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

      Highlights

      • The interplay between the β2-AR and insulin pathways plays a critical role in the maintenance of glucose homeostasis.
      • The suppression of β2-AR stimulation contributes to the development of early progression of hepatic insulin resistance.
      • β2-AR deletion is associated to selective hepatic insulin resistance and preserved skeletal muscle insulin sensitivity.
      • β2-AR regulates insulin induced hepatic AKT full activation by Grb2 mediated SRC recruitment and Gi independent mechanism.

      Abstract

      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 Gi-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.

      Keywords

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