Actions of Agonists and Antagonists of the ghrelin/GHS-R Pathway on GH Secretion, Appetite, and cFos Activity

Abstract

The stimulatory effects of ghrelin, a 28-AA acylated peptide originally isolated from stomach, on growth hormone (GH) secretion and feeding are exclusively mediated through the growth hormone secretagogue 1a receptor (GHS-R1a), the only ghrelin receptor described so far. Several GHS-R1a agonists and antagonists have been developed to treat metabolic or nutritional disorders but their mechanisms of action in the central nervous system remain poorly understood. In the present study, we compared the activity of BIM-28163, a GHS-R1a antagonist, and of several agonists, including native ghrelin and the potent synthetic agonist, BIM-28131, to modulate food intake, GH secretion, and cFos activity in arcuate nucleus (ArcN), nucleus tractus solitarius (NTS), and area postrema (AP) in wild-type and NPY-GFP mice. BIM-28131 was as effective as ghrelin in stimulating GH secretion, but more active than ghrelin in inducing feeding. It stimulated cFos activity similarly to ghrelin in the NTS and AP but was more powerful in the ArcN, suggesting that the super-agonist activity of BIM-28131 is mostly mediated in the ArcN. BIM-28163 antagonized ghrelin-induced GH secretion but not ghrelin-induced food consumption and cFos activation, rather it stimulated food intake and cFos activity without affecting GH secretion. The level of cFos activation was dependent on the region considered: BIM-28163 was as active as ghrelin in the NTS, but less active in the ArcN and AP. All compounds also induced cFos immunoreactivity in ArcN NPY neurons but BIM-28131 was the most active. In conclusion, these data demonstrate that two peptide analogs of ghrelin, BIM-28163, and BIM-28131, are powerful stimulators of appetite in mice, acting through pathways and key brain regions involved in the control of appetite that are only partially superimposable from those activated by ghrelin. A better understanding of the molecular pathways activated by these compounds could be useful in devising future therapeutic applications, such as for cachexia and anorexia.

Receptors of Peptides as Therapeutic Targets in Epilepsy Research

“…BIM-28131, a small peptide ghrelin agonist, and BIM-28163, a full-length ghrelin analog antagonist were used in some studies on hypothalamic actions of ghrelin [228]. Also, some peptidomimetics have been produced including the pseudotripeptide EP01572 (H-Aib-(D)-Trp-(D)-gTrp-formyl) with increased stability and oral bioavailability [229] even in human [230], and JMV 1843 [231] shown in (Fig.…”

New Perspectives on the Development of Antiobesity Drugs

“…However, results obtained in the presence of some ghrelin antagonists/inverse agonists showed that the effect on BW and feeding not always correlates with the in vitro actions on ghrelin receptor. A full-length ghrelin analog BIM-28163 (also called RM-28163), a selective antagonist at the ghrelin receptor, reduces pulsatile growth hormone (GH) secretion in rats, an effect exerted by ghrelin, but increases food intake and weight gain as effectively as ghrelin [77]. GSK-1614343, a ghrelin antagonist, was shown to be able to increase food intake and BW, effects abolished in the ghrelin receptor null mice [78].…”

Evaluation of Pharmacological Modification of Growth Hormone Secretagogue Receptor in a Mouse Model of Non-Obese Type 2 Diabetes Mellitus

“…Our results showed that the injections of ghrelin receptor antagonist significantly suppressed pulsatile GH secretion ( Figure 5.1A-C). Similarly, another ghrelin receptor antagonist BIM-28163 was reported to inhibit ghrelin-induced GH secretion but not ghrelin-induced food consumption (338). The reason for why GH secretion was inhibited while food intake was not inhibited upon chronic treatment in this study, is not clear.…”

“…In consistent with that, BIM-28163 appears to have greater activity in the NTS, however, is not as effective as ghrelin in stimulating cFos in the arcuate neurons (338). Some studies postulated that blocking the GHS-R1a with the antagonist may allow UAG to stimulate feeding through a GHS-R1a independent pathway (339).…”

“…Similarly, there have even been a number of reported GHS-R1a antagonists which exhibit orexigenic effects. Although the antagonist BIM-28163 inhibits GH secretion through blocking ghrelin-induced GHS-R1a activation, this compound elicits increases in food intake and body weight (338). Furthermore, GSK1614343 increased food intake and body weight in vivo, but knockout of the GHS-R1a abolished this effect, indicating that the antagonist was working via this receptor (192).…”