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Improved glucose homeostasis in mice overexpressing human UCP3: a role for AMP-kinase?

International Journal of Obesity volume 28, pages 824–828 (2004)Cite this article

Abstract

OBJECTIVE: An unexplained phenotype of mice overexpressing human UCP3 is their improved glucose homeostasis. Since overexpression of UCP3 might affect the energy charge of the cell, we investigated whether these mice have an increased AMP-activated protein kinase (AMPK) activity.

METHODS: Mitochondrial localisation of UCP3 was determined by immunoelectronmicroscopy and AMPK activity was measured in medial gastrocnemius of control mice and mice overexpressing human UCP3.

RESULTS: Mice overexpressing human UCP3 had 5.8 fold higher levels of UCP3 protein, for which mitochondrial localisation was confirmed by immunoelectronmicroscopy. The ATP/AMP ratio was significantly lower in mice over-expressing UCP3 compared to the wild-type (10.9±1.6 vs 20.4±1.9 AU, P=0.03). Over-expression of UCP3 resulted in increased AMPK α1 activity (1.23±0.05 vs 1.00±0.06 normalized values, P=0.004) and a tendency towards increased AMPK α2 activity (1.18±0.08 vs 1.00±0.10 normalized values, P=0.08).

CONCLUSION: Increased AMPK activity provides a plausible explanation for the improved glucose tolerance characteristic for these mice.

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Acknowledgements

The research of Dr P Schrauwen has been made possible by a fellowship of the Royal Netherlands Academy of Arts and Sciences. Dr DG Hardie was supported by a Programme Grant from the Wellcome Trust and a Project Grant from Diabetes UK. We thank Lawrence J Slieker from Eli Lilly and Company for providing us with the UCP3 antibody. The skilful technical assistance of Hans Duimel in preparing and staining the samples for immunogold EM is gratefully acknowledged. This work was supported by a grant from the Human Nutrition Institute of the International Life Sciences Institute Research Foundation (ILSI RF). The opinions expressed herein are those of the author(s) and do no necessarily represent the views of ILSI RF.

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Author notes

  1. J C Clapham

    Present address: Cell Biology and Biochemistry, AstraZeneca R&D, Mölndal, Sweden

Authors and Affiliations

  1. Department of Human Biology, Maastricht University, The Netherlands

    P Schrauwen & B Roorda

  2. Wellcome Trust Biocentre, University of Dundee, Dundee, Scotland, UK

    D G Hardie, M Thomason-Hughes & K Green

  3. Department of Vascular Biology, GlaxoSmithKline, Harlow, Essex, UK

    J C Clapham

  4. Department of Comparative genetics, GlaxoSmithKline, Harlow, Essex, UK

    A Abuin

  5. EM-unit, Maastricht University, The Netherlands

    P M Frederik

  6. Department of Movement Sciences, Maastricht University, The Netherlands

    M K C Hesselink

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  1. P Schrauwen
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Correspondence to P Schrauwen.

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Schrauwen, P., Hardie, D., Roorda, B. et al. Improved glucose homeostasis in mice overexpressing human UCP3: a role for AMP-kinase?. Int J Obes 28, 824–828 (2004). https://doi.org/10.1038/sj.ijo.0802629

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