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Subcutaneous oxyntomodulin analogue administration reduces body weight in lean and obese rodents

International Journal of Obesity volume 34, pages 1715–1725 (2010)Cite this article

Subjects

Abstract

Objective:

To determine the efficacy of a long-acting oxyntomodulin (OXM) analogue, OXM6421, in inhibiting food intake and decreasing body weight in lean and diet-induced obese (DIO) rodents.

Research design and methods:

The glucagon-like peptide-1 (GLP-1) receptor binding affinity and efficacy, sensitivity to enzymatic degradation in vitro and persistence in the circulation after peripheral administration were investigated for OXM6421 and compared with native OXM. The chronic effect of OXM6421 on food intake, body weight and energy expenditure was examined in lean rats, and its anti-obesity potential was evaluated in DIO mice.

Results:

OXM6421 showed enhanced GLP-1 receptor binding affinity and cyclic adenosine monophosphate (cAMP) stimulation, and higher resistance to enzymatic degradation by dipeptidyl peptidase IV (DPP-IV) and neutral endopeptidase (NEP) compared with native OXM. OXM6421 persisted longer in the circulation than OXM after peripheral administration. Acute administration of OXM6421 potently inhibited food intake in lean rodents, with cumulative effects lasting up to 24 h. In lean rats, daily subcutaneous (s.c.) administration of OXM6421 caused greater weight loss than the pair-fed animals, and a higher rate of oxygen consumption than both the pair-fed and the saline controls. In DIO mice, continuous s.c. infusion of OXM6421 resulted in a significant weight loss, accompanied by an improvement in glucose homeostasis and an increase in circulating adiponectin levels. Once-daily s.c. administration of OXM6421 for 21 days caused sustained weight loss in DIO mice.

Conclusion:

OXM6421 induces negative energy balance in both lean and obese rodents, suggesting that long-acting OXM analogues may represent a potential therapy for obesity.

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Acknowledgements

This research was funded in part by programme grants from the MRC (G7811974) and Wellcome Trust (072643/Z/03/Z) and by an EU FP6 Integrated Project Grant LSHM-CT-2003-503041. We are also grateful for support from the NIHR Biomedical Research Centre funding scheme.

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Author notes

  1. M R Druce

    Present address: 3Current address: William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, Centre for Endocrinology, St Bartholomew's Hospital, West Smithfield, London EC1A 7BE, UK,

  2. Y-L Liu and H E Ford: These authors contributed equally to this project.

Authors and Affiliations

  1. Department of Investigative Medicine, Imperial College Faculty of Medicine, Hammersmith Hospital, London, UK

    Y-L Liu, H E Ford, M R Druce, J S Minnion, B C T Field, J C Shillito, J Baxter, K G Murphy, M A Ghatei & S R Bloom

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Correspondence to S R Bloom.

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Competing interests

YLL, HF, JSM, BCTF, JCS, JB and KGM have nothing to declare. MAG and MRD receive royalties from and SRB is an inventor of United Kingdom patent application no. PCT/GB02/04082 and PCT/GB/04/00017. SRB is a consultant from Thiakis, a subsidiary of Wyeth Pharmaceuticals (Pfizer). The company will reveal the structure of the oxyntomodulin analogue and give legitimate investigators the compound for experimental use under the condition that they sign a confidentiality agreement.

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Liu, YL., Ford, H., Druce, M. et al. Subcutaneous oxyntomodulin analogue administration reduces body weight in lean and obese rodents. Int J Obes 34, 1715–1725 (2010). https://doi.org/10.1038/ijo.2010.110

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