BRL37344 stimulates GLUT4 translocation and glucose uptake in skeletal muscle via β2-adrenoceptors without causing classical receptor desensitization

Author:

Mukaida Saori1,Sato Masaaki1,Öberg Anette I.2,Dehvari Nodi2,Olsen Jessica M.2,Kocan Martina1,Halls Michelle Louise1,Merlin Jon1,Sandström Anna L.2,Csikasz Robert I.2,Evans Bronwyn Anne1,Summers Roger James13,Hutchinson Dana Sabine13ORCID,Bengtsson Tore2

Affiliation:

1. Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia

2. Department of Molecular Biosciences, The Wenner-Gren Institute, The Arrhenius Laboratories F3, Stockholm University, Stockholm, Sweden

3. Department of Pharmacology, Monash University, Clayton, Victoria, Australia

Abstract

The type 2 diabetes epidemic makes it important to find insulin-independent ways to improve glucose homeostasis. This study examines the mechanisms activated by a dual β2-/β3-adrenoceptor agonist, BRL37344, to increase glucose uptake in skeletal muscle and its effects on glucose homeostasis in vivo. We measured the effect of BRL37344 on glucose uptake, glucose transporter 4 (GLUT4) translocation, cAMP levels, β2-adrenoceptor desensitization, β-arrestin recruitment, Akt, AMPK, and mammalian target of rapamycin (mTOR) phosphorylation using L6 skeletal muscle cells as a model. We further tested the ability of BRL37344 to modulate skeletal muscle glucose metabolism in animal models (glucose tolerance tests and in vivo and ex vivo skeletal muscle glucose uptake). In L6 cells, BRL37344 increased GLUT4 translocation and glucose uptake only by activation of β2-adrenoceptors, with a similar potency and efficacy to that of the nonselective β-adrenoceptor agonist isoprenaline, despite being a partial agonist with respect to cAMP generation. GLUT4 translocation occurred independently of Akt and AMPK phosphorylation but was dependent on mTORC2. Furthermore, in contrast to isoprenaline, BRL37344 did not promote agonist-mediated desensitization and failed to recruit β-arrestin1/2 to the β2-adrenoceptor. In conclusion, BRL37344 improved glucose tolerance and increased glucose uptake into skeletal muscle in vivo and ex vivo through a β2-adrenoceptor-mediated mechanism independently of Akt. BRL37344 was a partial agonist with respect to cAMP, but a full agonist for glucose uptake, and importantly did not cause classical receptor desensitization or internalization of the receptor.

Funder

Department of Health, Australian Government | National Health and Medical Research Council (NHMRC)

Australian Research Council

Monash University, Australia

Wenner-Gren Foundation, Sweden

Henning and Johan Throne-Holst Foundation, Sweden

Svenska Sällskapet för Medicinsk Forskning (Swedish Society for Medical Research)

Vetenskapsrådet (Swedish Research Council)

Svenska Diabetesforbundets Forskningsfond

Magnus Bergvall Foundation, Sweden

Carl Tryggers Stiftelse för Vetenskaplig Forskning (Carl Trygger Foundation for Scientific Research)

Publisher

American Physiological Society

Subject

Physiology (medical),Physiology

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