Molecular Signaling Section, Laboratory of Bioorganic Chemistry, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 20892, USA.
Departments of Nutrition, Exercise and Sports, University of Copenhagen, København, Denmark.
Nat Commun. 2022 Jan 10;13(1):22. doi: 10.1038/s41467-021-27540-w.
Activation of the sympathetic nervous system causes pronounced metabolic changes that are mediated by multiple adrenergic receptor subtypes. Systemic treatment with βadrenergic 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 β-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 β-adrenergic receptors and the stimulatory G protein, G. Unbiased transcriptomic and metabolomic analyses showed that chronic β-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 β-adrenergic receptor-dependent signaling pathways may prove beneficial as antidiabetic drugs.
交感神经系统的激活会引起明显的代谢变化，这些变化是由多种肾上腺素能受体亚型介导的。全身给予β肾上腺素能受体激动剂会产生多种有益的代谢效应，包括改善葡萄糖稳态。为了阐明潜在的细胞和分子机制，我们用克仑特罗（一种选择性β-肾上腺素能受体激动剂）对野生型小鼠和几种新开发的突变体小鼠进行了慢性治疗。克仑特罗给药可显著改善葡萄糖稳态，并预防β细胞功能障碍和胰岛素抵抗小鼠模型中的代谢缺陷。骨骼肌特异性突变体小鼠的研究表明，这些代谢改善需要激活骨骼肌β肾上腺素能受体和刺激 G 蛋白，G。无偏转录组学和代谢组学分析表明，慢性β肾上腺素能受体刺激会导致骨骼肌代谢重编程，表现为葡萄糖利用增强。这些发现强烈表明，通过调节β肾上腺素能受体依赖性信号通路靶向骨骼肌代谢的药物可能作为抗糖尿病药物是有益的。
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