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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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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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