Physiological significance of ghrelin revealed by studies using genetically engineered mouse models with modifications in the ghrelin system [Review]

Abstract

Abstract. Ghrelin, an endogenous ligand for the growth hormone (GH) secretagogue receptor (GHS-R or ghrelin receptor), is a 28-amino acid acylated peptide mainly produced in the stomach. The pharmacological administration of ghrelin is known to exert diverse effects, such as stimulating GH secretion, promoting food intake, and increasing adiposity. In recent years, genetically engineered mouse models have provided important insights into the physiology of various hormones. In this review, we discuss current knowledge regarding the physiological significance of ghrelin on the basis of studies using genetically engineered mouse models with modifications in the ghrelin system. Key word: GhrelinGHRELIN, an endogenous ligand for the growth hormone (GH) secretagogue receptor (GHS-R or ghrelin receptor), is a 28-amino acid acylated peptide [1]. Acyl-modification of ghrelin is essential for binding to ghrelin receptor, and is mediated by the membrane-bound ghrelin O-acyltransferase (GOAT) [2,3]. Ghrelin is mainly produced in the stomach, but is also expressed in the upper intestinal tract, pancreas, pituitary, and hypothalamus [1,4,5]. By contrast, the ghrelin receptor is expressed in the anterior pituitary and hypothalamus, suggesting that ghrelin/GHS-R signaling is involved in energy homeostasis and GH release [6][7][8]. Indeed, peripheral administration of ghrelin induces multiple effects, such as stimulating GH secretion, promoting food intake, and increasing adiposity [1,[9][10][11][12]. Using more sensitive PCR techniques, expression of ghrelin receptor has also been identified in the stomach, small intestine, pancreas, ventricular myocardium, aorta, adipose tissue, and lymphocytes [13][14][15]. The wide distribution of ghrelin and its receptor suggests that ghrelin might play a range of physiological roles.In order to investigate the physiological significance of hormones, genetically engineered mouse models have been widely utilized, and these models are also used as preclinical tools for exploring the novel therapeutic approaches for human disease. In this review, we discuss an outline of the physiological roles of ghrelin on the basis of research using genetically engineered mouse models, such as ghrelin-null, ghrelin receptor-null, ghrelin o-acyltransferase-null, and ghrelin-overexpressing mice. Secretion of GhrelinDate et al. reported that ghrelin-producing cells are X/A-like cells that account for about 20% of the endocrine cell population in rat and human oxyntic glands [16,17]. Ghrelin mRNA is most abundant in the stomach, and plasma ghrelin levels in totally gastrectomized patients were reduced to 35% of those in normal subjects, indicating that the stomach is a major source of circulating ghrelin [4]. Earlier studies revealed that circulating ghrelin levels reflect both acute and chronic energy status. In the acute phase, plasma ghrelin levels increase before meal and decrease after meal [4,[18][19][20]. In the chronic phase, plasma ghrelin levels are negatively correlated with BMI; for example, they ar...

The effect of adiposity, age and deletion of acyl-ghrelin on pulsatile growth hormone release in male mice

“…While studies across modified-ghrelin mouse models (Ariyasu and Akamizu 2015) suggest that the functionality of ghrelin is age-dependent (Al Massadi, et al 2015), it is uncertain whether a change in the magnitude of the rate of decline in pulsatile GH secretion relative to age would occur in the absence of acyl-ghrelin, alongside a continued decline in pulsatile GH secretion with increased adiposity. Moreover, ghrelin deficiency is thought to protect mice from an age-associated…”