Oxyntomodulin (OXM) is a circulating gut hormone released post prandially from cells of the gastrointestinal mucosa in proportion to energy intake. It is derived from proglucagon. The other proglucagon (PG)-derived peptides include glucagon-like peptide-1, glucagon-like peptide-2 and glicentin. The gene encoding proglucagon, the biosynthetic precursor of glucagon, is expressed in the pancreatic islets and in endocrine cells of the gastrointestinal mucosa. All the above peptides are secreted into the blood in response to ingestion of carbohydrates and lipids. Annu Rev Physiol. 1997;59:257-71. Only Oxyntomodulin and GLP-1 have proven biological activity; Oxyntomodulin probably interacts with GLP-1 and glucagon receptors, although with lower affinity than GLP-1 itself, to effect a reduction in food intake. Circulating OXM levels are raised in conditions associated with anorexia.
Effects of OXM administration
When given ICV to rats, it inhibits food intake and promotes weight loss. Peripheral administration of OXM dose-dependently inhibits food intake without delaying gastric emptying. Peripheral OXM administration also inhibits fasting plasma Ghrelin. OXM injected directly into the arcuate nucleus produced a potent and sustained reduction in re-feeding after a fast. Seven-day peripheral administration of OXM caused a reduction in the rate of body weight gain and adiposity. Endocrinology. 2004 Jun;145(6):2687-95.
A randomized, double-blind, placebo-controlled, cross-over study in 13 healthy people with IV infusion of OXM demonstrated a significant reduction (approx 20%) in energy intake with significant hunger score reduction. This was effected without nausea or affecting palatability of food. Ghrelin levels were shown to be significantly suppressed by OXM. J Clin Endocrinol Metab. 2003 Oct;88(10):4696-701. A 4-week subcutaneous adminstration of Oxyntomodulin three times a day in obese and overweight subjects in a randomised controlled double blind study was shown to reduce food intake with a decrease in body weight by 0.45-kg per week. Diabetes. 2005 Aug;54(8):2390-5 A concomitant reduction in Leptin and increase in adiponectin was noted.
Mechanism of action:
C-fos immunoreactivity, a marker of neuronal activation, is increased in the arcuate nucleus when OXM was administered. Prior intra-arcuate administration of the glucagon-like peptide-1 (GLP-1) receptor antagonist, exendin(9-39) blocked the anorectic actions of peripherally administered OXM. This suggests that the arcuate nucleus, which lacks a complete blood-brain barrier, could be a potential site of action for circulating OXM. Endocrinology. 2001 Oct;142(10):4244-50.The actions of peripheral GLP-1, however, were not blocked by prior intra-arcuate administration of exendin(9-39), indicating the potential existence of different OXM and GLP-1 pathways. Circulating OXM may have a role in the regulation of food intake and body weight. Endocrinology. 2004 Jun;145(6):2687-95.
OXM inhibits pancreatic secretion at physiologic doses, through a vagal neural indirect mechanism, and probably through a glicentin-related peptide-specific receptor Pancreas. 2000 May;20(4):348-60 Oxyntomodulin has no effect on intestinal cell proliferation unlike GLP-2. Oxyntomodulin has inhibitory effects on gastrointestinal secretion (inhibiting both basal and postprandial acid secretion) and motility (decreased gastric emptying) Dig Dis Sci. 1989 Sep;34(9):1411-9.