Delgado, Complutense University of Madrid, Spain

                Reviewed by: Kouhei Matsuda, University of Toyama, Japan; Hélène Volkoff, Memorial University of Newfoundland, Canada; Hiroyuki Kuwano, Gunma University, Japan

                *Correspondence: Takio Kitazawa tko-kita@ 123456rakuno.ac.jp

                This article was submitted to Neuroendocrine Science, a section of the journal Frontiers in Endocrinology

                Article
                10.3389/fendo.2019.00278
                6533539
                31156548
                911720d1-b634-4c6f-8e15-73856bc4e8d6
                Copyright © 2019 Kitazawa and Kaiya.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 16 January 2019
                : 16 April 2019
                Page count
                Figures: 3, Tables: 3, Equations: 0, References: 149, Pages: 17, Words: 14539
                Categories
                Endocrinology
                Review

                Endocrinology & Diabetes
                energy homeostasis,ghrelin,motilin,gastrointestinal motility,vertebrates,evolution

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