Chronic Beta2‐Adrenergic Receptor Stimulation Improves Whole‐Body Glucose Homeostasis through Skeletal Muscle Metabolic Reprogramming

作者：Jaroslawna Meister, Derek B.J. Bone, Jonas R. Knudsen, Regina Lee, Amanda Cohen, Maximilian Kleinert, Rebecca Berdeaux, Erik A. Richter, Jürgen Wess · 发表于：The FASEB Journal · 年份：2018 · DOI：10.1096/fasebj.2018.32.1_supplement.533.43 · 研究领域：Pharmacological Effects and Assays、Adipose Tissue and Metabolism、Receptor Mechanisms and Signaling

Type 2 diabetes (T2D) has emerged as a major health problem worldwide. Since skeletal muscle (SKM) is the major site of insulin‐stimulated glucose disposal in the body, SKM insulin resistance plays a crucial role in the pathogenesis of this disorder. Drugs that could enhance or mimic insulin action in SKM hold great therapeutic potential for the treatment of obesity and T2D. Previous work carried out with cultured SKM cells indicates that activation of SKM β 2 ‐adrenergic receptors (β 2 ‐ARs) can promote glucose uptake. In rodent models of T2D, chronic administration of clenbuterol, a selective β 2 ‐AR agonist, greatly improves glucose tolerance. However, the mechanism and in vivo tissue(s) responsible for the actions of clenbuterol are still unclear. This study was designed to test the hypothesis that the beneficial metabolic effects of clenbuterol observed in vivo are mediated by SKM β 2 ‐ARs. For this purpose, we generated mice that lack β 2 ‐ARs or the Gα s subunit selectively in SKM (SKM‐β 2 ‐AR‐KO and SKM‐Gs‐KO mice, respectively). We also generated transgenic mice expressing a Gs‐DREADD selectively in SKM (SKM‐Gs‐DREADD mice). As expected, chronic administration of clenbuterol via drinking water improved glucose tolerance in wild‐type (WT) mice without affecting glucose‐stimulated insulin secretion or insulin tolerance. The SKM selectivity of this chronic clenbuterol effect was confirmed using SKM‐β 2 ‐KO, SKM‐Gs‐KO, and SKM‐Gs‐DREADD mice. RNA‐seq and functional data ...