Ghrelin gene products, receptors, and GOAT enzyme: biological and pathophysiological insight

Abstract

Ghrelin is a 28-amino acid acylated hormone, highly expressed in the stomach, which binds to its cognate receptor (GHSR1a) to regulate a plethora of relevant biological processes, including food intake, energy balance, hormonal secretions, learning, inflammation, etc. However, ghrelin is, in fact, the most notorious component of a complex, intricate regulatory system comprised of a growing number of alternative peptides (e.g. obestatin, unacylated ghrelin, and In1-ghrelin, etc.), known (GHSRs) and, necessarily unknown receptors, as well as modifying enzymes (e.g. ghrelin-O-acyl-transferase), which interact among them as well as with other regulatory systems in order to tightly modulate key (patho)-physiological processes. This multiplicity of functions and versatility of the ghrelin system arise from a dual, genetic and functional, complexity. Importantly, a growing body of evidence suggests that dysregulation in some of the components of the ghrelin system can lead to or influence the development and/or progression of highly concerning pathologies such as endocrine-related tumors, inflammatory/cardiovascular diseases, and neurodegeneration, wherein these altered components could be used as diagnostic, prognostic, or therapeutic targets. In this context, the aim of this review is to integrate and comprehensively analyze the multiple components and functions of the ghrelin system described to date in order to define and understand its biological and (patho)-physiological significance.

Ghrelin O-Acyl Transferase in Zebrafish Is an Evolutionarily Conserved Peptide Upregulated During Calorie Restriction

“…14 We observed alterations in GOAT mRNA in the brain and the gut of zebrafish under various feeding conditions. Our results indicate that the expression of GOAT mRNA in both brain and gut are influenced by daily feeding period and nutrient status.…”

“…44 Several studies in mammals also confirmed that acylated ghrelin and/or GOAT mRNA increases following fasting. 14,40,45 In contrast, other studies either failed to detect an increase in ghrelin or GOAT following fasting, or observed a decrease. 39,46 These discrepancies among studies might be related to the time of food withdrawal, strain of animal used, time of sample collection, type of rodent chow provided, and/ or the method of euthanasia.…”

“…[8][9][10][11] The ghrelinergic system exerts multifunctional regulatory effects in an endocrine, paracrine, and autocrine manner to modulate food intake, energy expenditure, hormone secretion, and reproduction. 5,[12][13][14] So far, ghrelin has been identified in various fishes. [15][16][17][18][19][20][21][22] As in mammals, [23][24][25][26][27] ghrelin increases food intake and promotes body weight gain in fishes.…”

Uroguanylin levels in intestine and plasma are regulated by nutritional status in a leptin-dependent manner

“…In the intestine, the large list of hormones include gastrin, cholecystokinin, oxyntomodulin, glucagon-like peptide one and peptide YY [2], all of which act as anorectic agents. In the stomach, among other hormones, there is also ghrelin [3][4][5][6], the only one peptidic hormone that stimulates food intake and adiposity [7].…”

Novel bioluminescent receptor-binding assays for peptide hormones: using ghrelin as a model

“…Ghrelin was identified in 1999 by screening the endogenous agonist of the growth hormone secretagogue receptor GSHR1a (Howard et al 1996;Kojima et al 1999). Ghrelin is known to be involved in multiple biological functions, such as stimulation of growth hormone secretion, increase of appetite and food intake, and regulation of glucose homeostasis and cardiovascular functions, mediated via the known G protein-coupled receptor GSHR1a or other as yet unknown receptors (Delporte 2013;Gahete et al 2013;Heppner and Tong 2014;Labarthe et al 2014;Pradhan et al 2013;RakMardyla 2013). To prepare a novel bioluminescent ghrelin tracer for non-radioactive receptor-binding assays, a chemically synthesized ghrelin analog (ghrelin-Cys) with a unique cysteine residue at the C-terminus was site-specifically conjugated with an engineered NanoLuc (Luc-Cys) carrying a unique exposed cysteine residue at the C-terminus via a reversible disulfide linkage.…”