Acute β-adrenoceptor mediated glucose clearance in brown adipose tissue; a distinct pathway independent of functional insulin signaling
Autor: | Jessica M. Olsen, Alice Åslund, Muhammad Hamza Bokhari, Dana S. Hutchinson, Tore Bengtsson |
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Rok vydání: | 2019 |
Předmět: |
PI3Kα
Male lcsh:Internal medicine Epinephrine Brief Communication Glucose clearance Brown adipose tissue Mitochondrial Proteins Mice Norepinephrine Phosphatidylinositol 3-Kinases Adipose Tissue Brown Receptors Adrenergic beta Animals Insulin lcsh:RC31-1245 Uncoupling Protein 1 Phosphoinositide-3 Kinase Inhibitors Akt Thermogenesis Adrenergic beta-Agonists Mice Inbred C57BL Adipocytes Brown Glucose Diabetes Mellitus Type 2 Receptors Adrenergic beta-3 Energy Metabolism GLUT1 Signal Transduction |
Zdroj: | Molecular Metabolism Molecular Metabolism, Vol 30, Iss, Pp 240-249 (2019) |
ISSN: | 2212-8778 |
Popis: | Objective β-adrenoceptor mediated activation of brown adipose tissue (BAT) has been associated with improvements in metabolic health in models of type 2 diabetes and obesity due to its unique ability to increase whole body energy expenditure, and rate of glucose and free fatty acid disposal. While the thermogenic arm of this phenomenon has been studied in great detail, the underlying mechanisms involved in β-adrenoceptor mediated glucose uptake in BAT are relatively understudied. As β-adrenoceptor agonist administration results in increased hepatic gluconeogenesis that can consequently result in secondary pancreatic insulin release, there is uncertainty regarding the importance of insulin and the subsequent activation of its downstream effectors in mediating β-adrenoceptor stimulated glucose uptake in BAT. Therefore, in this study, we made an effort to discriminate between the two pathways and address whether the insulin signaling pathway is dispensable for the effects of β-adrenoceptor activation on glucose uptake in BAT. Methods Using a specific inhibitor of phosphoinositide 3-kinase α (PI3Kα), which effectively inhibits the insulin signaling pathway, we examined the effects of various β-adrenoceptor agonists, including the physiological endogenous agonist norepinephrine on glucose uptake and respiration in mouse brown adipocytes in vitro and on glucose clearance in mice in vivo. Results PI3Kα inhibition in mouse primary brown adipocytes in vitro, did not inhibit β-adrenoceptor stimulated glucose uptake, GLUT1 synthesis, GLUT1 translocation or respiration. Furthermore, β-adrenoceptor mediated glucose clearance in vivo did not require insulin or Akt activation but was attenuated upon administration of a β3-adrenoceptor antagonist. Conclusions We conclude that the β-adrenergic pathway is still functionally intact upon the inhibition of PI3Kα, showing that the activation of downstream insulin effectors is not required for the acute effects of β-adrenoceptor agonists on glucose homeostasis or thermogenesis. Graphical abstract Image 1 Highlights • PI3Kα/Akt are dispensable for β-AR mediated glucose clearance in vivo. • PI3Kα inhibition in brown adipocytes does not inhibit GLUT1 synthesis/translocation. • Acute β-AR induced thermogenesis in brown adipocytes is independent of PI3Kα/Akt. • Glucose uptake in brown adipocytes does not require a functional insulin pathway. |
Databáze: | OpenAIRE |
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