Role of Skeletal Muscle in Beta2-adrenergic Receptor Mediated Improvements in Whole Body Glucose Homeostasis

Authors

• J Meister
• D Bone
• R Lee
• D Akhmedov
• R Berdeaux
• J Wess

Abstract

Skeletal muscle (SKM) insulin resistance is a hallmark of type 2 diabetes (T2D), one of the largest health problems worldwide. Previous work with cultured SKM cells indicates that activation of SKM beta2-adrenergic receptors (beta2-ARs) can promote glucose uptake. This study tested whether the in vivo treatment with clenbuterol (beta2-AR agonist) improves glucose metabolism by SKM beta2-AR stimulation. For this purpose, we generated mice that lack beta2-ARs or Gs-alpha selectively in SKM (SKM-ß2-AR-KO, SKM-Gs-KO mice). We also generated mice expressing a Gs-DREADD selectively in SKM (SKM-Gs-DREADD mice). As expected, WT mice showed improved glucose tolerance after both acute clenbuterol injection and following chronic clenbuterol treatment. Surprisingly, the specific tissues involved in mediating this effect were dependent on the mode of clenbuterol administration. The ability of acute clenbuterol treatment to promote improved glucose tolerance was fully maintained in SKM-beta2-AR-KO and SKM-Gs-KO mice. In fact, acute clenbuterol injection greatly enhanced glucose-stimulated insulin secretion. Additionally, acute clenbuterol impaired insulin tolerance through enhanced SKM glycogenolysis. Consistent with this observation, acute CNO treatment of SKM-Gs-DREADD mice caused reduced glucose tolerance by decreasing glucose uptake selectively in SKM. In contrast, the ability of chronic clenbuterol treatment to improve glucose tolerance was completely abolished in mice lacking beta2-AR or Gs selectively in SKM. Similarly, chronic treatment of SKM-Gs-DREADD mice with CNO resulted in improved glucose tolerance through enhanced glucose uptake into SKM. Our study provides an example for the complexity of GPCR signaling in vivo and indicates that caution needs to be exercised when extrapolating in vitro findings.

Scientific Focus Area: Molecular Biology and Biochemistry

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