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Diet-resistant obesity is characterized by a distinct plasma proteomic signature and impaired muscle fiber metabolism

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Inter-individual variability in weight loss during obesity treatment is complex and poorly understood. Here we use whole body and tissue approaches to investigate fuel oxidation characteristics in skeletal muscle fibers, cells, and distinct circulating protein biomarkers before and after a high fat meal (HFM) challenge in those who lost the most (obese diet-sensitive; ODS), vs the least (obese diet-resistant; ODR) amount of weight in a highly controlled weight management program.


In 20 weight stable matched ODS and ODR women who previously completed a standardized clinical weight loss program, we analyzed whole body energetics, and metabolic parameters in vastus lateralis biopsies and plasma samples that were obtained in the fasting state and 6 h after a defined HFM, equivalent to 35% of total daily energy requirements.


At baseline (fasting) and post-HFM, muscle fatty acid oxidation and maximal oxidative phosphorylation were significantly greater in ODS vs ODR, as was reactive oxygen species emission. Plasma proteomics of 1130 proteins pre, and 1, 2, 5 and 6 h after the HFM demonstrated distinct group and interaction differences. Group differences identified s-formyl glutathione hydratase, heat shock 70 kDA protein 1A/B (HSP72), and eukaryotic translation initiation factor 5 (eIF-5) to be higher in ODS vs ODR. Group-time differences included aryl hydrocarbon interacting protein (AIP), peptidylpropyl isomerase D (PPID) and tyrosine protein kinase Fgr, which increased in ODR vs ODS over time. HSP72 levels correlated with muscle oxidation and citrate synthase activity. These proteins circulate in exosomes; exosomes isolated from ODS plasma increased resting, leak and maximal respiration rates in C2C12 myotubes by 58, 21, and 51%, respectively vs those isolated from ODR plasma.


Findings demonstrate distinct muscle metabolism and plasma proteomics in fasting and post-HFM states corresponding in diet-sensitive vs diet-resistant obese women.

Author information

Author notes

    • R Dent
    • , R McPherson
    •  & M-E Harper

    Co-Senior Authors


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

    • A B Thrush
    • , G Antoun
    • , D A Patten
    • , C DeVlugt
    • , B L Beauchamp
    •  & M-E Harper
  2. Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Canada

    • M Nikpay
    • , P Lau
    •  & R McPherson
  3. Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Canada

    • D A Patten
    • , R Reshke
    • , D Gibbings
    •  & R Slack
  4. School of Human Kinetics, Faculty of Health Sciences, University of Ottawa, Canada

    • J-F Mauger
    • , É Doucet
    •  & P Imbeault
  5. School of Kinesiology, University of British Columbia, Vancouver, Canada

    • R Boushel
  6. Nestle Institute of Health Sciences, Lausanne, Switzerland

    • J Hager
    •  & A Valsesia
  7. Newborn Screening Ontario, Children's Hospital of Eastern Ontario, Ottawa, Canada

    • O Y Al-Dirbashi
  8. Faculty of Medicine and Health Sciences, United Arab Emirates University, Al-Ain, United Arab Emirates

    • O Y Al-Dirbashi
  9. Ottawa Hospital Weight Management Clinic, Ottawa, Canada

    • R Dent


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Corresponding author

Correspondence to M-E Harper.

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