Ghrelin Inhibits the Development of Mouse Preimplantation Embryos in Vitro

Abstract

Although ghrelin acts as a modulator of feeding behavior and energy metabolism in the central nervous system, recent studies have implicated the peripheral actions of ghrelin in reproductive tissues. Here, we investigated the expression of ghrelin and its receptor (GHS-R) in mouse oocyte and preimplantation embryos, and we examined the role of ghrelin in the regulation of early embryo development. Both ghrelin and GHS-R mRNAs were detected in morula or more advanced embryo stages. As for the origin of ghrelin, both ghrelin mRNA and protein were identified in the uterine endometrium. The levels of ghrelin in uterine fluid as well as plasma were significantly increased in fasting mice compared with animals with free access to foods. Addition of ghrelin to culture media inhibited the development of two-cell embryos to the hatched blastocysts, and the inhibitory effects of ghrelin were abolished by an antagonist for the GHS-R. In addition, ghrelin significantly decreased the number of total cells, inner cell mass, and trophectoderm cells in blastocysts. These observations suggest that ghrelin could inhibit the development of preimplantation embryos during fasting. Thus, ghrelin may act as a peripheral factor to avoid the excess metabolic demands imposed by pregnancy during malnutritional states.

Role of ghrelin in reproduction

“…In addition, ghrelin levels in uterine fluid have been proven to dramatically increase during fasting in mice, and ghrelin has been recently reported to inhibit the development of mouse preimplantation embryos in vitro (Kawamura et al 2003). In good agreement, we have recently observed that chronic ghrelin treatment during the first half of pregnancy in the rat induced a significant reduction in the litter size (Fernandez-Fernandez et al 2005).…”

Ghrelin and reproductive disorders

“…Ghrelin also negatively regulates cell viability and proliferation (Cassoni et al, 2000;Cassoni et al 2001;Ghe et al, 2002). Taken together, these findings suggest that during fasting ghrelin may act as a peripheral factor, pre-empting the increased metabolic demand induced by pregnancy and lactation, by inhibiting the development of preimplantation mouse embryos through its specific receptor (Kawamura et al, 2003). The involvement of ghrelin in embryo implantation has been demonstrated by its spatial-temporal expression (like that of its receptors) around the time of implantation .…”

“…Both ghrelin and GHSR mRNAs have been detected in the morula and in more advanced stages of embryo development (Kawamura et al, 2003). In addition, ghrelin protein is produced and secreted by the reproductive tract into uterine fluid (Kawamura et al, 2003) where its expression increases during fasting, as occurs in plasma (Gualillo et al, 2002). Ghrelin also negatively regulates cell viability and proliferation (Cassoni et al, 2000;Cassoni et al 2001;Ghe et al, 2002).…”

Diabetes, Ghrelin And Related Peptides: From Pathophysiology To Vasculopathy

“…Its expression was also described in other areas of the CNS and in some peripheral tissues as: thyroid gland, pancreas, spleen, myocardium, adrenal glands [11,14,42,43], rat testis, ovary [44], human T lymphocytes [12], morula, blastocyts and embryos [13]. There were identified binding sites in the myocardium (highest binding capacity), adrenal gland, gonads, arteries, lung, liver, skeletal muscle, kidney, pituitary, thyroid gland, adipose tissue, veins, uterus, skin and lymph nodes [45].…”

“…Ghrelin is also produced in the X/A cells of the intestine and in some others tissues such as the pancreas, kidney, placenta, lymphatics, *Address correspondence to this author at the Department of Physiology, Faculty of Medicine, Alameda Professor Hernâni Monteiro, 4200-319 Porto, Portugal; Tel: +351 225513644; Fax: +351 225513646; E.mail: arsousa@med.up.pt # Both authors had the same contribution to the article gonads, adrenal, thyroid gland, heart, lung, pituitary, hypothalamus, eye [10], human B-and T-lymphocytes, neutrophils [1,[10][11][12], morula, blastocyts and embryos [13]. Ghelardoni observed that ghrelin gene expression and its protein were, in some tissues, dissociated [14].…”