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Clenbuterol exerts antidiabetic activity through metabolic reprogramming of skeletal muscle cells

Author

Listed:
  • Jaroslawna Meister

    (National Institute of Diabetes and Digestive and Kidney Diseases)

  • Derek B. J. Bone

    (National Institute of Diabetes and Digestive and Kidney Diseases)

  • Jonas R. Knudsen

    (University of Copenhagen)

  • Luiz F. Barella

    (National Institute of Diabetes and Digestive and Kidney Diseases)

  • Thomas J. Velenosi

    (University of British Columbia)

  • Dmitry Akhmedov

    (Houston Medical School)

  • Regina J. Lee

    (National Institute of Diabetes and Digestive and Kidney Diseases)

  • Amanda H. Cohen

    (National Institute of Diabetes and Digestive and Kidney Diseases)

  • Oksana Gavrilova

    (National Institute of Diabetes and Digestive and Kidney Diseases)

  • Yinghong Cui

    (National Institute of Diabetes and Digestive and Kidney Diseases)

  • Gerard Karsenty

    (Vagelos College of Physicians and Surgeons, Columbia University)

  • Min Chen

    (National Institute of Diabetes and Digestive and Kidney Diseases)

  • Lee S. Weinstein

    (National Institute of Diabetes and Digestive and Kidney Diseases)

  • Maximilian Kleinert

    (University of Copenhagen
    German Institute of Human Nutrition)

  • Rebecca Berdeaux

    (Houston Medical School)

  • Thomas E. Jensen

    (University of Copenhagen)

  • Erik A. Richter

    (University of Copenhagen)

  • Jürgen Wess

    (National Institute of Diabetes and Digestive and Kidney Diseases)

Abstract

Activation of the sympathetic nervous system causes pronounced metabolic changes that are mediated by multiple adrenergic receptor subtypes. Systemic treatment with β2-adrenergic receptor agonists results in multiple beneficial metabolic effects, including improved glucose homeostasis. To elucidate the underlying cellular and molecular mechanisms, we chronically treated wild-type mice and several newly developed mutant mouse strains with clenbuterol, a selective β2-adrenergic receptor agonist. Clenbuterol administration caused pronounced improvements in glucose homeostasis and prevented the metabolic deficits in mouse models of β-cell dysfunction and insulin resistance. Studies with skeletal muscle-specific mutant mice demonstrated that these metabolic improvements required activation of skeletal muscle β2-adrenergic receptors and the stimulatory G protein, Gs. Unbiased transcriptomic and metabolomic analyses showed that chronic β2-adrenergic receptor stimulation caused metabolic reprogramming of skeletal muscle characterized by enhanced glucose utilization. These findings strongly suggest that agents targeting skeletal muscle metabolism by modulating β2-adrenergic receptor-dependent signaling pathways may prove beneficial as antidiabetic drugs.

Suggested Citation

  • Jaroslawna Meister & Derek B. J. Bone & Jonas R. Knudsen & Luiz F. Barella & Thomas J. Velenosi & Dmitry Akhmedov & Regina J. Lee & Amanda H. Cohen & Oksana Gavrilova & Yinghong Cui & Gerard Karsenty , 2022. "Clenbuterol exerts antidiabetic activity through metabolic reprogramming of skeletal muscle cells," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
  • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-021-27540-w
    DOI: 10.1038/s41467-021-27540-w
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    Cited by:

    1. Sten M. M. Beek & Yvonne M. H. Bruls & Froukje Vanweert & Ciarán E. Fealy & Niels J. Connell & Gert Schaart & Esther Moonen-Kornips & Johanna A. Jörgensen & Frédéric M. Vaz & Ellen T. H. C. Smeets & P, 2023. "Effect of β2-agonist treatment on insulin-stimulated peripheral glucose disposal in healthy men in a randomised placebo-controlled trial," Nature Communications, Nature, vol. 14(1), pages 1-15, December.

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