Journal of Medical Sciences (2010); 3(2): 92-95 Review Article Open Access Discovery of Ghrelin and Its Physiological Function stimulating activities (Fig. 1)1,2. The name "ghrelin" is based on "ghre", a word root in Masayasu Kojima Proto-Indo-European languages for "grow", in Molecular Genetics, Institute of Life Science, reference to its ability to stimulate GH release. Kurume University, Kurume, Fukuoka, Japan The rat and human ghrelin precursors are both composed of 117 amino acids. In these pre- cursors, the 28-amino-acid active ghrelin sequence immediately follows the signal peptide. Ghrelin is a peptide hormone, in which the serine 3 (Ser3) is n-octanoylated and Abstract this modification is essential for ghrelin's The endogenous ligand for growth-hormone secreta- activity. An enzyme that catalyzes the acyl- gogue receptor (GHS-R) was discovered in 1999 from modification of ghrelin has not yet been stomach and named it "ghrelin," after a word root ("ghre") identified. However, the universal incorpora- in Proto-Indo-European languages meaning "grow", since tion of n-octanoic acid in mammals, fish, birds, ghrelin stimulates growth hormone (GH) release from and amphibians suggests that this putative pituitary. In addition, ghrelin stimulates appetite and enzyme is rather specific in its choice of increases food intake by acting on the hypothalamic medium-chain fatty acid substrates3. arcuate nucleus, a region known to control food intake. Thus, ghrelin plays important roles for maintaining growth In all vertebrate species, ghrelin is mainly pro- hormone release and energy homeostasis in vertebrates. duced in the stomach. Ghrelin-containing cells The diverse functions of ghrelin raise the possibility of its in the stomach are more abundant in the 4 clinical application for GH deficiency, eating disorder, fundus than in the pylorus . The X/A-like cells in gastrointestinal disease, cardiovascular disease, osteo- the oxyntic mucosa contain round, compact, porosis and aging, etc. electron-dense granules that are filled with ghrelin. Ghrelin producing cells are also found in the duodenum, jejunum, ileum, colon, Keywords: Ghrelin, acyl-modification, stomach, growth hormone releasing pancreas, kidney and placenta 5. Moreover, activity, appetite stimulation. ghrelin content of the brain was found to be very low; ghrelin has been found in the hypothalamic arcuate nucleus, an important 1. Introduction of Ghrelin region for controlling appetite. In addition, a Ghrelin, purified from stomach, exerts potent recent study has reported the presence of growth hormone releasing and appetite ghrelin in previously uncharacterized hypotha- lamic neurons adjacent to the third ventricle between the dorsal, ventral, paraventricular, and arcuate hypothalamic nuclei. These ghrelin-containing neurons send efferent fibers Correspondence MASAYASU KOJIMA to neurons that contain neuro-peptide Y (NPY) Molecular Genetics and Agouti-related protein (AgRP) and may Institute of Life Science stimulate the release of these orexigenic Kurume University, Kurume peptides. Fukuoka, Japan RT-PCR analyses demonstrated ghrelin recep- E-mail: [email protected] tor mRNA expression in many peripheral 92 DISCOVERY OF GHRELIN AND ITS PHYSIOLOGICAL FUNCTION Journal of Medical Sciences (2010); 3(2) Fig. (1). Structure and summary of ghrelin. organs, including heart, lung, liver, kidney, Ghrelin stimulates GH release from cultured pancreas, stomach, small and large intestines, primary pituitary cells, which indicates that adipose tissue and immune cells, indicating ghrelin can act directly on the pituitary. How- that ghrelin has multiple functions in these ever, the involvement of the hypothalamus in tissues. In fact, ghrelin shows not only GH ghrelin-mediated stimulation of GH release has release and appetite stimulation but also been strongly suggested. Patients with organic cardiovascular effects, increase of gastric lesions in the hypothalamic region showed movement and secretion of gastric acid, insufficiency of GH release even when stimu- suppression of symphathetic nerve and lated by ghrelin. Moreover, when using primary regulation of glucose metabolism. pituitary cells, the ghrelin treatment only increased GH release by 2-3 times above the 2. Physiological Functions of Ghrelin basal level, which is lower than the level of 2.1. Growth Hormone Releasing Activity induction seen when ghrelin is administered to Ghrelin acts on the ghrelin receptor (GHS-R), rats in vivo. These facts suggest that other increasing intracellular Ca2+ concentration via factors are involved in vivo in order for the IP3 to stimulate GH release from pituitary. maximal level of GH release to be achieved Ghrelin stimulates growth-hormone release by ghrelin administration. One possibility is both in vitro and in vivo in a dose-dependent transmission via the vagus nerve. When the manner 1. Intravenous injection of ghrelin vagus nerve is cut, GH release after ghrelin induces potent GH release both in mamma- injection is dramatically decreased, indicating lian and non-mammalian vertebrates. In term that the vagus nerve is needed for the of both the area under the curve and mean maximal stimulatory effects of of ghrelin. peak GH levels, the GH-releasing activity of Another possibility is the lack of GHRH in ghrelin is similar to that of GHRH when injected primary pituitary cells. Co-administration of intravenously into rats. However, the maximal ghrelin and GHRH had a synergistic effect on stimulation effected by ghrelin is 2 to 3 times GH secretion; that is, co-administration results greater than that of GHRH. 93 Journal of Medical Sciences (2010); 3(2) MASAYASU KOJIMA in more GH release than does either GHRH or Intravenous injection of ghrelin also stimulates ghrelin alone. Synergistic effect on GH release NPY/AgRP neurons in the hypothalamus. was also observed by co-administration of Studies with knockout mice of NPY, AgRP or GHSs, synthetic ghrelin agonists, and GHRH. both confirms these results. Although deletion This finding implies that GHRH is necessary for of either NPY or AgRP caused a modest or no GH release to be maximally effective in effect on the orexigenic action of ghrelin, the inducing GH release by ghrelin. double knockout mice lacked the action of 2.2. Appetite Regulation ghrelin completely. Recent identification of appetite-regulating Peripherally injected ghrelin activates hypo- humoral factors reveal regulatory mechanisms thalamic neurons and stimulates food intake. not only in the central nervous system, but also In general, peptides injected peripherally do in the peripheral system mediated by factors not pass the blood-brain barrier. Indeed, the secreted from peripheral tissues. Leptin, rate at which peripheral ghrelin passes the produced in adipose tissues, is an appetite- barrier has shown to be very low. Thus, peri- suppressing factor that transmits satiety signals pheral ghrelin must activate the appropriate to the brain. Hunger signals from peripheral hypothalamic regions via an indirect pathway. tissues, however, had remained unidentified The detection of ghrelin receptor mRNA on until the recent discovery of ghrelin. Ghrelin is vagal afferent neurons in the rat nodose produced primarily in gastrointestinal organs in ganglion suggests that ghrelin signals from the response to hunger and starvation, and stomach are transmitted to the brain via the circulates in the blood, serving as a peripheral vagus nerve. Moreover, the observation that signal telling the central nervous system to ICV administration of ghrelin induces c-Fos in stimulate feeding. When ghrelin is injected into the dorsomotor nucleus of the vagus and the cerebral ventricles of rats, their food intake stimulates gastric-acid secretion indicates that is potently stimulated 6. Moreover, not only ICV ghrelin activates the vagus system. injection, but also IV and subcutaneous In contrast, vagotomy inhibits the ability of injection of ghrelin have been shown to ghrelin to stimulate food intake and GH increase food intake. release. A similar effect was also observed In the brain, the hypothalamic arcuate when capsaicin, a specific afferent neuro- nucleus is the main site of ghrelin's appetite toxin, was applied to vagus nerve fibers to stimulating activity 6. At least a part of the induce sensory denervation. On the other orexigenic effect of ghrelin is mediated by hand, fasting-induced elevation of plasma upregulating the genes encoding potent ghrelin levels is completely abolished by sub- appetite stimulants, such as NPY and AgRP, diaphragmatic vagotomy or atropine treat- since ICV injection of ghrelin induces Fos ment. These results indicate that the response expression in NPY/AgRP-expressing neurons of ghrelin to fasting is transmitted through and increases the amount of NPY/AgRP vagal afferent transmission. mRNAs in the arcuate nucleus. In contrast, the 3. Clinical Application of Ghrelin appetite-stimulating effects of ghrelin are The diverse functions of ghrelin raise the blocked by ICV injection of a NPY receptor 1 possibility of its clinical application (Fig. 2). antagonist, an AgRP inhibitor, anti-NPY IgG, Attempts for clinical use of ghrelin are now in and anti-AgRP IgG. Immunohistochemical progress. Basically ghrelin is a peptide hor- analysis indicated that ghrelin neuron fibers mone that endows cells with nutrition and directly contact NPY/AgRP neurons. These energy and regulates the metabolic activities. results indicate that ghrelin exerts its feeding The target diseases of ghrelin