Peripheral oxyntomodulin reduces food intake and body weight gain in rats.
Oxyntomodulin (OXM) is a circulating gut hormone released post prandially from cells of the gastrointestinal mucosa. Given intracerebroventricularly to rats, it inhibits food intake and promotes weight loss. Here we report that peripheral (ip) administration of OXM dose-dependently inhibited both fast-induced and dark-phase food intake without delaying gastric emptying. Peripheral OXM administration also inhibited fasting plasma ghrelin. In addition, there was a significant increase in c-fos immunoreactivity, a marker of neuronal activation, in the arcuate nucleus (ARC). OXM injected directly into the ARC caused a potent and sustained reduction in refeeding after a fast. The anorectic actions of ip OXM were blocked by prior intra-ARC administration of the glucagon-like peptide-1 (GLP-1) receptor antagonist, exendin(9-39), suggesting that the ARC, lacking a complete blood-brain barrier, could be a potential site of action for circulating OXM. The actions of ip GLP-1, however, were not blocked by prior intra-ARC administration of exendin(9-39), indicating the potential existence of different OXM and GLP-1 pathways. Seven-day ip administration of OXM caused a reduction in the rate of body weight gain and adiposity. Circulating OXM may have a role in the regulation of food intake and body weight.
Endocrine Unit, Department of Metabolic Medicine, Imperial College Faculty of Medicine, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom.
Catherine L
CL
Dakin
Caroline J
CJ
Small
Rachel L
RL
Batterham
Nicola M
NM
Neary
Mark A
MA
Cohen
Michael
M
Patterson
Mohammad A
MA
Ghatei
Stephen R
SR
Bloom
D000818:Animals; D001067:Appetite Depressants / Q000494:pharmacology; D001111:Arcuate Nucleus of Hypothalamus / Q000378:metabolism; D003624:Darkness; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004435:Eating / Q000187:drug effects / Q000502:physiology*; D005215:Fasting; D005746:Gastric Emptying / Q000502:physiology; D054439:Ghrelin; D005934:Glucagon / Q000008:administration & dosage; D052216:Glucagon-Like Peptide 1; D000067757:Glucagon-Like Peptide-1 Receptor; D004763:Glucagon-Like Peptides / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D007267:Injections; D007274:Injections, Intraperitoneal; D008297:Male; D053772:Oxyntomodulin; D010446:Peptide Fragments / Q000008:administration & dosage; D036361:Peptide Hormones / Q000097:blood; D017440:Photoperiod; D011498:Protein Precursors / Q000008:administration & dosage; D051381:Rats; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000502:physiology; D015430:Weight Gain / Q000187:drug effects / Q000502:physiology*
D001067:Appetite Depressants; C000593833:GLP1R protein, human; D054439:Ghrelin; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D053772:Oxyntomodulin; D010446:Peptide Fragments; D036361:Peptide Hormones; D011498:Protein Precursors; D018027:Receptors, Glucagon; D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1; D005934:Glucagon