Recent identification of novel appetite-regulating hormones has revealed the complex interactions of these humoral factors in the regulation of feeding behavior in mammals. One of these hormones, ghrelin, a natural ligand of the orphan receptor GHS-R, purified from stomach, is able to stimulate growth hormone release from pituitary cells. Ghrelin is a 28 amino acid peptide containing an n-octanoylated serine 3 residue that is essential for its activity. Ghrelin stimulates appetite by acting on the hypothalamic arcuate nucleus, the region known to control food intake. As an orexigenic peptide, ghrelin is therefore an endogenous regulator of feeding behavior from the peripheral tissues to the central nervous system.
Ghrelin was named from ghre, a word root in Proto-Indo-European languages for ‘grow’. Its name also implies that this peptide stimulates GH release. The purification steps of ghrelin are outlined in Figure 1. By screening several tissues, a high amount of ghrelin was unexpectedly found in stomach extracts. Purified ghrelin is a 28 amino acid peptide with an essential n-octanoyl modification at serine 3 (Figure 2), the first-known example of a bioactive peptide modified by an acyl acid. In fact,
We also determined the amino acid sequences of mouse, bovine, porcine, ovine and canine ghrelins (Figure 3) and found them to be well conserved. In particular, the N-terminal ten amino acids are universally identical. The structural conservation and strictly required acyl modification indicate that the N-terminal portion of the peptide is of central importance in its activity peptide. Bovine and ovine ghrelins comprise 27 amino acids, like des-Gln 14-ghrelin, the second endogenous form of rat
Ghrelin is mainly produced in the stomach. In situ hybridization and immunohistochemical analysis has indicated that ghrelin is produced in a distinct endocrine cell type found in the mucosal layer of the stomach. These cells, known as X/A-like cells, contain round, compact, electron-dense granules and are filled with ghrelin. Fetal stomach exhibits no ghrelin expression, whereas after birth ghrelin expression increases in the stomach. Ghrelin-immunoreactive cells are also found in
The active form of ghrelin is an acyl-modified ghrelin, and the modification of ghrelin is easily cleaved during the extraction of samples. Moreover, peptide samples are easily digested by many cellular proteases. To measure ghrelin concentrations correctly in the plasma and tissues, we therefore have to inhibit the cleavage of the acyl modification of ghrelin and the protease digestion of the ghrelin peptide portion. To measure plasma ghrelin concentrations, it is necessary to use EDTA and
Ghrelin secretion is controlled by feeding. Plasma ghrelin concentration is increased during fasting conditions and decreased after food intake. It is not clear what factors are involved in the regulation of ghrelin secretion, but blood glucose levels may be critical. Indeed, the oral or intravenous administration of glucose decreases plasma ghrelin concentration. On the other hand, gastric distention by water intake alone does not affect ghrelin levels. Plasma ghrelin
Although GH release from the pituitary is known to be stimulated by hypothalamic GH-releasing hormone (GHRH), ghrelin induces GH release via a different pathway from that of GHRH. GHRH acts on the GHRH receptor to increase intracellular cAMP, which serves as a second messenger. On the other hand, ghrelin acts on the ghrelin receptor (GHS-R), increasing intracellular calcium concentration via inositol 1,4,5-trisphosphate signal transduction. Ghrelin stimulates GH release both in vitro
Immunohistochemical analyses indicate that ghrelin-containing neural cells are found in the arcuate nucleus of the hypothalamus, a region involved in the regulation of appetite. In addition, recent report indicates that ghrelin has also been detected in previously uncharacterized hypothalamic neurons lying adjacent to the third ventricle between the dorsal, ventral, paraventricular and arcuate hypothalamic nuclei. These ghrelin-containing neurons send efferents fibers to the neurons
Gastric bypass surgery is often performed to treat severe obesity. The purpose of the gastric bypass operation is to reduce the amount of space available for food in the gastric cavity and hence reduce the total calorie intake. The exact mechanism of action underlying this operation is, however, unknown. Recent research has revealed that ghrelin might contribute to the body weight-reducing effects of gastric bypass surgery. After gastric bypass resulting in an
The fact that mRNA expression of the ghrelin receptor is observed in the heart and aorta, and that the intravenous injection of ghrelin into human volunteers induces a fall in blood pressure, indicates that ghrelin has some cardiovascular action. An intravenous bolus of human ghrelin (10 μg/kg) significantly decreased mean arterial pressure (−12 mmHg) without a significant change in heart rate. Ghrelin increased the cardiac index and stroke volume indices. Rats with chronic
A relationship between ghrelin genome variant and obesity has been suggested. In humans, two polymorphisms have been reported: Arg51Gln and Leu72Met (Figure 7). The former polymorphism changes the C-terminal processing site of ghrelin, resulting in a lack of the normal cleavage that is necessary to produce 28 amino acid ghrelin, but it may produce a pro-ghrelin peptide of 94 amino acids. For both variations, allelic frequencies were similar in obese patients and controls.
Anorexia nervosa is a syndrome often seen in young women that combines weight loss, amenorrhea and behavioral changes. Some of these changes are reversible with weight gain. Plasma ghrelin levels in AN patients are high and returned to control levels after renutrition. Moreover, plasma GH levels are markedly elevated in AN patients. The high ghrelin and GH levels in AN patients return to basal levels after weight gain resulting from treatment. More research is needed to determine
Prader-Willi syndrome (PWS) is a complex genetic disorder characterized by mild mental retardation, hyperphagia, short stature, muscular hypotonia and distinctive behavioral features. The excessive appetite seen in PWS causes progressive severe obesity, which in turn leads to increased cardiovascular morbidity and mortality. The PWS genotype is characterized by a loss of one or more paternal genes in the region q11–q13 on chromosome 15. It is assumed that the genetic alteration leads to a
The discovery of the endogenous ligand for GHS-R, ghrelin, opened up a new field in hormone research. Ghrelin is a peptide hormone in which the third amino acid, usually serine but in some species threonine, is modified by an acyl acid; this modification is essential for ghrelin's activity. Ghrelin exists not only in mammalian species, but also in non-mammalian species such as frog, chicken and fish. Ghrelin may thus be an essential hormone for maintaining GH release and energy homeostasis in
We would like to thank Hisayuki Matsuo, Yukari Date, Masamitsu Nakazato and Noboru Murakami for their help and collaboration. This work was supported by the Program for Promotion of Basic Research Activities for Innovative Biosciences (PROBRAIN), a Grant-in - Aid for Scientific Research (B) from the Ministry of Education, Culture, Sports, Science and Technology of Japan (to M.K.) and a Grant-in - Aid for the Promotion of Fundamental Studies in Health Science from the Organization for Pharmaceutical
