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  • Original Article
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Low birth weight is associated with adiposity, impaired skeletal muscle energetics and weight loss resistance in mice

International Journal of Obesity volume 39, pages 702–711 (2015)Cite this article

Subjects

Abstract

Background:

In utero undernutrition is associated with obesity and insulin resistance, although its effects on skeletal muscle remain poorly defined. Therefore, in the current study we explored the effects of in utero food restriction on muscle energy metabolism in mice.

Methods:

We used an experimental mouse model system of maternal undernutrition during late pregnancy to examine offspring from undernourished dams (U) and control offspring from ad libitum-fed dams (C). Weight loss of 10-week-old offspring on a 4-week 40% calorie-restricted diet was also followed. Experimental approaches included bioenergetic analyses in isolated mitochondria, intact (permeabilized) muscle and at the whole body level.

Results:

U have increased adiposity and decreased glucose tolerance compared to C. Strikingly, when U are put on a 40% calorie-restricted diet they lose half as much weight as calorie-restricted controls. Mitochondria from muscle overall from U had decreased coupled (state 3) and uncoupled (state 4) respiration and increased maximal respiration compared to C. Mitochondrial yield was lower in U than C. In permeabilized fiber preparations from mixed fiber-type muscle, U had decreased mitochondrial content and decreased adenylate-free leak respiration, fatty acid oxidative capacity and state 3 respiratory capacity through complex I. Fiber maximal oxidative phosphorylation capacity did not differ between U and C but was decreased with calorie restriction.

Conclusions:

Our results reveal that in utero undernutrition alters metabolic physiology through a profound effect on skeletal muscle energetics and blunts response to a hypocaloric diet in adulthood. We propose that mitochondrial dysfunction links undernutrition in utero with metabolic disease in adulthood.

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Acknowledgements

We would like to thank Jian Xuan for technical assistance with animal work, Linda Jui for preparation and staining of histological slides, and Gabrielle Côté for assistance with counting muscle fibers. This research was supported through grants from Canadian Institutes of Health Research (MOP57810, M-EH; MOP258677, AB), National Institutes of Health (P20MD000175, DK088319; SG) and American Heart Association (AHA10SDG4230068; SG). Scholarships were also awarded from Natural Sciences and Engineering Research Council of Canada (Canada Graduate Scholarship -Doctoral, BB; -Master’s, AC).

Author information

Authors and Affiliations

  1. Department of Biochemistry, Microbiology, and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada

    B Beauchamp, M W Dysart, G N Kanaan, A Chu, A Blais & M-E Harper

  2. Cardiovascular & Metabolic Disorders Program, Duke-NUS Graduate Medical School, Singapore, Singapore

    S Ghosh

  3. Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, Canada, Ontario

    A Chu, A Blais & M-E Harper

  4. Division of Neurosurgery, Department of Surgery, Faculty of Medicine, Ottawa Hospital Research Institute, University of Ottawa, Ottawa, Ontario, Canada

    K Rajamanickam & E C Tsai

  5. Division of Integrative Physiology and Metabolism, Joslin Diabetes Center, Boston, MA, USA

    M-E Patti

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  1. B Beauchamp
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Corresponding author

Correspondence to M-E Harper.

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Author Contributions

BB and M-EH conceived and/or designed the work; BB, MD, GNK, AC and KR performed experiments; BB, SG, MD, AC, AB, KR, ECT, M-EP and M-EH analyzed or interpreted results; BB and M-EH wrote the manuscript. All authors revised the manuscript and approved the final version.

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Beauchamp, B., Ghosh, S., Dysart, M. et al. Low birth weight is associated with adiposity, impaired skeletal muscle energetics and weight loss resistance in mice. Int J Obes 39, 702–711 (2015). https://doi.org/10.1038/ijo.2014.120

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  • DOI: https://doi.org/10.1038/ijo.2014.120

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