A-769662 inhibits adipocyte glucose uptake in an AMPK-independent manner
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A-769662 inhibits adipocyte glucose uptake in an AMPK-independent manner. / Kopietz, Franziska; Alshuweishi, Yazeed; Bijland, Silvia; Alghamdi, Fatmah; Degerman, Eva; Sakamoto, Kei; Salt, Ian P.; Göransson, Olga.
I: Biochemical Journal, Bind 478, Nr. 3, 2021, s. 633-646.Publikation: Bidrag til tidsskrift › Tidsskriftartikel › Forskning › fagfællebedømt
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T1 - A-769662 inhibits adipocyte glucose uptake in an AMPK-independent manner
AU - Kopietz, Franziska
AU - Alshuweishi, Yazeed
AU - Bijland, Silvia
AU - Alghamdi, Fatmah
AU - Degerman, Eva
AU - Sakamoto, Kei
AU - Salt, Ian P.
AU - Göransson, Olga
PY - 2021
Y1 - 2021
N2 - 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-β-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 AMPKβ1 S108A knock-in mice were employed to investigate the 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 AMPKβ1 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.
AB - 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-β-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 AMPKβ1 S108A knock-in mice were employed to investigate the 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 AMPKβ1 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.
U2 - 10.1042/BCJ20200659
DO - 10.1042/BCJ20200659
M3 - Journal article
C2 - 33493298
AN - SCOPUS:85100954427
VL - 478
SP - 633
EP - 646
JO - Biochemical Journal
JF - Biochemical Journal
SN - 0264-6021
IS - 3
ER -
ID: 258779245