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

Abstract

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 β2‐adrenergic receptors (β2‐ARs) can promote glucose uptake. In rodent models of T2D, chronic administration of clenbuterol, a selective β2‐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 β2‐ARs. For this purpose, we generated mice that lack β2‐ARs or the Gαs subunit selectively in SKM (SKM‐β2‐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‐β2‐KO, SKM‐Gs‐KO, and SKM‐Gs‐DREADD mice. RNA‐seq and functional data indicated increases in SKM glucose accumulation, glycolysis, and glycogen synthesis following chronic treatment, suggesting a switch of SKM metabolism towards enhanced glucose utilization.Multiple components of known, but also less studied metabolic pathways seem to be simultaneously involved in mediating the beneficial metabolic effects of chronic β2‐AR stimulation.Our study represents a striking example of the complexity of β2‐AR signaling in vivo. Further analysis of β2‐AR signaling pathways in SKM could help identify potential drug targets for new T2D treatments.Support or Funding InformationThis research was funded by the Intramural Research Program of the NIDDK.This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.