Oxyntomodulin is a 37 amino acid peptide that contains the 29 amino acid sequence of glucagon followed by an 8 amino acid carboxyterminal extension. Radioimmunoassays using antisera that are not specific for both the C-and N-terminus of oxyntomodulin will also cross-react with glucagon, and possibly glicentin. Hence much of the earlier literature assessing circulating oxyntomodulin using non-specific assays may not be 100% accurate.
The structure of oxyntomodulin was elucidated in 1981 by Bataille, Mutt and colleagues, who showed that this peptide stimulated cAMP accumulation in a rat stomach preparation. Bioactive enteroglucagon (oxyntomodulin): present knowledge on its chemical structure and its biological activities. Peptides. 1981;2 Suppl 2:41-4. Subsequent isolation of the peptide from the pig ileal mucosa confirmed the relationship between oxyntomodulin, glucagon, and glicentin, as described in Evidence that enteroglucagon (II) is identical with the C-terminal sequence (residues 33-69) of glicentin. Biochem J. 1982 Dec 1;207(3):381-8.
As outlined below, oxyntomodulin may function as a dual GLP-1-GCGR agonist, as it is capable of signaling through both the glucagon (GCGR) and GLP-1 (GLP-1R) receptors. Whether oxyntomodulin may also require additional signal modules, in conjunction with the GCGR and/or GLP-1R, to transduce its effects in different tissues and cell types, remains enigmatic. Landgraf et. al identified oxyntomodulin as the most potent peptide agonist capable of resetting Per-2-directed luciferase rhythms in liver slices ex vivo. GLP-1 had no effect in this system, whereas glucagon exerted a modest transient effect but at much higher concetrations relative to oxyntomodulin. These actions of oxyntomodulin were phase-dependent ex vivo, and were blocked by co-administration of a GCGR antagonist. Oxyntomodulin induced the expression of Per1 and Per2 in WT and Glp1r-/- liver, and increased the binding of CREB to a CRE in the Per1 promoter. Oxyntomodulin also induced hepatic Per1 and Per2 expression in mice after i.v. injection at Zeitgeber time 3. Furthermore, administration of oxyntomodulin to WT mice during the rest phase, while housed in constant darkness, also produced phase delays of Per2 and Dbp mRNA rhythms in the liver. Phase delays were also detected in the expression patterns and rhythms of key genes controlling hepatic carbohydrate metabolism. Notably, food-mediated Per activation was partly inhibited by treatment with purified anti-OXM immunoneutralizing antisera in wild-type and in Glp1r-/- mice. Similarly, the food-induced phase delay in heptic clock gene expression was also partly attenuated by immunoneutralizing antiera against oxyntomodulin. Collectively, these data suggest that L cell-derived oxyntomodulin functions as a nutrient-activated metabolic synchronizer of hepatic clocks. Oxyntomodulin regulates resetting of the liver circadian clock by food 10.7554/eLife.06253
Several studies have demonstrated that oxyntomodulin inhibits meal-stimulated gastric acid secretion in rodents. See Oxyntomodulin and its C-terminal octapeptide inhibit liquid meal-stimulated acid secretion. Peptides. 1986;7 Suppl 1:253-6. These actions resemble those recently described for GLP-1 and GLP-2. Similarly, oxyntomodulin displays weak affinity for the glucagon receptor and may mimic glucagon actions in the liver and pancreas. See Oxyntomodulin (glicentin-(33-69)): pharmacokinetics, binding to liver cell membranes, effects on isolated perfused pig pancreas, and secretion from isolated perfused lower small intestine of pigs. Regul Pept. 1988 May;21(1-2):151-66.
Oxyntomodulin also mimics the effects of GLP-1 and GLP-2 on gastric acid secretion and gut motility. See Oxyntomodulin: a potential hormone from the distal gut. Pharmacokinetics and effects on gastric acid and insulin secretion in man. Eur J Clin Invest. 1988 Oct;18(5):499-503 and Oxyntomodulin from distal gut. Role in regulation of gastric and pancreatic functions. Dig Dis Sci. 1989 Sep;34(9):1411-9 and Inhibitory effect of the C-terminal octapeptide of oxyntomodulin on pentagastrin-stimulated gastric acid secretion in man. Scand J Gastroenterol. 1989 Dec;24(10):1238-42
Oxyntomodulin has also been shown to inhibit food intake following icv administration in rats. Injection of oxyntomodulin directly into the paraventricular nucleus also resulted in reduced food intake. Oxyntomodulin appears to inhibit food intake both prior to the onset of dark phase, as well as in fasted rats in the am. Remarkably, the anorectic actions of oxyntomodulin were blocked by the GLP-1 receptor antagonist exendin (9-39). Whether oxyntomodulin exerts these actions through the CNS GLP-1 receptor, or through an as yet unidentified oxyntomodulin receptor, was not definitively determined in these studies. See Oxyntomodulin inhibits food intake in the rat. Endocrinology. 2001 142(10):4244-50
In related studies, peripheral administration of oxyntomodulin dose-dependently inhibited both fast-induced and dark phase food intake, but unlike GLP-1, had no effect on gastric emptying. OXM also reduced levels of fasting ghrelin and increased c-fos immunoreactivity, in the arcuate nucleus (ARC). Repeated seven-day IP administration of OXM caused a reduction in the rate of body weight gain and adiposity in rats as described in Peripheral oxyntomodulin reduces food intake and body weight gain in rats. Endocrinology. 2004 Mar 4. Delivery of oxyntomodulin into the GI tract of overweight BALB/C mice through a bacterial plasmid delivery system was associated with reduced food intake and weight gain, despite no changes in plasma OXM, as described in Bifidobacterium as an oral delivery carrier of oxyntomodulin for obesity therapy: inhibitory effects on food intake and body weight in overweight mice Int J Obes (Lond). 2010 Jan 12.
Studies of OXM action in mice have demonstrated that although OXM can activate both the glucagon and GLP-1 receptors, the anorectic actions of OXM require only the GLP-1 receptor, as icv OXM inhibits food intake in Gcgr-/- mice, but the anorectic effects of OXM are completely absent in GLP-1R-/- mice. Furthermore, exendin-4, but not OXM, regulates energy expenditure in mice. Hence, OXM appears to be a weak agonist at the GLP-1 receptor, when used in pharmacological concentrations. See Oxyntomodulin and glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure. Gastroenterology. 2004 Aug;127(2):546-58. Oxyntomodulin also mimics many of the actions of GLP-1 on the islet b-cell, including stimulation of glucose-dependent insulin secretion and activation of cell survival pathways leading to reduced b-cell apoptosis as outlined The GLP-1 receptor agonist oxyntomodulin enhances b-cell function but does not inhibit gastric emptying in mice Endocrinology published July 31, 2008 as doi:10.1210/en.2008-0336. Allosteric modulation of the GLP-1R using the small molecule GLP-1 receptor modulator, 4-(3-benzyloxyphenyl)-2-ethylsulfinyl-6-(trifluoromethyl)pyrimidine (BETP) increased the affinity of OXM for the GLP-1R and potentiated the insulinotropic actions of GLP-1 during an IVGTT in Wistar rats in vivo. Experiments in vitro suggested that BET enhances OXM action to increase cAMP accumulation and b-arrestin recruitment Small Molecule Allosteric Modulation of the Glucagon-Like Peptide-1 Receptor Enhances the Insulinotropic Effect of Oxyntomodulin Mol Pharmacol. 2012 Aug 28
These conclusions regarding the GLP-1R-dependency of OXM were subsequently challenged by studies from Kosinski and colleagues who compared the effects of an OXM analogue (Q3-E substitution) in WT and Glp1r-/- mice, with and without co-administration of a Gcgr antagonist. Although the OXM analogu was virtually devoid of activity at the Gcgr in vitro, co-administration of the Gcgr antagonist Cpd A blunted the effects of the agonist on food intake and body weight loss in vivo. Nevertheless, neither OXM or OXMQE produced WT loss in Glp1r-/- mice and the Gcgr antagonist, Cpd A produced weight loss alone, when administered in vivo. Hence, interpretation of these findings remains challenging. The Glucagon Receptor is Involved in Mediating the Body Weight Lowering Effects of Oxyntomodulin Obesity (Silver Spring). 2012 Mar 16. doi: 10.1038/oby.2012.67
The anorectic properties of oxyntomodulin to normal healthy human subjects. A 90 minute OXM infusion (increasing circulating OXM from 60 to ~900 pM) significantly decreased the sensation of hunger and inhibited meal-related energy intake and decreased cumulative 12h energy intake, but not 24h energy intake. Intriguingly, OXM infusion also decreased circulating levels of ghrelin in the fasting and postprandial state. See Oxyntomodulin suppresses appetite and reduces food intake in humans. J Clin Endocrinol Metab. 2003 Oct;88(10):4696-701
A subsequent study examined the effects of OXM on food intake and energy expenditure in overweight and obese human subjects. Oxyntomodulin (400 nmol) was self-administered three times a day before each meal for 4 days, BMI 25-40. The identical study protocol was followed on 3 separate occasions, with self administration of saline (twice) or OXM, for a total of 9 injections. OXM reduced energy intake by ~ 17%, with no effect on water intake. Body weight was reduced by 0.5 kg over the 4 day study. OXM had no effect on resting energy expenditure, but did increase daily activity and total energy expenditure. OXM levels during saline injection were 41 and 63 pMol/L, fasting and postprandial,, versus 658 pMol/L postprandial after OXM injection. OXM also increased levels of preprandial insulin from 57 to 121 pMol. See Oxyntomodulin increases energy expenditure in addition to decreasing energy intake in overweight and obese humans: a randomised controlled trial. Int J Obes (Lond). 2006 Apr 18; [Epub ahead of print]
Similarly, although oxyntomodulin has been described as a regulator of intestinal hexose transport, these actions resemble properties described for GLP-2. Compare Enteric glucagon 37 rather than pancreatic glucagon 29 stimulates glucose absorption in rat intestine. Gastroenterology. 1998 Nov;115(5):1163-71 and Oxyntomodulin stimulates intestinal glucose uptake in rats. Gastroenterology. 1997 Jun;112(6):1961-7 versus The effect of GIP and glucagon-like peptides on intestinal basolateral membrane hexose transport. Am J Physiol. 1996 Sep;271(3 Pt 1):G477-82 and Upregulation of SGLT-1 transport activity in rat jejunum induced by GLP-2 infusion in vivo. Am J Physiol. 1997 Dec;273(6 Pt 2):R1965-71
Although the precise mechanisms utilized by oxyntomodulin for transduction of various biological actions remain unclear, occasional studies demonstrate a dissociation between actions of oxyntomodulin and those of GLP-1. For example, see Oxyntomodulin inhibits pancreatic secretion through the nervous system in rats. Pancreas. 2000 20(4):348-60.
The importance of oxyntomodulin as a biologically active peptide would be greatly strengthened by the identification of a separate oxyntomodulin receptor, or by studies employing specific oxyntomodulin antagonists or immunoneutralizing antisera that blocked actions of oxyntomodulin but not glucagon or GLP-1.
GLP-1 exerts multiple actions on the cardiovascular system via the known GLP-1 and the cardiovascular system
The cardiovascular effects of OXM were examined in conscious and freely moving mice. Peripherally administered OXM significantly increased HR in wildtype mice, and even in Glp1R -/- mice. Hence OXM modulates murine intrinsic HR through a GLP-1R independent mechanism, perhaps via the glucagon receptor or an unidentified OXM receptor. See Oxyntomodulin increases intrinsic heart rate in mice independent of the glucagon-like peptide-1 receptor. Am J Physiol Regul Integr Comp Physiol. 2006 Oct 12;