BRL37344 stimulates GLUT4 translocation and glucose uptake in skeletal muscle via β 2 -adrenoceptors without causing classical receptor desensitization

Saori Mukaida, Masaaki Sato, Anette I. Öberg, Nodi Dehvari, Jessica M. Olsen, Martina Kocan, Michelle Louise Halls, Jon Merlin, Anna L. Sandström, Robert I. Csikasz, Bronwyn Anne Evans, Roger James Summers, Dana Sabine Hutchinson, Tore Bengtsson

Research output: Contribution to journalArticleResearchpeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)R666-R677
Number of pages12
JournalAmerican journal of physiology. Regulatory, integrative and comparative physiology
Volume316
Issue number5
DOIs
Publication statusPublished - 1 May 2019

Keywords

  • BRL37344
  • glucose uptake
  • GLUT4
  • isoprenaline
  • receptor desensitization
  • skeletal muscle
  • β-adrenoceptor
  • β-arrestin

Cite this

@article{9d33cfbc6f404b5ba2f003a5926f612a,
title = "BRL37344 stimulates GLUT4 translocation and glucose uptake in skeletal muscle via β 2 -adrenoceptors without causing classical receptor desensitization",
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.",
keywords = "BRL37344, glucose uptake, GLUT4, isoprenaline, receptor desensitization, skeletal muscle, β-adrenoceptor, β-arrestin",
author = "Saori Mukaida and Masaaki Sato and {\"O}berg, {Anette I.} and Nodi Dehvari and Olsen, {Jessica M.} and Martina Kocan and Halls, {Michelle Louise} and Jon Merlin and Sandstr{\"o}m, {Anna L.} and Csikasz, {Robert I.} and Evans, {Bronwyn Anne} and Summers, {Roger James} and Hutchinson, {Dana Sabine} and Tore Bengtsson",
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BRL37344 stimulates GLUT4 translocation and glucose uptake in skeletal muscle via β 2 -adrenoceptors without causing classical receptor desensitization. / Mukaida, Saori; Sato, Masaaki; Öberg, Anette I.; Dehvari, Nodi; Olsen, Jessica M.; Kocan, Martina; Halls, Michelle Louise; Merlin, Jon; Sandström, Anna L.; Csikasz, Robert I.; Evans, Bronwyn Anne; Summers, Roger James; Hutchinson, Dana Sabine; Bengtsson, Tore.

In: American journal of physiology. Regulatory, integrative and comparative physiology, Vol. 316, No. 5, 01.05.2019, p. R666-R677.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - BRL37344 stimulates GLUT4 translocation and glucose uptake in skeletal muscle via β 2 -adrenoceptors without causing classical receptor desensitization

AU - Mukaida, Saori

AU - Sato, Masaaki

AU - Öberg, Anette I.

AU - Dehvari, Nodi

AU - Olsen, Jessica M.

AU - Kocan, Martina

AU - Halls, Michelle Louise

AU - Merlin, Jon

AU - Sandström, Anna L.

AU - Csikasz, Robert I.

AU - Evans, Bronwyn Anne

AU - Summers, Roger James

AU - Hutchinson, Dana Sabine

AU - Bengtsson, Tore

PY - 2019/5/1

Y1 - 2019/5/1

N2 - 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.

AB - 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.

KW - BRL37344

KW - glucose uptake

KW - GLUT4

KW - isoprenaline

KW - receptor desensitization

KW - skeletal muscle

KW - β-adrenoceptor

KW - β-arrestin

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U2 - 10.1152/ajpregu.00285.2018

DO - 10.1152/ajpregu.00285.2018

M3 - Article

VL - 316

SP - R666-R677

JO - American Journal of Physiology - Regulatory Integrative and Comparative Physiology

JF - American Journal of Physiology - Regulatory Integrative and Comparative Physiology

SN - 1522-1490

IS - 5

ER -