Gastric estrogen directly induces ghrelin expression and production in the rat stomach

Abstract

Ghrelin, an endogenous ligand for the GH secretagogue receptor, is predominantly produced in the stomach. Little is known about the regulation mechanism of gastric ghrelin. Here, we report that estrogen synthesized in the stomach induces rat gastric ghrelin gene expression and production. We established a gastric ghrelin cell enrichment method using Percoll centrifugation and then studied the effect of estrogen and/or its antagonist on ghrelin expression and production. Treatment with estrogen for 8 h significantly increased the level of ghrelin expression, and ICI-182 780, an estrogen receptor (ER) antagonist, completely reversed this effect.Reverse transcriptase-PCR analysis clearly showed that ERa and aromatase are expressed in the female rat stomach. Moreover, treatment with an aromatase inhibitor, 4-hydroxyandrostenedione (formestane), significantly decreased the level of ghrelin mRNA expression in minced stomach tissue. In vivo studies revealed that the ghrelin mRNA expression and production did not change in gonadectomized rat 3 weeks after surgery. These results strongly suggest that estrogen produced in the stomach directly induces ghrelin expression and production in both female and male rat stomachs.

PET of Aromatase in Gastric Parietal Cells Using 11C-Vorozole

“…Ghrelin, an endogenous ligand for the growth hormone secretagogue receptor, is predominantly produced in the stomach (25), and its expression and release are thought to be regulated by gastric estrogen in a paracrine fashion (26). Recently, ghrelin levels have been observed to be upregulated in a chronic stress model in rats (27), which was originally developed by our group as a comprehensive fatigue model (21).…”

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

“…In that study, we found that estrogen treatment significantly stimulated ghrelin mRNA expression ( Figure 3A) and production in a dose-dependent manner and that treatment of minced stomach tissue with formestane, an aromatase inhibitor, decreased ghrelin expression level [23] . Given that a significant increase in estrogen concentration in the portal vein compared with that in the artery was observed in intact rats, but not in gastrectomized rats [22] , the concentration of gastric estrogen must be higher than that of plasma estrogen.…”

“…Therefore, in a previous study, using isolated stomach cells, which are rich in ghrelin cells, we determined the direct effect of estrogen on stomach ghrelin expression and production [23] . In that study, we found that estrogen treatment significantly stimulated ghrelin mRNA expression ( Figure 3A) and production in a dose-dependent manner and that treatment of minced stomach tissue with formestane, an aromatase inhibitor, decreased ghrelin expression level [23] .…”

“…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/mm ghrelin concentration was altered by gonadectomy [23] . Furthermore, ghrelin cells and aromatase mRNAexpressing cells were found to be located close together in the gastric mucosa ( Figure 3B and C), suggesting that ghrelin cells are exposed to gastric estrogen.…”

Ghrelin and reproductive disorders

“…In one study, ovariectomy or orchiectomy in female and Page 21 of 41 A c c e p t e d M a n u s c r i p t 21 male adult rats, respectively, did not affect gastric ghrelin mRNA expression (Gualillo et al, 2001). By contrast, others found that estradiol produced locally in the stomach was able to stimulate ghrelin gene expression even after gonadectomy (Sakata et al, 2006). Another study reported suppressive effects of ovarian estradiol on stomach ghrelin gene expression as well as on the plasma ghrelin concentration (Matsubara et al, 2004).…”