Maternal Ghrelin Plays an Important Role in Rat Fetal Development during Pregnancy

Abstract

Ghrelin, an acylated peptide serving as an endogenous ligand for GH secretagogue receptor (GHS-R), was originally isolated from rat and human stomach. In this study, we report the critical role of maternal ghrelin in fetal development. High levels of ghrelin receptor (GHS-R) mRNA were detected in various peripheral fetal tissues beginning at embryonic d 14 and lasting until birth. Fetal GHS-R expression was also confirmed in fetal tissues by immunohistochemistry. Autoradiography revealed that both des-acyl ghrelin and acyl ghrelin bind to fetal tissues. Chronic treatment of mothers with ghrelin resulted in a significant increase in birth weight in comparison to newborns from saline-treated mothers. Even when maternal food intake after ghrelin treatment was restricted through paired feeding, significant stimulation of fetal development still occurred. Conversely, active immunization of mothers against ghrelin decreased fetal body weight during pregnancy. A single ghrelin injection into the mother increased circulating ghrelin levels in the fetus within 5 min of injection, suggesting that maternal ghrelin transits easily to the fetal circulation. High levels of des-acyl ghrelin were detected in fetal blood and amniotic fluid. Both acylated and des-acyl ghrelin increased [3H]thymidine and 5-bromo-2'-deoxyuridine incorporation of cultured fetal skin cells in a dose-dependent manner, and calcium-imaging analysis revealed that acyl and des-acyl ghrelin increased the Ca2+ influx in discrete cultured fetal skin cells, respectively. These results indicate that maternal ghrelin regulates fetal development during the late stages of pregnancy.

Ghrelin and reproductive disorders

“…This is A c c e p t e d M a n u s c r i p t 17 consistent with the concept that maternal ghrelin affects fetal development by mechanisms which are relatively independent of increased maternal nutritional state (Nakahara et al, 2006). This effect has been related to the capacity of ghrelin to favor fetal growth through stimulation of cell proliferation (Nakahara et al, 2006). However, the ghrelin amounts in the fetus are not totally of maternal origin, since it can also be produced in the human fetus (Cortelazzi et al, 2003).…”

“…This has been confirmed by the finding that fetuses from mothers receiving chronic ghrelin treatment had significantly higher birthweight compared to newborns from saline-treated mothers, and that their growth was significantly favored even in conditions of restricted maternal food intake (Nakahara et al, 2006). This is A c c e p t e d M a n u s c r i p t 17 consistent with the concept that maternal ghrelin affects fetal development by mechanisms which are relatively independent of increased maternal nutritional state (Nakahara et al, 2006).…”

“…Ghrelin can cross the feto-placental barrier (Nakahara et al, 2006), therefore a role in fetal development has been hypothesized. This has been confirmed by the finding that fetuses from mothers receiving chronic ghrelin treatment had significantly higher birthweight compared to newborns from saline-treated mothers, and that their growth was significantly favored even in conditions of restricted maternal food intake (Nakahara et al, 2006).…”

Ghrelin as a novel locally produced relaxing peptide of the iris sphincter and dilator muscles

“…Also in the fetal development des-octanoylghrelin has some capacity to bind to a different GHS receptor, which has an important role in the embryologic process (Santos et al, 2006). In these conditions the authors presumed that fetal tissue could express a GHSR different subtype that binds to des-octanoyl-ghrelin (Nakahara et al, 2006). The results of the present study also suggest that the relaxing effects of ghrelin on the iris sphincter muscle are not mediated by GHSR-1a, as they were also observed in response to des-octanoyl-ghrelin.…”

Ghrelin and the growth hormone secretagogue receptor in growth and development

“…Injection of ghrelin to the dam during the last week of gestation caused a 10-20% increase in birth weight, an effect attributed to the transplacental transfer of the injected ghrelin and direct anabolic action in the fetus. 35 Administration of ghrelin to the lactating dam during the first 8 days after delivery increased milk production and caused a 30-40% weight increase in the pups. In humans, we recently observed a modest decrease in total ghrelin concentrations during the second and third trimesters of pregnancy compared with the early postpartum period.…”