Characterizing Adrenergic Regulation of Glucose Transporter 4-Mediated Glucose Uptake and Metabolism in the Heart

Aleksandra Jovanovic; Bing Xu; Chaoqun Zhu; Di Ren; Hao Wang; Meredith Krause-Hauch; E Dale Abel; Ji Li; Yang K Xiang

doi:10.1016/j.jacbts.2022.11.008

Characterizing Adrenergic Regulation of Glucose Transporter 4-Mediated Glucose Uptake and Metabolism in the Heart

JACC Basic Transl Sci. 2023 Feb 22;8(6):638-655. doi: 10.1016/j.jacbts.2022.11.008. eCollection 2023 Jun.

Authors

Aleksandra Jovanovic¹, Bing Xu^{1

2}, Chaoqun Zhu¹, Di Ren³, Hao Wang³, Meredith Krause-Hauch^{3

4}, E Dale Abel⁵, Ji Li^{3

4}, Yang K Xiang^{1

2}

Affiliations

¹ Department of Pharmacology, University of California at Davis, Davis, California, USA.
² Veterans Affairs Northern California Health Care System, Mather, California, USA.
³ Department of Surgery, University of South Florida, Tampa, Florida, USA.
⁴ James A. Haley Veterans Affairs Hospital, Tampa, Florida, USA.
⁵ Department of Medicine, David Geffen School of Medicine at University of California-Los Angeles, Los Angeles, California, USA.

Abstract

Whereas adrenergic stimulation promotes cardiac function that demands more fuel and energy, how this receptor controls cardiac glucose metabolism is not defined. This study shows that the cardiac β₂ adrenoreceptor (β₂AR) is required to increase glucose transporter 4 (GLUT4)-mediated glucose uptake in myocytes and glucose oxidation in working hearts via activating the cardiac β₂AR and promotes the G inhibitory-phosphoinositide 3-kinase-protein kinase B cascade to increase phosphorylation of TBC1D4 (aka AS160), a Rab guanosine triphosphatase-activating protein, which is a key enzyme to mobilize GLUT4. Furthermore, deleting G-protein receptor kinase phosphorylation sites of β₂AR blocked adrenergic stimulation of GLUT4-mediated glucose uptake in myocytes and hearts. This study defines a molecular pathway that controls cardiac GLUT4-mediated glucose uptake and metabolism under adrenergic stimulation.

Keywords: Akt substrate of 160 kDa; G-protein receptor kinase 2; adrenergic receptor; glucose oxidation; glucose transporter 4; glucose uptake.