Treatments in Endocrinology

, Volume 5, Issue 5, pp 265–272 | Cite as


A Novel Potential Treatment for Obesity
  • Maralyn R. Druce
  • Stephen R. Bloom
Leading Article


The prevalence of obesity is increasing rapidly and the associated morbidity and mortality has led to an urgent need for potential therapeutic targets to reduce appetite and food intake. Gut hormones released after eating that coordinate digestive activity and promote satiety are novel potential treatments for obesity. Oxyntomodulin is a gut hormone that is produced by the L cells in the small intestine and reduces food intake. It is timely to review some of the original literature on oxyntomodulin, to evaluate what is already known about the peptide, and also to set the recent findings on its effects on food intake and bodyweight into context.

Recent studies have shown that long-term peripheral administration of oxyntomodulin to rats leads to reduced food intake and reduced weight gain. Studies in humans have demonstrated that acute administration reduces food intake by 19%. When given preprandially by subcutaneous injection three times daily, oxyntomodulin resulted in a reduction in food intake and mean weight loss of 2.8kg over 4 weeks. Oxyntomodulin thus represents a potential therapy for obesity.

The mechanism of action of oxyntomodulin is not known. Current evidence suggests that it acts via the glucagon-like peptide 1 (GLP-1) receptor. There may be an additional receptor in the gastric mucosa mediating its effects on gastric acid secretion. Although oxyntomodulin probably acts via the GLP-1 receptor, the two peptides differentially regulate food intake and energy expenditure in the mouse.

Oxyntomodulin represents a potential therapy for obesity. Further work will help to clarify its mechanisms of action.


Glucagon Gastric Emptying Acid Secretion Gastric Acid Secretion Exenatide 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Flegal KM, Carroll MD, Ogden CL, et al. Prevalence and trends in obesity among US adults, 1999–2000. JAMA 2002; 288: 1723–7PubMedCrossRefGoogle Scholar
  2. 2.
    Joint Health Survey (on behalf of the Department of Health). Health survey for England 2000. London: The Stationery Office, 2001Google Scholar
  3. 3.
    Kopelman PG. Obesity as a medical problem. Nature 2000; 404: 635–43PubMedGoogle Scholar
  4. 4.
    Foxcroft DR, Milne R. Orlistat for the treatment of obesity: rapid review and cost-effectiveness model. Obes Rev 2000; 1: 121–6PubMedCrossRefGoogle Scholar
  5. 5.
    Finer N. Sibutramine: its mode of action and efficacy. Int J Obes Relat Metab Disord 2002; 26 Suppl. 4: S29–33PubMedCrossRefGoogle Scholar
  6. 6.
    Finer N. Pharmacotherapy of obesity. Best Pract Res Clin Endocrinol Metab 2002; 16: 717–42PubMedCrossRefGoogle Scholar
  7. 7.
    Kopelman PG. Clinical treatment of obesity: are drugs and surgery the answer? Proc Nutr Soc 2005; 64: 65–71PubMedCrossRefGoogle Scholar
  8. 8.
    Wynne K, Stanley S, McGowan B, et al. Appetite control. J Endocrinol 2005; 184: 291–318PubMedCrossRefGoogle Scholar
  9. 9.
    Bloom S, Wynne K, Chaudhri O. Gut feeling: the secret of satiety? Clin Med 2005 Mar-Apr; 5(2): 147–52PubMedGoogle Scholar
  10. 10.
    Schwartz MW, Woods SC, Porte Jr D, et al. Central nervous system control of food intake. Nature 2000; 404: 661–71PubMedGoogle Scholar
  11. 11.
    Holst JJ. Evidence that enteroglucagon (II) is identical with the C-terminal sequence (residues 33–69) of glicentin. Biochem J 1982; 207: 381–8PubMedGoogle Scholar
  12. 12.
    Bataille D, Coudray AM, Carlqvist M, et al. Isolation of glucagon-37 (bioactive enteroglucagon/oxyntomodulin) from porcine jejuno-ileum: isolation of the peptide. FEBS Lett 1982; 146: 73–8PubMedCrossRefGoogle Scholar
  13. 13.
    Bataille D, Gespach C, Coudray AM, et al. ‘Enteroglucagon’: a specific effect on gastric glands isolated from the rat fundus: evidence for an ‘oxyntomodulin’ action. Biosci Rep 1981; 1: 151–5PubMedCrossRefGoogle Scholar
  14. 14.
    Dubrasquet M, Bataille D, Gespach C. Oxyntomodulin (glucagon-37 or bioactive enteroglucagon): a potent inhibitor of pentagastrin-stimulated acid secretion in rats. Biosci Rep 1982; 2: 391–5PubMedCrossRefGoogle Scholar
  15. 15.
    Jarrousse C, Audousset-Puech MP, Dubrasquet M, et al. Oxyntomodulin (glucagon-37) and its C-terminal octapeptide inhibit gastric acid secretion. FEBS Lett 1985; 188: 81–4PubMedCrossRefGoogle Scholar
  16. 16.
    Schjoldager BT, Baldissera FG, Mortensen PE, et al. Oxyntomodulin: a potential hormone from the distal gut: pharmacokinetics and effects on gastric acid and insulin secretion in man. Eur J Clin Invest 1988; 18: 499–503PubMedCrossRefGoogle Scholar
  17. 17.
    Schjoldager B, Mortensen PE, Myhre J, et al. Oxyntomodulin from distal gut: role in regulation of gastric and pancreatic functions. Dig Dis Sci 1989; 34: 1411–9PubMedCrossRefGoogle Scholar
  18. 18.
    Dakin CL, Gunn I, Small CJ, et al. Oxyntomodulin inhibits food intake in the rat. Endocrinology 2001; 142: 4244–50PubMedCrossRefGoogle Scholar
  19. 19.
    Dakin CL, Small CJ, Park AJ, et al. Repeated ICV administration of oxyntomodulin causes a greater reduction in body weight gain than in pair-fed rats. Am J Physiol Endocrinol Metab 2002; 283: E1173–7PubMedGoogle Scholar
  20. 20.
    Dakin CL, Small CJ, Batterham RL, et al. Peripheral oxyntomodulin reduces food intake and body weight gain in rats. Endocrinology 2004; 145: 2687–95PubMedCrossRefGoogle Scholar
  21. 21.
    Cohen MA, Ellis SM, Le Roux CW, et al. Oxyntomodulin suppresses appetite and reduces food intake in humans. J Clin Endocrinol Metab 2003; 88: 4696–701PubMedCrossRefGoogle Scholar
  22. 22.
    Wynne K, Park AJ, Small CJ, et al. Subcutaneous oxyntomodulin reduces body weight in overweight and obese subjects: a double-blind, randomized, controlled trial. Diabetes 2005; 54: 2390–5PubMedCrossRefGoogle Scholar
  23. 23.
    Holst JJ. Enteroglucagon. Annu Rev Physiol 1997; 59: 257–71PubMedCrossRefGoogle Scholar
  24. 24.
    Drucker DJ. Minireview: the glucagon-like peptides. Endocrinology 2001; 142: 521–7PubMedCrossRefGoogle Scholar
  25. 25.
    Blache P, Kervran A, Bataille D. Oxyntomodulin and glicentin: brain-gut peptides in the rat. Endocrinology 1988; 123: 2782–7PubMedCrossRefGoogle Scholar
  26. 26.
    Ghatei MA, Uttenthal LO, Bryant MG, et al. Molecular forms of glucagon-like immunoreactivity in porcine intestine and pancreas. Endocrinology 1983; 112: 917–23PubMedCrossRefGoogle Scholar
  27. 27.
    Le Quellec A, Kervran A, Blache P, et al. Oxyntomodulin-like immunoreactivity: diurnal profile of a new potential enterogastrone. J Clin Endocrinol Metab 1992; 74: 1405–9PubMedCrossRefGoogle Scholar
  28. 28.
    Ghatei MA, Uttenthal LO, Christofides ND, et al. Molecular forms of human enteroglucagon in tissue and plasma: plasma responses to nutrient stimuli in health and in disorders of the upper gastrointestinal tract. J Clin Endocrinol Metab 1983; 57: 488–95PubMedCrossRefGoogle Scholar
  29. 29.
    Mentlein R, Gallwitz B, Schmidt WE. Dipeptidyl-peptidase IV hydrolyses gastric inhibitory polypeptide, glucagon-like peptide-1(7-36)amide, peptide histidine methionine and is responsible for their degradation in human serum. Eur J Biochem 1993; 214: 829–35PubMedCrossRefGoogle Scholar
  30. 30.
    Zhu L, Tamvakopoulos C, Xie D, et al. The role of dipeptidyl peptidase IV in the cleavage of glucagon family peptides: in vivo metabolism of pituitary adenylate cyclase activating polypeptide-(1-38). J Biol Chem 2003; 278: 22418–23PubMedCrossRefGoogle Scholar
  31. 31.
    Pospisilik JA, Hinke SA, Pederson RA, et al. Metabolism of glucagon by dipeptidyl peptidase IV (CD26). Regul Pept 2001; 96: 133–41PubMedCrossRefGoogle Scholar
  32. 32.
    Hinke SA, Pospisilik JA, Demuth HU, et al. Dipeptidyl peptidase IV (DPIV/CD26) degradation of glucagon: characterization of glucagon degradation products and DPIV-resistant analogs. J Biol Chem 2000; 275: 3827–34PubMedCrossRefGoogle Scholar
  33. 33.
    Deacon CF, Kelstrup M, Trebbien R, et al. Differential regional metabolism of glucagon in anesthetized pigs. Am J Physiol Endocrinol Metab 2003; 285: E552–60PubMedGoogle Scholar
  34. 34.
    Le Quellec A, Clapie M, Callamand P, et al. Circulating oxyntomodulin-like immunoreactivity in healthy children and children with celiac disease. J Pediatr Gastroenterol Nutr 1998; 27: 513–8PubMedCrossRefGoogle Scholar
  35. 35.
    Besterman HS, Cook GC, Sarson DL, et al. Gut hormones in tropical malabsorption. BMJ 1979; 2: 1252–5PubMedCrossRefGoogle Scholar
  36. 36.
    Holst JJ, Sorensen TI, Andersen AN, et al. Plasma enteroglucagon after jejunoileal bypass with 3: 1 or 1: 3 jejunoileal ratio. Scand J Gastroenterol 1979; 14: 205–7PubMedCrossRefGoogle Scholar
  37. 37.
    Sarson DL, Scopinaro N, Bloom SR. Gut hormone changes after jejunoileal (JIB) or biliopancreatic (BPB) bypass surgery for morbid obesity. Int J Obes 1981; 5: 471–80PubMedGoogle Scholar
  38. 38.
    Le Quellec A, Kervran A, Blache P, et al. Diurnal profile of oxyntomodulin-like immunoreactivity in duodenal ulcer patients. Scand J Gastroenterol 1993; 28: 816–20PubMedCrossRefGoogle Scholar
  39. 39.
    Naslund E, King N, Mansten S, et al. Prandial subcutaneous injections of glucagon-like peptide-1 cause weight loss in obese human subjects. Br J Nutr 2004; 91: 439–46PubMedCrossRefGoogle Scholar
  40. 40.
    Zander M, Madsbad S, Madsen JL, et al. Effect of 6-week course of glucagon-like peptide 1 on glycaemic control, insulin sensitivity, and beta-cell function in type 2 diabetes: a parallel-group study. Lancet 2002; 359: 824–30PubMedCrossRefGoogle Scholar
  41. 41.
    Poon T, Nelson P, Shen L, et al. Exenatide improves glycemic control and reduces body weight in subjects with type 2 diabetes: a dose-ranging study. Diabetes Technol Ther 2005; 7: 467–77PubMedCrossRefGoogle Scholar
  42. 42.
    DeFronzo RA, Ratner RE, Han J, et al. Effects of exenatide (exendin-4) on glycemic control and weight over 30 weeks in metformin-treated patients with type 2 diabetes. Diabetes Care 2005; 28: 1092–100PubMedCrossRefGoogle Scholar
  43. 43.
    Halatchev IG, Cone RD. Peripheral administration of PYY(3-36) produces conditioned taste aversion in mice. Cell Metab 2005; 1: 159–68PubMedCrossRefGoogle Scholar
  44. 44.
    Thiele TE, van Dijk G, Campfield LA, et al. Central infusion of GLP-1, but not leptin, produces conditioned taste aversions in rats. Am J Physiol 1997; 272: R726–30PubMedGoogle Scholar
  45. 45.
    Baggio LL, Huang Q, Brown TJ, et al. Oxyntomodulin and glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure. Gastroenterology 2004; 127: 546–58PubMedCrossRefGoogle Scholar
  46. 46.
    Wynne KM, Park AJ, Small CJ, et al. Oxyntomodulin increases energy expenditure in addition to decreasing energy intake in overweight and obese humans: a randomised controlled trial. Int J Obes (Lond). Epub 2006 Apr 18Google Scholar
  47. 47.
    Schepp W, Dehne K, Riedel T, et al. Oxyntomodulin: a cAMP-dependent stimulus of rat parietal cell function via the receptor for glucagon-like peptide-1 (7-36)NH2. Digestion 1996; 57: 398–405PubMedCrossRefGoogle Scholar
  48. 48.
    Jarrousse C, Carles-Bonnet C, Niel H, et al. Inhibition of gastric acid secretion by oxyntomodulin and its 19–37 fragment in the conscious rat. Am J Physiol 1993; 264: G816–23PubMedGoogle Scholar
  49. 49.
    Carles-Bonnet C, Martinez J, Jarrousse C, et al. H-Lys-Arg-Asn-Lys-Asn-Asn-OH is the minimal active structure of oxyntomodulin. Peptides 1996; 17: 557–61PubMedCrossRefGoogle Scholar
  50. 50.
    Jarrousse C, Niel H, Audousset-Puech MP, et al. Oxyntomodulin and its C-terminal octapeptide inhibit liquid meal-stimulated acid secretion. Peptides 1986; 7 Suppl. 1: 253–6PubMedCrossRefGoogle Scholar
  51. 51.
    Carles-Bonnet C, Jarrousse C, Niel H, et al. Oxyntomodulin and its (19-37) and (30-37) fragments inhibit histamine-stimulated gastric acid secretion in the conscious rat. Eur J Pharmacol 1991; 203: 245–52PubMedCrossRefGoogle Scholar
  52. 52.
    Gehl J, Jeppesen JL, Poulsen SS, et al. The gastric acid secretagogue gastrin-releasing peptide and the inhibitor oxyntomodulin do not exert their effect directly on the parietal cell in the rat. Digestion 1988; 40: 144–51PubMedCrossRefGoogle Scholar
  53. 53.
    Gros L, Demirpence E, Jarrousse C, et al. Characterization of binding sites for oxyntomodulin on a somatostatin-secreting cell line (RIN T3). Endocrinology 1992; 130: 1263–70PubMedCrossRefGoogle Scholar
  54. 54.
    Tani T, Le Quellec A, Jarrousse C, et al. Oxyntomodulin and related peptides control somatostatin secretion in RIN T3 cells. Biochim Biophys Acta 1991; 1095: 249–54PubMedCrossRefGoogle Scholar
  55. 55.
    Dubrasquet JM, Audousset-Puech MP, Martinez J, et al. Somatostatin enhances the inhibitory effect of oxyntomodulin and its C-terminal octapeptide on acid secretion. Peptides 1986; 7 Suppl. 1: 257–9PubMedCrossRefGoogle Scholar
  56. 56.
    Beauclair F, Eto B, Pansu D, et al. Oxyntomodulin reduces hydromineral transport through rat small intestine. Dig Dis Sci 1998; 43: 1814–23PubMedCrossRefGoogle Scholar
  57. 57.
    Biedzinski TM, Bataille D, Devaux MA, et al. The effect of oxyntomodulin (glucagon-37) and glucagon on exocrine pancreatic secretion in the conscious rat. Peptides 1987; 8: 967–72PubMedCrossRefGoogle Scholar
  58. 58.
    Anini Y, Jarrousse C, Chariot J, et al. Oxyntomodulin inhibits pancreatic secretion through the nervous system in rats. Pancreas 2000; 20: 348–60PubMedCrossRefGoogle Scholar
  59. 59.
    Rodier G, Magous R, Mochizuki T, et al. Effect of glicentin, oxyntomodulin and related peptides on isolated gastric smooth muscle cells. Pflugers Arch 1997; 434: 729–34PubMedCrossRefGoogle Scholar
  60. 60.
    Rodier G, Magous R, Mochizuki T, et al. A target cell to oxyntomodulin and glicentin: the antral smooth muscle cell. Ann N Y Acad Sci 1998; 865: 458–62PubMedCrossRefGoogle Scholar
  61. 61.
    Rodier G, Magous R, Mochizuki T, et al. Glicentin and oxyntomodulin modulate both the phosphoinositide and cyclic adenosine monophosphate signaling pathways in gastric myocytes. Endocrinology 1999; 140: 22–8PubMedCrossRefGoogle Scholar
  62. 62.
    Pellissier S, Sasaki K, Le Nguyen D, et al. Oxyntomodulin and glicentin are potent inhibitors of the fed motility pattern in small intestine. Neurogastroenterol Motil 2004; 16: 455–63PubMedCrossRefGoogle Scholar
  63. 63.
    Baldissera FG, Holst JJ, Knuhtsen S, et al. 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; 21: 151–66PubMedCrossRefGoogle Scholar
  64. 64.
    Jarrousse C, Bataille D, Jeanrenaud B. A pure enteroglucagon, oxyntomodulin (glucagon 37), stimulates insulin release in perfused rat pancreas. Endocrinology 1984; 115: 102–5PubMedCrossRefGoogle Scholar
  65. 65.
    Schmidtler J, Dehne K, Allescher HD, et al. Rat parietal cell receptors for GLP-1- (7-36) amide: northern blot, cross-linking, and radioligand binding. Am J Physiol 1994; 267: G423–32PubMedGoogle Scholar
  66. 66.
    Fehmann HC, Jiang J, Schweinfurth J, et al. Stable expression of the rat GLP-I receptor in CHO cells: activation and binding characteristics utilizing GLP-I(7-36)-amide, oxyntomodulin, exendin-4, and exendin(9-39). Peptides 1994; 15: 453–6PubMedCrossRefGoogle Scholar
  67. 67.
    Gros L, Thorens B, Bataille D, et al. Glucagon-like peptide-1-(7-36) amide, oxyntomodulin, and glucagon interact with a common receptor in a somatostatin-secreting cell line. Endocrinology 1993; 133: 631–8PubMedCrossRefGoogle Scholar
  68. 68.
    Turton MD, O’Shea D, Gunn I, et al. A role for glucagon-like peptide-1 in the central regulation of feeding. Nature 1996; 379: 69–72PubMedCrossRefGoogle Scholar
  69. 69.
    Carles-Bonnet C, Jarrousse C, Niel H, et al. N-acetyl oxyntomodulin30-37: pharmacokinetics and activity on gastric acid secretion. Naunyn Schmiedebergs Arch Pharmacol 1992; 345: 57–63PubMedCrossRefGoogle Scholar

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© Adis Data Information BV 2006

Authors and Affiliations

  1. 1.Department of Metabolic Medicine, Hammersmith Hospital CampusImperial College LondonLondonUK

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