Beyond the metabolic role of ghrelin: A new player in the regulation of reproductive function

Abstract

Ghrelin is a gastric peptide, discovered by Kojima et al. (1999) [55] as a result of the search for an endogenous ligand interacting with the “orphan receptor” GHS-R1a (growth hormone secretagogue receptor type 1a). Ghrelin is composed of 28 aminoacids and is produced mostly by specific cells of the stomach, by the hypothalamus and hypophysis, even if its presence, as well as that of its receptors, has been demonstrated in many other tissues, not least in gonads. Ghrelin potently stimulates GH release and participates in the regulation of energy homeostasis, increasing food intake, decreasing energy output and exerting a lipogenetic effect. Furthermore, ghrelin influences the secretion and motility of the gastrointestinal tract, especially of the stomach, and, above all, profoundly affects pancreatic functions. Despite of these previously envisaged activities, it has recently been hypothesized that ghrelin regulates several aspects of reproductive physiology and pathology. In conclusion, ghrelin not only cooperates with other neuroendocrine factors, such as leptin, in the modulation of energy homeostasis, but also has a crucial role in the regulation of the hypothalamic–pituitary gonadal axis. In the current review we summarize the main targets of this gastric peptide, especially focusing on the reproductive system.

Introduction

It has just passed 10 years since the identification of the natural ligand for GHS-R (growth hormone secretagogue-receptor) type 1a from stomach [55]. This acylated 28 residues peptide is mainly produced by the oxyntic cells in the gastric mucosa, although it is also produced in other organs, such as proximal intestine, pancreas, pituitary, and hypothalamus.

Biological actions of ghrelin are much more diverse than those originally described, such as stimulation of growth hormone secretion, and include endocrine and nonendocrine effects [57], [58], [112].

Among these functions, a pivotal role of ghrelin is the regulation of energy homeostasis, promoting food intake and weight gain [59], [112]. Ghrelin's control of energy homeostasis by its orexigenic action is partly due to the activation of the genes encoding the potent appetite stimulators agouti-related peptide (AgRP) and neuropeptide Y (NPY) and the binding to anorexigenic pro-opiomelanocortin (POMC) neurons, respectively stimulating and inhibiting their activity and peptide release [15]. The net orexigenic effect of ghrelin results functionally opposite to that produced by leptin [120], and many data support the notion that both hormones act in a complementary fashion in providing the CNS information about the energy balance for the maintenance of homeostasis [45], [50], [76], [95], [111]. Serum ghrelin levels are influenced by both short and long term changes in energy homeostasis (i.e., with glucose, insulin and somatostatin levels).

Some data suggest that whole body insulin responsiveness plays a direct or an indirect role in the meal-related ghrelin inhibition [70]. Additionally, a long term decrease or increase in the body's energy stores (i.e., anorexia or obesity) leads to hyper- and hypo-ghrelinemia, respectively, with a negative correlation observed between body mass index (BMI) and ghrelin levels and a trend toward normalization of ghrelin levels after therapy [99]. Thus, ghrelin fulfills the criteria to be considered as a signal of starvation or energy insufficiency.

Ghrelin stimulates GH release from primary rat cultured pituitary cells, indicating a direct action on the gland [55]. Intriguingly, exogenous GH reduced both stomach ghrelin mRNA expression and plasma ghrelin, suggesting that pituitary GH may exert a feedback inhibition on stomach ghrelin production and secretion [83]. Moreover, ghrelin stimulates pituitary GH secretion also through hypothalamic GHRH modulation, via the afferent vagal nerve pathway [18].

Ghrelin increases food intake and reduces fat utilization in rodents inducing adiposity, and its adipogenic and orexigenic effects are independent of its ability to stimulate GH secretion [110].

Other central and peripheral effects have also been ascribed to ghrelin; for example, in the hippocampus it alters neuron morphology and associated functions, enhancing learning and memory [20] through its ability to modulate synaptic plasticity [81]. In addition, ghrelin and its receptor are widely distributed in cardiovascular tissues, suggesting a direct effect on this system [48]. In fact, intravenous ghrelin induces vasodilation, increases cardiac output in healthy humans [73] and enhances cardiac performance in patients with chronic heart failure, decreasing mean arterial pressure without affecting the heart rate, and increasing cardiac and stroke volume indices without inducing renal side-effects [74]. Recent data indicate that ghrelin inhibits insulin resistance induced by glucotoxicity and lipotoxicity in cardiomyocyte, evidencing a possible efficacy of protection by ghrelin for the clinical treatment of myocardial disease in diabetes mellitus [10].

Besides all these well-documented effects, ghrelin has been also involved in the control of the reproductive function by affecting the synthesis and release of reproductive factors from brain and pituitary, and by regulating gonadal physiology [4], [108]. Up to date, its role as novel regulator of the gonadotropic axis is clearly emerging [67].