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Chronic Beta2‐Adrenergic Receptor Stimulation Improves Whole‐Body Glucose Homeostasis through Skeletal Muscle Metabolic Reprogramming
Author(s) -
Meister Jaroslawna,
Bone Derek,
Knudsen Jonas Roland,
Lee Regina,
Cohen Amanda,
Kleinert Maximilian,
Berdeaux Rebecca,
Richter Erik,
Wess Jürgen
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.533.43
Subject(s) - medicine , endocrinology , clenbuterol , insulin resistance , stimulation , glucose uptake , glucose homeostasis , insulin , agonist , skeletal muscle , glycolysis , receptor , type 2 diabetes mellitus , biology , diabetes mellitus , metabolism
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 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 β 2 ‐AR stimulation. Our study represents a striking example of the complexity of β 2 ‐AR signaling in vivo . Further analysis of β 2 ‐AR signaling pathways in SKM could help identify potential drug targets for new T2D treatments. Support or Funding Information This 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 .