Due to the versatility of the ghrelin system

Due to the versatility of the ghrelin system and its multiple functions, dysregulation in some of the components of the ghrelin system, such as ghrelin, GOAT, and GHSR, might lead to pathogenesis of many endocrine-related diseases, including obesity, short stature, cancer, inflammatory, and cardiovascular diseases. These components could also be used as diagnostic or therapeutic targets for these endocrine diseases. Next, we summarize the mutations in GHSR that have been identified so far.
Summary During the past two decades, extensive genetic and pharmacological studies have demonstrated that ghrelin/GHSR system plays important roles in multiple physiological processes, especially in GH secretion and appetite regulation. In addition, naturally occurring mutations in GHSR are associated with obesity and short stature from different backgrounds, suggesting GHSR might be another important pathogenic cause for obesity and short stature. Targeting GHSR and its ligand ghrelin might represent promising approaches toward treatment of obesity, diabetes, and short stature.
Introduction Ghrelin is a 28 amino Atglistatin acylated peptide that is mainly released from the stomach and was first discovered as an endogenous ligand for the orphan growth hormone secretagogue receptor (GHS-R1a) [23]. This G protein-coupled receptor had been expression-cloned using a small synthetic molecule, MK-677, which was one of a family of synthetic compounds including GHRP-6, shown to stimulate the release of growth hormone (GH) in vitro from pituitary somatotrophs through the activation of a PLC-dependent pathway [3], [6], [7], [19], [31], [32]. Furthermore, MK-677 oral treatment restored the GH pulse amplitude in elderly subjects to a young adult profile, and increased total lean mass [5]. Ghrelin has been shown to exert many actions, of which regulation of the GH axis is but one. Ghrelin injections induced food intake in humans and rodents, and adiposity in rodents [28], [39], [43], [44]. In the last decade, countless studies have shown that acute pharmacologic doses of ghrelin increase feeding behavior. Upon ghrelin binding, activation of GHS-R1a in hypothalamic neuropeptide Y (NPY)/agouti-related peptide (AGRP) neurons leads to the release of orexigenic or appetite stimulating neurotransmitters into other hypothalamic nuclei, which results in increased food intake [10], [18]. The association of ghrelin with obesity is derived largely from pharmacology experiments in rodents, and clear interpretation of the results is confounded by the fact that acute administration of ghrelin causes a number of hormonal perturbations including release of GH, ACTH and glucocorticoids. The profile of plasma ghrelin concentrations epitomized by sharp peaks and valleys in these studies is quite different from what is observed in vivo. By contrast, the long-acting oral agonists of GHS-R1a administered chronically for up to 12 months provide a smoother agonist profile and do not cause elevations in ACTH or cortisol. Indeed, 2-month treatment of obese subjects with MK-677 increased fat-free mass and energy expenditure without affecting fat mass [37]. The sights of expression of the GHS-R1a also indicate the significance of ghrelin in energy balance. The GHS-R1a is mainly expressed in β-cells of pancreatic islets, distinct areas of the hypothalamus, pituitary somatotrophs [17], [32], hippocampus, the ventral tegmental area (VTA), the substantia nigra (SN) and the dorsal raphe nucleus [1], [17], [20], [32]. Ghrelin actions include the regulation of memory and learning, activation of reward-related pathways and neuroprotection. An additional intriguing aspect of ghrelin biology is its link with immune function as illustrated by expression of GHS-R1a in the thymus, thymocytes and lymphocytes [13]; indeed, ghrelin treatment was shown to promote thymopoiesis in old mice [13]. In this review, we will examine the diverse physiological roles of ghrelin based on evidence collected from experimental studies in ghrelin−/− and ghsr−/− mice.