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  • Original Article
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Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures

International Journal of Obesity volume 30, pages 1332–1340 (2006)Cite this article

Abstract

Background:

Exenatide (exendin-4) is an incretin mimetic currently marketed as an antidiabetic agent for patients with type 2 diabetes. In preclinical models, a reduction in body weight has also been shown in low-fat-fed, leptin receptor-deficient rodents.

Objective:

To more closely model the polygenic and environmental state of human obesity, we characterized the effect of exenatide on food intake and body weight in high-fat-fed, normal (those with an intact leptin signaling system) rodents. As glucagon-like peptide-1 receptor agonism has been found to elicit behaviors associated with visceral illness in rodents, we also examined the effect of peripheral exenatide on kaolin consumption and locomotor activity.

Methods and results:

High-fat-fed C57BL/6 mice and Sprague–Dawley rats were treated with exenatide (3, 10 and 30 μg/kg/day) for 4 weeks via subcutaneously implanted osmotic pumps. Food intake and body weight were assessed weekly. At 4 weeks, body composition and plasma metabolic profiles were measured. Kaolin consumption and locomotor activity were measured in fasted Sprague–Dawley rats following a single intraperitoneal injection of exenatide (0.1–10 μg/kg). Exenatide treatment in mice and rats dose-dependently decreased food intake and body weight; significant reductions in body weight gain were observed throughout treatment at 10 and 30 μg/kg/day (P<0.05). Decreased body weight gain was associated with a significant decrease in fat mass (P<0.05) with sparing of lean tissue. Plasma cholesterol, triglycerides and insulin were also significantly reduced (P<0.05). Exenatide at 10 μg/kg significantly reduced food intake (P<0.05) but failed to induce kaolin intake. In general, locomotor activity was reduced at doses of exenatide that decreased food intake, although a slightly higher dose was required to produce significant changes in activity.

Conclusion:

Systemic exenatide reduces body weight gain in normal, high-fat-fed rodents, a model that parallels human genetic variation and food consumption patterns, and may play a role in metabolic pathways mediating food intake.

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References

  1. Eng J, Kleinman WA, Singh L, Singh G, Raufman JP . Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom: further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem 1992; 267: 7402–7405.

    CAS  PubMed  Google Scholar 

  2. Göke R, Fehmann HC, Linn T, Schmidt H, Krause M, Eng J et al. Exendin-4 is a high potency agonist and truncated exendin-(9-39)-amide an antagonist at the glucagon-like peptide 1-(7-36)- amide receptor of insulin-secreting beta-cells. J Biol Chem 1993; 268: 19650–19655.

    PubMed  Google Scholar 

  3. Thorens B . Expression cloning of the pancreatic β cell receptor for the gluco-incretin hormone glucagon-like peptide 1. Proc Natl Acad Sci USA 1992; 89: 8641–8645.

    Article  CAS  Google Scholar 

  4. Chen YE, Drucker DJ . Tissue specific expression of unique mRNAs that encode proglucagon-derived peptides or exendin 4 in the lizard. J Biol Chem 1997; 272: 4108–4115.

    Article  CAS  Google Scholar 

  5. Parkes D, Jodka C, Smith P, Nayak S, Rinehart L, Gingerich R et al. Pharmacokinetic actions of exendin-4 in the rat: comparison with glucagon-like peptide-1. Drug Dev Res 2001; 53: 260–267.

    Article  CAS  Google Scholar 

  6. Young AA, Gedulin BR, Bhavsar S, Bodkin N, Jodka C, Hansen B et al. Glucose-lowering and insulin-sensitizing actions of exendin-4: studies in obese diabetic (ob/ob, db/db) mice, diabetic fatty Zucker rats, and diabetic rhesus monkeys (Macaca mulatta). Diabetes 1999; 48: 1026–1034.

    Article  CAS  Google Scholar 

  7. Drucker DJ . Enhancing incretin action for the treatment of type 2 diabetes. Diabetes Care 2003; 26: 2929–2940.

    Article  CAS  Google Scholar 

  8. Holz GG, Chepurny OG . Glucagon-like peptide-1 synthetic analogs: new therapeutic agents for use in the treatment of diabetes mellitus. Curr Med Chem 2003; 10: 2471–2483.

    Article  CAS  Google Scholar 

  9. Nauck MA . Glucagon-like peptide 1 (GLP-1) in the treatment of diabetes. Horm Metab Res 2004; 36: 852–858.

    Article  CAS  Google Scholar 

  10. Buse JB, Henry RR, Han J, Kim DD, Fineman MS, Baron AD . Effects of exenatide (exendin-4) on glycemic control over 30 weeks in sulfonylurea-treated patients with type 2 diabetes. Diabetes Care 2004; 27: 2628–2635.

    Article  CAS  Google Scholar 

  11. Defronzo RA, Ratner RE, Han J, Kim D, Fineman MS, Baron AD . 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: 1092–1100.

    Article  CAS  Google Scholar 

  12. Kendall DM, Riddle MC, Rosenstock J, Zhuang D, Kim DD, Fineman MS et al. Effects of exenatide (exendin-4) on glycemic control over 30 weeks in patients with type 2 diabetes mellitus treated with metformin and a sulfonylurea. Diabetes Care 2005; 28: 1083–1091.

    Article  CAS  Google Scholar 

  13. Eng J, Gutterman V, Nicolis C . Exendin(9–39)amide inhibits the insulin secretagogue activity of exendin 4 and GLP-1 but enhances that of glucagon in dogs. Digestion 1993; 54: 354–367.

    Article  Google Scholar 

  14. Mojsov S, Weir GC, Habener JF . Insulinotropin: glucagon-like peptide 1 (7–37) co-encoded in the glucagon gene is a potent stimulator of insulin release in the perfused rat pancreas. J Clin Invest 1987; 79: 616–619.

    Article  CAS  Google Scholar 

  15. Kolterman OG, Buse JB, Fineman MS, Gaines E, Heintz S, Bicsak TA et al. Synthetic exendin-4 (exenatide) significantly reduces postprandial and fasting plasma glucose in subjects with type 2 diabetes. J Clin Endocrinol Metab 2003; 88: 3082–3089.

    Article  CAS  Google Scholar 

  16. Kolterman OG, Kim DD, Shen L, Ruggles JA, Nielsen LL, Fineman MS et al. Pharmacokinetics, pharmacodynamics, and safety of exenatide in patients with type 2 diabetes mellitus. Am J Health Syst Pharm 2005; 62: 173–181.

    Article  CAS  Google Scholar 

  17. Degn KB, Brock B, Juhl CB, Djurhuus CB, Grubert J, Kim D et al. Effect of intravenous infusion of exenatide (synthetic exendin-4) on glucose-dependent insulin secretion and counterregulation during hypoglycemia. Diabetes 2004; 53: 2397–2403.

    Article  CAS  Google Scholar 

  18. Gedulin BR, Nikoulina SE, Smith PA, Gedulin G, Nielsen LL, Baron AD et al. Exenatide (exendin-4) improves insulin sensitivity and β-cell mass in insulin-resistant obese fa/fa Zucker rats independent of glycemia and body weight. Endocrinology 2005; 146: 2069–2076.

    Article  CAS  Google Scholar 

  19. Nielsen LL, Young AA, Parkes D . Pharmacology of exenatide (synthetic exendin-4): a potential therapeutic for improved glycemic control of type 2 diabetes. Regul Pept 2004; 117: 77–88.

    Article  CAS  Google Scholar 

  20. Tang-Christensen M, Larsen PJ, Goke R, Fink-Jensen A, Jessop DS, Moller M et al. Central administration of GLP-1 (7–36) amide inhibits food and water intake in rats. Am J Physiol 1996; 271: R848–R856.

    CAS  PubMed  Google Scholar 

  21. Van Dijk G, Thiele TE, Seeley RJ, Woods SC, Bernstein IL . Glucagon-like peptide-1 and satiety. Nature 1997; 385: 214.

    Article  CAS  Google Scholar 

  22. Turton MD, O'Shea D, Gunn I, Beak SA, Edwards CMB, Meeran K et al. A role for glucagon-like peptide-1 in central regulation of feeding. Nature 1996; 379: 69–72.

    Article  CAS  Google Scholar 

  23. Van Dijk G, Thiele TE, Donahey JC, Campfield LA, Smith FJ, Burn P et al. Central infusions of leptin and GLP-1-(7–36) amide differentially stimulate c-FLI in the rat brain. Am J Physiol 1996; 271: R1096–R1100.

    CAS  PubMed  Google Scholar 

  24. Larsen PJ, Vrang N, Tang-Christensen M . Central pre-proglucagon derived peptides: opportunities for treatment of obesity. Curr Pharm Des 2003; 9: 1373–1382.

    Article  CAS  Google Scholar 

  25. Navarro M, Rodriguez de Fonseca F, Alvarez E, Chowen JA, Zueco JA, Gomez R et al. Colocalization of glucagon-like peptide-1 (GLP-1) receptors, glucose transporter GLUT-2, and glucokinase mRNAs in rat hypothalamic cells: evidence for a role of GLP-1 receptor agonists as an inhibitory signal for food and water intake. J Neurochem 1996; 67: 1982–1991.

    Article  CAS  Google Scholar 

  26. Al-Barazanji KA, Arch JR, Buckingham RE, Tadayyon M . Central exendin-4 infusion reduces body weight without altering plasma leptin in (fa/fa) Zucker rats. Obes Res 2000; 8: 317–323.

    Article  CAS  Google Scholar 

  27. Rodriquez de Fonseca F, Navarro M, Alvarez E, Roncero I, Chowen JA, Maestre O et al. Peripheral versus central effects of glucagon-like peptide-1 receptor agonists on satiety and body weight loss in Zucker obese rats. Metabolism 2000; 49: 709–717.

    Article  CAS  Google Scholar 

  28. Szayna M, Doyle ME, Betkey JA, Holloway HW, Spencer RGS, Greig NH et al. Exendin-4 decelerates food intake, weight gain, and fat deposition in Zucker rats. Endocrinology 2000; 141: 1936–1941.

    Article  CAS  Google Scholar 

  29. Aziz A, Anderson GH . Exendin-4, a GLP-1 receptor agonist, interacts with proteins and their products to suppress food intake in rats. J Nutr 2003; 133: 2326–2330.

    Article  CAS  Google Scholar 

  30. Peters CT, Choi YH, Brubaker PL, Anderson PL . A glucagon-like peptide receptor agonist and an antagonist modify macronutrient selection by rats. J Nutr 2001; 131: 2164–2170.

    Article  CAS  Google Scholar 

  31. Talsania T, Anini Y, Siu S, Drucker DJ, Brubaker PL . Peripheral exendin-4 and peptide YY (3–36) synergistically reduce food intake through different mechanisms in mice. Endocrinology 2005; 146: 3748–3756.

    Article  CAS  Google Scholar 

  32. Wang T, Edwards GL, Baile CA . Glucagon-like peptide-1 (7–36) amide administered into the third cerebroventricle inhibits water intake in rats. Proc Soc Exp Biol Med 1998; 219: 85–91.

    Article  CAS  Google Scholar 

  33. Thiele TE, Van Dijk G, Campfield LA, Smith FJ, Burn P, Woods SC et al. Central infusion of GLP-1, but not leptin, produces conditioned taste aversion in rats. Am J Physiol Regul Integr Comp Physiol 1997; 272: R726–R730.

    Article  CAS  Google Scholar 

  34. Seeley RJ, Blake K, Rushing PA, Benoit S, Eng J, Woods SC et al. The role of CNS glucagons-like peptide-1 (7–36) amide receptors in mediating the visceral illness effects of lithium chloride. J Neurosci 2000; 20: 1616–1621.

    Article  CAS  Google Scholar 

  35. Takeda N, Hasegawa S, Morita M, Matsunaga T . Pica in rats is analogous to emesis: an animal model in emesis research. Pharmacol Biochem Behav 1993; 45: 817–821.

    Article  CAS  Google Scholar 

  36. Mack CM, Wilson JK, Young A, Parkes DG . Effect of systemic 28-day exposure to exenatide (synthetic exendin-4) on food intake and body weight in high fat-fed rats. Diabetes 2004; 53 (Suppl 2): A409.

    Google Scholar 

  37. Moore C, Jodka C, Hoyt J, Young A, Sams-Dodd F . Chronic administration of exenatide (synthetic exendin-4) reduces body weight and improves glycemic control in C57BL/6J mice fed a high fat diet. Diabetes 2003; 52 (Suppl 1): A389.

    Google Scholar 

  38. Smith BK, Andrews K, West DB . Macronutrient diet selection in thirteen mouse strains. Am J Physiol Regul Integr Comp Physiol 2000; 278: R797–R805.

    Article  CAS  Google Scholar 

  39. Cuniff P (ed). Total Fat, Soxhlet Extraction. AOAC International, 960.39 Fat (Crude) or Ether Extract in Meat (Modified), Offical Methods of Analysis, Vol. 2, 16th edn. AOAC International: Gaithersburg, MD, 1995.

    Google Scholar 

  40. AOAC International. Protein (N X 6.25) Dumas Method. Official Methods of Analysis of AOAC International, Official Methods 968.06 and 992.15. (Modified) 17th edn., AOAC International: Gaithersburg, MD, USA, 2000.

  41. Hiles R, Carpenter T, Serota D, Schafer K, Ross P, Nelson D et al. Exenatide does not cause pancreatic tumors or malignancies in rats and mice following a 2-year period of exposure. Diabetes 2004; 53 (Suppl 2): A380.

    Google Scholar 

  42. Blonde L, Han J, Mac S, Poon T Taylor K, Kim D . Exenatide (exendin-4) reduced A1C and weight over 82 weeks in overweight patients with type 2 diabetes. Diabetes 2005; 54 (Suppl 1): A118.

    Google Scholar 

  43. Fineman M, Young A, Gaines E, Prickett K . Dose-response for postprandial glucose-lowering effect of synthetic exendin-4 (AC2993) in subjects with type 2 diabetes. Diabetes 200l; 49 (Suppl 1): A106.

    Google Scholar 

  44. Baron A, Fineman M, Young A, Gaines E, Prickett K . Synthetic exendin-4 (AC2993) reduces post-prandial glycemia, glucagon levels and slows gastric emptying in subjects with type 2 diabetes. Diabetologia 2000; 43 (Suppl 1): A190.

    Google Scholar 

  45. Baggio LL, Huang Q, Brown TJ, Drucker DD . Oxyntomodulin and glucagon-like peptide-1 differentially regulate murine food intake and energy expenditure. Gastroenterology 2004; 127: 546–558.

    Article  CAS  Google Scholar 

  46. Edwards CM, Stanley SA, Davis R, Brynes AE, Frost GS, Seal LJ et al. Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers. Am J Physiol Endocrinol Metab 2001; 281: E155–E161.

    Article  CAS  Google Scholar 

  47. Flint A, Raben A, Ersboll AK, Holst JJ, Astrup A . The effect of physiological levels of glucagon-like peptide-1 on appetite, gastric emptying, energy and substrate metabolism in obesity. Int J Obes Relat Metab Disord 2001; 25: 781–792.

    Article  CAS  Google Scholar 

  48. Kendall DM, Kim D, Poon T, Han J, Schnabel C, Fineman M et al. Improvement in cardiovascular risk factors accompanied sustained effects on glycaemia and weight reduction in patients with type 2 diabetes treated with exenatide for 82 weeks. Diabetes 2005; 54 (Suppl 1): A4–A5.

    Google Scholar 

  49. Kinzig KP, D'Alessio DA, Seeley RJ . The diverse roles of specific GLP-1 receptors in the control of food intake and the response to visceral illness. J Neurosci 2002; 22: 10470–10476.

    Article  CAS  Google Scholar 

  50. McMahon LR, Wellman PJ . PVN infusion of GLP-1-(7–36) amide suppresses feeding but does not induce aversion or alter locomotion in rats. Am J Physiol 1998; 274: R23–R29.

    CAS  PubMed  Google Scholar 

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Acknowledgements

We thank Dr Bronislava Gedulin, Dr Frank Sams-Dodd and Pamela Smith for their contributions to the development of obesity animal models, and Justin Watkins and Robin La Chappel for their technical expertise.

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Authors and Affiliations

  1. Amylin Pharmaceuticals Inc., San Diego, CA, USA

    C M Mack, C X Moore, C M Jodka, S Bhavsar, J K Wilson, J A Hoyt, J L Roan, C Vu, K D Laugero, D G Parkes & A A Young

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Correspondence to C M Mack.

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Mack, C., Moore, C., Jodka, C. et al. Antiobesity action of peripheral exenatide (exendin-4) in rodents: effects on food intake, body weight, metabolic status and side-effect measures. Int J Obes 30, 1332–1340 (2006). https://doi.org/10.1038/sj.ijo.0803284

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