Small-molecule ghrelin receptor antagonists improve glucose tolerance, suppress appetite, and promote weight loss.
Ghrelin, through action on its receptor, GH secretagogue receptor type 1a (GHS-R1a), exerts a variety of metabolic functions including stimulation of appetite and weight gain and suppression of insulin secretion. In the present study, we examined the effects of novel small-molecule GHS-R1a antagonists on insulin secretion, glucose tolerance, and weight loss. Ghrelin dose-dependently suppressed insulin secretion from dispersed rat islets. This effect was fully blocked by a GHS-R1a antagonist. Consistent with this observation, a single oral dose of a GHS-R1a antagonist improved glucose homeostasis in an ip glucose tolerance test in rat. Improvement in glucose tolerance was attributed to increased insulin secretion. Daily oral administration of a GHS-R1a antagonist to diet-induced obese mice led to reduced food intake and weight loss (up to 15%) due to selective loss of fat mass. Pair-feeding experiments indicated that weight loss was largely a consequence of reduced food intake. The impact of a GHS-R1a antagonist on gastric emptying was also examined. Although the GHS-R1a antagonist modestly delayed gastric emptying at the highest dose tested (10 mg/kg), delayed gastric emptying does not appear to be a requirement for weight loss because lower doses produced weight loss without an effect on gastric emptying. Consistent with the hypothesis that ghrelin regulates feeding centrally, the anorexigenic effects of potent GHS-R1a antagonists in mice appeared to correspond with their brain exposure. These observations demonstrate that GHS-R1a antagonists have the potential to improve the diabetic condition by promoting glucose-dependent insulin secretion and promoting weight loss.
Bayer Research Center, Bayer Healthcare, West Haven, CT 06516, USA. william.esler@pfizer.com
William P
WP
Esler
Joachim
J
Rudolph
Thomas H
TH
Claus
Weifeng
W
Tang
Nicole
N
Barucci
Su-Ellen
SE
Brown
William
W
Bullock
Michelle
M
Daly
Lynn
L
Decarr
Yaxin
Y
Li
Lucinda
L
Milardo
David
D
Molstad
Jian
J
Zhu
Stephen J
SJ
Gardell
James N
JN
Livingston
Laurel J
LJ
Sweet
D000818:Animals; D001066:Appetite / Q000187:drug effects*; D001067:Appetite Depressants / Q000494:pharmacology / Q000627:therapeutic use*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D054439:Ghrelin / Q000037:antagonists & inhibitors; D018149:Glucose Intolerance / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D010880:Piperidines / Q000494:pharmacology / Q000627:therapeutic use; D052999:Quinazolinones / Q000494:pharmacology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D054440:Receptors, Ghrelin / Q000037:antagonists & inhibitors*; D015431:Weight Loss / Q000187:drug effects*
D001067:Appetite Depressants; D054439:Ghrelin; D007004:Hypoglycemic Agents; D010880:Piperidines; D052999:Quinazolinones; D054440:Receptors, Ghrelin; C524424:YIL 781; C524425:YIL 870