Opposite effects of β₂-adrenoceptor gene deletion on insulin signaling in liver and skeletal muscle

Background and aim β₂-Adrenoceptors (β₂-ARs) are G protein-coupled receptors (GPCRs) expressed in the major insulin target tissues. The interplay between β₂-AR and insulin pathways is involved in the maintenance of glucose homeostasis. The aim of this study was to explore the consequences of β₂-ARs deletion on insulin sensitivity and insulin signaling cascade in metabolically active tissues. Methods and results We evaluated glucose homeostasis in skeletal muscle and liver of β₂-AR-null mice (β₂-AR^−/−) by performing in vivo (glucose tolerance test and insulin tolerance test) and ex vivo (glucose uptake and glycogen determination) experiments. β₂-AR gene deletion is associated with hepatic insulin resistance and preserved skeletal muscle insulin sensitivity. Importantly, we demonstrate that hepatic β₂-AR regulates insulin-induced AKT activation via Grb2-mediated SRC recruitment through a G_i-independent mechanism. Conclusions β-AR stimulation contributes to the development of early stages of insulin resistance progression in the liver. Our findings indicate that the cross-talk between β₂-AR and insulin signaling represents a fundamental target towards the development of novel therapeutic approaches to treat type 2 diabetes and metabolic syndrome.