Clenbuterol exerts antidiabetic activity through metabolic reprogramming of skeletal muscle cells

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, Min Chen, Lee S. Weinstein, Maximilian Kleinert, Rebecca Berdeaux, Thomas E. Jensen, Erik A. Richter and Jürgen Wess ()
Additional contact information
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
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

Nature Communications, 2022, vol. 13, issue 1, 1-14

Abstract: 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.

Date: 2022
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DOI: 10.1038/s41467-021-27540-w

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