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.
Highlights
Activation of the sympathetic nervous system causes pronounced metabolic changes that are mediated by multiple adrenergic receptor subtypes
We provide convincing evidence that the beneficial metabolic effects of chronic clenbuterol depend on the stimulation of skeletal muscle (SKM) β2-adrenergic receptor (β2-AR), and that the coupling of these receptors to SKM Gs is essential for the manifestation of the clenbuterol-induced metabolic improvements
Comprehensive unbiased metabolomic and RNA-Seq studies provided important clues regarding the molecular mechanisms underlying the clenbuterol-induced improvements in SKM glucose homeostasis
Summary
Activation of the sympathetic nervous system causes pronounced metabolic changes that are mediated by multiple adrenergic receptor subtypes. 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 β2adrenergic 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. 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 β2adrenergic receptor-dependent signaling pathways may prove beneficial as antidiabetic drugs. SKM insulin resistance is a key metabolic defect in the pathogenesis of T2D2 For these reasons, SKM is a very attractive target for the development of novel classes of antidiabetic drugs. Activated β2-ARs, such as other GPCRs, can recruit β-arrestins (β-arrestin-1 and -2), which can act as signaling proteins[13–15]
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