Hypothalamic injection of oxyntomodulin suppresses circulating ghrelin-like immunoreactivity.
Ghrelin is a gastric peptide that regulates appetite and GH secretion. Circulating ghrelin levels are elevated by fasting and suppressed postprandially. However, the mechanisms regulating circulating ghrelin levels are unclear. Oxyntomodulin is an anorexic peptide hormone released from L cells in the gut. We investigated the effects of intracerebroventricular (icv) administration of oxyntomodulin on circulating ghrelin levels. The icv administration of 1, 3, or 10 nmol oxyntomodulin reduced circulating acylated and total (acylated and des-acylated) ghrelin 60 min after icv injection. Administration of 1 nmol oxyntomodulin directly into the arcuate nucleus of the hypothalamus significantly reduced total and acylated ghrelin levels, and administration of 3 nmol oxyntomodulin into the lateral ventricle induced c-fos mRNA expression in arcuate nucleus neurons expressing the glucagon-like peptide-1 (GLP-1) receptor. In a final study, the reduction in total ghrelin observed after icv injection of 3 nmol oxyntomodulin was blocked by coadministration of the GLP-1 receptor antagonist exendin (9-39). These studies suggest oxyntomodulin reduces peripheral ghrelin levels via GLP-1 receptor-dependent hypothalamic pathways. Postprandial release of anorexic gut hormones may thus act centrally to contribute to the postprandial reduction in circulating ghrelin.
Department of Metabolic Medicine, Hammersmith Hospital, Imperial College London, London W12 0NN, United Kingdom.
Michael
M
Patterson
Kevin G
KG
Murphy
Sejal R
SR
Patel
Neekhil A
NA
Patel
Hannah C
HC
Greenwood
Jenny H
JH
Cooke
Daniel
D
Campbell
Gavin A
GA
Bewick
Mohammad A
MA
Ghatei
Stephen R
SR
Bloom
D000818:Animals; D001786:Blood Glucose / Q000187:drug effects; D004435:Eating / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D015870:Gene Expression / Q000187:drug effects; D054439:Ghrelin / Q000097:blood*; D000067757:Glucagon-Like Peptide-1 Receptor; D007031:Hypothalamus / Q000187:drug effects* / Q000378:metabolism*; D007267:Injections; D007328:Insulin / Q000097:blood; D008297:Male; D051379:Mice; D053772:Oxyntomodulin / Q000008:administration & dosage / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics; D011863:Radioimmunoassay; D051381:Rats; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000037:antagonists & inhibitors / Q000378:metabolism
D001786:Blood Glucose; D054439:Ghrelin; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D053772:Oxyntomodulin; D010446:Peptide Fragments; D016760:Proto-Oncogene Proteins c-fos; D018027:Receptors, Glucagon; C083773:exendin (9-39)