Among all the biological actions of ghrelin, particular attention has been focused on its role in the regulation of appetite and energy balance.
Long before ghrelin was discovered, different reports in rodents indicated that some GHS pos sess orexigenic activity . Moreover, in the last decade, a substantial amount of data showed that GHS were able to activate neurons in hypothalam-ic areas strictly involved in the control of energy balance [41, 42]. Accordingly, ghrelin emerged as one of the most powerful orexigenic and adi-pogenic agents known so far [3,6,15,43]. At first, it was puzzling to link adipogenic effects to a hormone that was originally discovered as a potent secretagogue of GH, a lipolytic hormone, but progressively, ghrelin resulted as a previously unidentified interface between energy balance regulation, glucose homeostasis, and hypothalamic neu-ropeptides [3,6,43].
Ghrelin dose-dependently stimulates food intake in rodents, particularly after central administration [17,44]. Unlike other potent orexigenic agents (e.g. neuropeptide Y [NPY], agouti-related protein [AgRP], melanin-concentrating hormone [MCH]) that are active only when injected intracerebroventricularly, ghrelin has orexi-genic and adipogenic effects even after systemic administration . The efficacy of ghrelin as an orexigenic agent after peripheral administration would be explained by its transport across the blood-brain barrier in a blood-to-brain direction. The hypothalamic areas playing a crucial role in the regulation of energy homeostasis, such as the ventromedial part of the arcuate nucleus, are not completely protected by the blood-brain barrier, contain neurons expressing GHS-R , and might therefore mediate ghrelin effects [45,46].
It has also been demonstrated that ghrelin's influence on appetite and energy balance is, at least partially, mediated by hypothalamic leptin-responsive neurons [46-51].
Among the major hypothalamic pathways mediating ghrelin's influence on energy balance [48,49,51], one involves NPY neurons [52,53] and the other involves melanocortin receptors . Ghrelin increases AgRP and NPY expression after both acute and chronic administration in rats [47, 48, 51, 53]. Thus, NPY and AgRP likely co-mediate ghrelin's effects on energy balance; NPY might be more important for acute effects while AgRP might be involved in both chronic and acute ghre-lin action in the hypothalamus .
Accordingly, whereas deletion of either NPY or
AgRP causes only a modest effect on the orexi-genic effect of ghrelin, simultaneous genetic ablation completely abolishes ghrelin's modulatory action on food intake . However, other agents are likely to be involved in mediating the impact of ghrelin on appetite, food intake and energy balance; these include orexins, pro-opiomelanocortin (POMC), cocaine- and amphetamine-related transcript (CART), MCH, ciliary neurotropic factor (CNTF), gamma amino butyric acid (GABA), galanin, corticotropin-releasing hormone (CRH) and somatostatin [46, 50,56]. Besides the increase of appetite and food intake, reduced cellular fat oxidation and promotion of adipogenesis reportedly contributes to increased fat mass induced by ghrelin [10,50].
It is noteworthy that ghrelin regulation of energy homeostasis seems to be mediated by efferent and afferent fibres of the vagal nerve . Intravenously administered ghrelin decreases the afferent activity of the gastric vagal nerve at low doses . Moreover, the blockade of the gastric vagal afferent fibres abolishes ghrelin-induced feeding, GH secretion, and activation of NPY-pro-ducing and growht hormone-releasing hormone (GHRH)-producing neurons in rats. Cholinergic influence on systemic ghrelin secretion has already been reported both in animals and humans [20, 58-60]. Nevertheless, cholinergic agonists and antagonists do not influence the endocrine response to ghrelin administration in humans .
Overall, as a result of central and peripheral actions, ghrelin administration in rodents causes weight gain [3, 6, 17, 43]. This effect is not due to longitudinal growth or an increase in lean mass as one would expect to occur after stimulation of GH secretion . Data in rodents clearly showed that ghrelin-induced weight gain is based on accretion of fat mass without changes in longitudinal skeletal growth and with a decrease of lean mass .
Despite all these data, it has to be taken into account that ghrelin-null mice do not differ from controls in terms of food intake, size, growth rate and body composition  and even GHS-R-null mice show normal appetite and body composition, with only a mild reduction in body weight compared with controls .
Was this article helpful?