Characteristic features of ghrelin cells in the gastrointestinal tract and the regulation of stomach ghrelin expression and production

Abstract

Ghrelin was isolated as an endogenous ligand for the GH secretagogue receptor from the rat stomach. Although physiological effects of ghrelin have been revealed by numerous studies, the regulation of stomach ghrelin remains obscure, and the factor that directly regulates ghrelin expression and production has not been identified. Here, we show some data regarding the characteristic features of ghrelin cells and the regulation of stomach ghrelin. In the gastrointestinal tract, ghrelin cells were identified as opened- and closed-type cells, and it was found that the number of ghrelin cells decreased from the stomach to the colon. The postnatal change in number of ghrelin cells in the stomach showed a sexually dimorphic pattern, indicating a role of estrogen in the regulation of stomach ghrelin. In vitro studies revealed that estrogen stimulated both ghrelin expression and production and that treatment with formestane, an aromatase (estrogen synthetase) inhibitor, decreased ghrelin expression level. On the other hand, leptin was found to inhibit both basal and estrogen-stimulated ghrelin expression. Moreover, both aromatase mRNA-expressing cells and leptin cells were found to be located close to ghrelin cells in the gastric mucosa. Furthermore, we found an inverse relationship between gastric ghrelin and leptin levels in a fasting state, and we revealed relative changes in expression of gastric ghrelin, estrogen and leptin in the postnatal rats. We propose that gastric estrogen and leptin directly regulate stomach ghrelin and that the balance control through gastric estrogen and leptin contributes to the altered ghrelin expression level in some physiological states.

Figure 1

Representative microphotographs of ghrelin-ip cells in the rat gastrointestinal tract[16]. A: Closed-type ghrelin cells (arrow) were found in the crypt of the duodenum; B: Opened-type ghrelin cells (arrow) in contact with the lumen were found in the villi of the duodenum. Bar = 10 μm. VI: Villi; LU: Lumen.

Figure 2

Changes in ghrelin mRNA levels and the densities of ghrelin-ip cells during the postneonatal period in the rat stomach[20]. The data in (A) and (B) are shown as the % of 1-wk-old (1 wk) rats (100%) and each bar represents the mean ± SE (n = 3). A: Ghrelin mRNA levels in the male stomach; B: Ghrelin mRNA levels in the female stomach; C: The densities of ghrelin-ip cells (cells/mm²) in the male stomach; D: The densities of ghrelin-ip cells (cells/mm²) in the female stomach.

Figure 3

In vitro effects of estrogen and leptin on ghrelin mRNA expression and distributions of aromatase mRNA-expressing, leptin-ip and ghrelin-ip cells in the gastric mucosa[23,27]. A: Changes in ghrelin mRNA expression after estrogen treatment; B: Aromatase mRNA-expressing cells were found in the glandular body of the fundic gland; C: Ghrelin-ip cells were found sporadically throughout the gastric mucosa; D: Changes in ghrelin mRNA expression after leptin treatment. Ghrelin mRNA level is expressed relative to β-actin mRNA level; E: Leptin-ip cells (arrow) were found in the lower half of the fundic gland; F: Ghrelin-ip cells (arrowhead) were found in the gastric mucosa. (A, D) Data are presented as mean ± SE. n = 3-4/group. ^aP < 0.05; ^bP < 0.01. Bar = 100 μm (B, C) and 20 μm (E, F) respectively. MU: Mucosa; SL: Smooth muscle layer.

Figure 4

mRNA expression levels of gastric ghrelin and leptin under different feeding conditions[27]. (A) Effects of 48 h of fasting and 5 h of refeeding on gastric ghrelin expression; (B) Effects of 48 h of fasting and 5 h of refeeding on gastric leptin expression. Ghrelin and leptin mRNA levels are expressed relative to β-actin mRNA levels. Data are presented as mean ± SE. n = 3-4/group. ^aP < 0.05; ^bP < 0.01.