Metabolic effects of skeletal muscle-specific deletion of beta-arrestin-1 and -2 in mice.

Meister J, Bone DBJ, Godlewski G, Liu Z, Lee RJ, Vishnivetskiy SA, Gurevich VV, Springer D, Kunos G, Wess J
PLoS Genet. 2019 15 (10): e1008424

PMID: 31622341 · PMCID: PMC6818801 · DOI:10.1371/journal.pgen.1008424

Type 2 diabetes (T2D) has become a major health problem worldwide. Skeletal muscle (SKM) is the key tissue for whole-body glucose disposal and utilization. New drugs aimed at improving insulin sensitivity of SKM would greatly expand available therapeutic options. β-arrestin-1 and -2 (Barr1 and Barr2, respectively) are two intracellular proteins best known for their ability to mediate the desensitization and internalization of G protein-coupled receptors (GPCRs). Recent studies suggest that Barr1 and Barr2 regulate several important metabolic functions including insulin release and hepatic glucose production. Since SKM expresses many GPCRs, including the metabolically important β2-adrenergic receptor, the goal of this study was to examine the potential roles of Barr1 and Barr2 in regulating SKM and whole-body glucose metabolism. Using SKM-specific knockout (KO) mouse lines, we showed that the loss of SKM Barr2, but not of SKM Barr1, resulted in mild improvements in glucose tolerance in diet-induced obese mice. SKM-specific Barr1- and Barr2-KO mice did not show any significant differences in exercise performance. However, lack of SKM Barr2 led to increased glycogen breakdown following a treadmill exercise challenge. Interestingly, mice that lacked both Barr1 and Barr2 in SKM showed no significant metabolic phenotypes. Thus, somewhat surprisingly, our data indicate that SKM β-arrestins play only rather subtle roles (SKM Barr2) in regulating whole-body glucose homeostasis and SKM insulin sensitivity.

MeSH Terms (18)

Animals beta-Arrestin 1 beta-Arrestin 2 Diabetes Mellitus, Type 2 Diet, High-Fat Disease Models, Animal Glucose Glucose Clamp Technique Glycogen Humans Insulin Insulin Resistance Male Mice Mice, Knockout Muscle, Skeletal Obesity Signal Transduction

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