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And Des-Acyl Ghrelin European Journal of Endocrinology (2012) 167 601–608 ISSN 0804-4643 REVIEW MECHANISMS IN ENDOCRINOLOGY Ghrelin: the differences between acyl- and des-acyl ghrelin Patric J D Delhanty, Sebastian J Neggers and Aart J van der Lely Department of Medicine, Erasmus University MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands (Correspondence should be addressed to A J van der Lely; Email: [email protected]) Abstract Des-acyl ghrelin (DAG) is one of the three preproghrelin gene-encoded peptides. Compared with ghrelin and obestatin, it has not received the attention it deserves. DAG has long been considered an inert degradation product of acyl ghrelin (AG). Recent evidence, however, indicates that DAG behaves like a separate hormone. DAG can act together with AG, can antagonize AG, and seems to have AG-independent effects. Therefore, it is believed that DAG must activate its own receptor and that it may also interact with AG at this receptor. Of potential clinical importance is that an increasing number of studies suggest that DAG might be a functional inhibitor of ghrelin and that DAG can suppress ghrelin levels in humans. Therefore, DAG or DAG analogs might be good candidates for future treatment of metabolic disorders or other conditions in which antagonism of AG actions could be beneficial, such as diabetes, obesity, and Prader–Willi syndrome. European Journal of Endocrinology 167 601–608 Introduction We describe the properties of DAG not only as a functional antagonist of AG but also as a strong It is now more than 12 years since ghrelin was identified inhibitor of AG serum levels in vivo in animals and as the ligand of the GH secretagogue receptor type 1a men. Finally, we will describe the situations in which (GHSR1a). The story of des-acyl ghrelin (DAG; Fig. 1) DAG acts independently of AG. also began in 1999, when Kojima et al. described this peptide in the same report that introduced ghrelin to the scientific world (1, 2). The preproghrelin gene-derived peptides include acyl ghrelin (AG), DAG, and obestatin. The controversial aspects of the AG is produced mainly by the stomach and exerts its AG/DAG ratio central and peripheral effects through GHSR1a (1). The ghrelin peptide is acylated by the enzyme ghrelin O-acyl Although available data are still contradictory, several transferase (GOAT) (3,4,5), which is expressed studies have indicated that obese mice and humans predominantly in the stomach, gut, and pancreas but might have lower DAG levels than normal-weight also at other sites (6). subjects whereas AG levels are similar, indicating that The concept that emerged from Kojima’s paper and obesity could reflect a relative DAG deficiency and that many others was that DAG should be considered as the DAG levels might be regulated by body weight (8, 9, 10). degradation product of ghrelin without biological Moreover, insulin-resistant obese subjects have an activities. The obvious reason for this is that DAG is elevated AG/DAG ratio when compared with insulin- unable to bind and activate the GHSR1a in the sub- sensitive obese subjects (11, 12). St-Pierre et al. (9) micromolar, physiological range (1, 7). Therefore, DAG found that the dysregulation of ghrelin secretion profiles has never received the level of attention in research and during a euglycemic/hyperinsulinemic clamp (EHC) is the literature that it deserves, although a growing associated with insulin resistance (IR). They determined number of reports strongly suggest that DAG has intrinsic whether insulin-sensitive overweight or obese (ISO) and activities in a variety of physiological and pathophysio- insulin-resistant overweight or obese (IRO) individuals logical situations. Depending on the experimental display different AG and DAG profiles during a EHC in 89 circumstance, DAG can either antagonize or support nondiabetic overweight and obese postmenopausal the activities of ghrelin, while in other situations, DAG women. DAG levels were found to be significantly works completely independently of ghrelin. decreased for ISO and IRO individuals during the EHC, In this review, we will try to address some of these whereas only ISO subjects displayed a significant actions of DAG on (patho)physiological processes. reduction of AG levels. Also, the ratio of AG/DAG q 2012 European Society of Endocrinology DOI: 10.1530/EJE-12-0456 Online version via www.eje-online.org Downloaded from Bioscientifica.com at 09/24/2021 11:43:17PM via free access 602 P J D Delhanty and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2012) 167 Fat mass in rodents (29,30) Insulin sensitivity and postprandial (glucose) in humans and rodents (34,54) Inhibition of ghrelin in humans and rodents (17,19) Des-acyl ghrelin Muscle regeneration in rodents (27,39) Trophic and protective effects on β-cells in humans and rodents (16,21,55) Restoration of EPC/CAC number and function Figure 1 Overview of des-acyl ghrelin in DM patients and rodents (40) actions, along with some references for further reading. (fasting and area under the curve (AUC)) was hyperphagia of PWS (15). It was hypothesized that significantly decreased in ISO individuals (11). abnormal development or sensitivity of pathways Rodriguez et al. found that AG levels were increased, required for activity of these appetitive hormones (e.g. whereas DAG levels were decreased in obesity and in the CNS) may be responsible for the emergence of obesity-associated type 2 diabetes. Body mass index, hyperphagia in PWS. waist circumference, insulin, and homeostasis model assessment (HOMA) index were positively correlated with AG levels (13). However, it is noteworthy that in the latter study, blood samples were not collected in a DAG is a functional ghrelin antagonist way that prevents de-acylation of ghrelin; therefore, the data must be interpreted with caution. The first indications Barazzoni et al. determined potential differential It was the group of Broglio et al. (16) that shifted associations of ghrelin isoforms with IR and the impact the existing paradigm by suggesting that DAG should be of obesity on their plasma concentrations in 45 subjects considered as a separate hormone. Others later with metabolic syndrome. Plasma insulin and HOMA- supported their findings. Broglio et al. studied the IR were negatively associated with DAG but positively interaction of the combined administration of AG and with AG and AG/DAG ratios. Compared with the DAG in six normal young volunteers. As expected, AG nonobese, obese metabolic syndrome patients had administration alone markedly increased circulating lower DAG but comparable AG and higher AG/DAG GH, prolactin, ACTH, and cortisol levels. AG adminis- ratios. Apparently, obesity could alter circulating tration was also followed by a decrease in insulin levels ghrelin profiles, and a relative AG excess or DAG and an increase in plasma glucose levels. While DAG deficiency can contribute to obesity-associated IR in administration alone had no effects, DAG together with metabolic syndrome (12). AG diminished the insulin and glucose response to AG. Finally, Prader–Willi syndrome (PWS) is a leading Their findings indicated for the first time that DAG can genetic cause of obesity, characterized by hyperphagia, be metabolically active by counteracting the effects of endocrine, and developmental disorders. It is believed AG on insulin secretion and glucose metabolism. that the hyperphagia results from impaired gut Inhoff et al. (17) have also shown that the metabolic hormone signaling. Purtell et al. reported that compared effects of AG (administered i.p.) could be abrogated by with adiposity-matched controls, hyperphagia in PWS coadministered DAG in nonfasted rats. DAG alone did is not related to a lower postprandial glucagon-like not alter food intake, as was also reported by others, as, peptide-1 or peptide YY response. However, elevated e.g. by Neary et al. (18). Double labeling revealed that ghrelin levels in PWS did show a relation with increased nesfatin-1 immunoreactive neurons in the arcuate hunger, which was unrelated to insulin levels (14). nucleus are activated by simultaneous injection of AG Goldstone et al. investigated whether differences in and DAG. These results suggest that DAG suppresses appetite hormones may explain the development of AG-induced food intake by preventing the increase in abnormal eating behavior in 42 young (7 months–5 neuronal activity in the arcuate nucleus and recruiting years) children with PWS. No significant relationship nesfatin-1 immunopositive neurons (17).Kumaret al.also was found between eating behavior and the levels of any reported the antagonistic properties of DAG on AG (19). of the hormones measured or IR, independent of age. By using isolated mouse pancreatic islets, they However, even in these young children, PWS was studied suppression of spontaneous secretion of PP by associated with low levels of the anorexigenic pancrea- AG and obestatin. Interestingly, the PP-releasing effect tic polypeptide (PP), as has been described in older of AG, but not obestatin, was counteracted by children and adults. Only later in life do hyperghreline- coadministration of DAG. Apparently, AG and obestatin mia or hypoinsulinemia begin to contribute to the inhibit spontaneous PP secretion at physiologically www.eje-online.org Downloaded from Bioscientifica.com at 09/24/2021 11:43:17PM via free access EUROPEAN JOURNAL OF ENDOCRINOLOGY (2012) 167 Des-acyl ghrelin is a separate hormone 603 relevant concentrations by acting through separate [D-Lys3]-GHRP-6, which suggests that this GHSR1a receptors (19). antagonist (although not very selective for the GHSR1a Gauna et al. (20) reported that administration of (24, 25)) can block the hypothetical DAG receptor as AG in humans reduces insulin sensitivity, whereas the well (23). An independent report on the effects of AG combination of AG plus DAG strongly improves insulin and DAG in adipocytes by Rodriguez et al. (13) also sensitivity. They studied the effects of acute adminis- shows that AG and DAG can stimulate lipid accumu- tration of AG, DAG, and their combined administration lation in human visceral adipocytes.
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