A-769662 inhibits adipocyte glucose uptake in an AMPK-independent manner

Kopietz, F., Alshuweishi, Y., Bijland, S., Alghamdi, F., Degerman, E., Sakamoto, K., Salt, I. P. and Göransson, O. (2021) A-769662 inhibits adipocyte glucose uptake in an AMPK-independent manner. Biochemical Journal, 478(3), pp. 633-646. (doi: 10.1042/BCJ20200659) (PMID:33493298)

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Abstract

Activation of AMP-activated protein kinase (AMPK) is considered a valid strategy for the treatment of type 2 diabetes. However, despite the importance of adipose tissue for whole-body energy homeostasis, the effect of AMPK activation in adipocytes has only been studied to a limited extent and mainly with the AMP-mimetic 5-aminoimidazole-4-carboxamide-1-b-d-ribofuranoside (AICAR), which has limited specificity. The aim of this study was to evaluate the effect of the allosteric AMPK activators A‑769662 and 991 on glucose uptake in adipocytes. For this purpose, primary rat or human adipocytes, and cultured 3T3-L1 adipocytes, were treated with either of the allosteric activators, or AICAR, and basal and insulin-stimulated glucose uptake was assessed. Additionally, the effect of AMPK activators on insulin-stimulated phosphorylation of Akt and Akt substrate of 160 kDa was assessed. Furthermore, primary adipocytes from ADaM site binding drug-resistant AMPKb1 S108A knock-in mice were employed to investigate specificity of the drugs for the observed effects. Our results show that insulin-stimulated adipocyte glucose uptake was significantly reduced by A‑769662 but not 991, yet neither activator had any clear effects on basal or insulin-stimulated Akt/AS160 signaling. The use of AMPKb1 S108A mutant-expressing adipocytes revealed that the observed inhibition of glucose uptake by A‑769662 is most likely AMPK-independent, a finding which is supported by the rapid inhibitory effect A-769662 exerts on glucose uptake in 3T3-L1 adipocytes. These data suggest that AMPK activation per se does not inhibit glucose uptake in adipocytes and that the effects of AICAR and A-769662 are AMPK-independent.

Item Type:Articles
Status:Published
Refereed:Yes
Glasgow Author(s) Enlighten ID:Alghamdi, Fatmah and Bijland, Dr Silvia and Salt, Dr Ian and Alshuweishi, Yazeed Abdullah I
Authors: Kopietz, F., Alshuweishi, Y., Bijland, S., Alghamdi, F., Degerman, E., Sakamoto, K., Salt, I. P., and Göransson, O.
College/School:College of Medical Veterinary and Life Sciences > School of Cardiovascular & Metabolic Health
College of Medical Veterinary and Life Sciences > School of Infection & Immunity
College of Medical Veterinary and Life Sciences > School of Molecular Biosciences
Journal Name:Biochemical Journal
Publisher:Portland Press
ISSN:0264-6021
ISSN (Online):1470-8728
Published Online:25 January 2021
Copyright Holders:Copyright © 2021 The Authors
First Published:First published in Biochemical Journal 478(3):633–646
Publisher Policy:Reproduced in accordance with the publisher copyright policy

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
166701The role of AMP-activated protein kinase in adipocyte glucose transport and insulin signalling - utilising a knockout mouse modelIan SaltDiabetes UK (DIABETUK)09/0003904Institute of Cardiovascular & Medical Sciences
190426The sensitive assessment of the activity of cellular signalling pathways regulating insulin action and the cardiovascular complications of diabetesIan SaltDiabetes UK (DIABETUK)11/0004309Institute of Cardiovascular & Medical Sciences