The ULK1/2 and AMPK inhibitor SBI-0206965 blocks AICAR and insulin-stimulated glucose transport
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The ULK1/2 and AMPK inhibitor SBI-0206965 blocks AICAR and insulin-stimulated glucose transport. / Knudsen, Jonas Roland; Madsen, Agnete B; Persson, Kaspar W; Henríquez-Olguín, Carlos; Li, Zhencheng; Jensen, Thomas Elbenhardt.
In: International Journal of Molecular Sciences , Vol. 21, No. 7, 2344, 2020.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - The ULK1/2 and AMPK inhibitor SBI-0206965 blocks AICAR and insulin-stimulated glucose transport
AU - Knudsen, Jonas Roland
AU - Madsen, Agnete B
AU - Persson, Kaspar W
AU - Henríquez-Olguín, Carlos
AU - Li, Zhencheng
AU - Jensen, Thomas Elbenhardt
N1 - CURIS 2020 NEXS 138
PY - 2020
Y1 - 2020
N2 - The small molecule kinase inhibitor SBI-0206965 was originally described as a specific inhibitor of ULK1/2. More recently, it was reported to effectively inhibit AMPK and several studies now report its use as an AMPK inhibitor. Currently, we investigated the specificity of SBI-0206965 in incubated mouse skeletal muscle, measuring the effect on analog 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)-stimulated AMPK-dependent glucose transport and insulin-stimulated AMPK-independent glucose uptake. Pre-treatment with 10 µM SBI-0206965 for 50 min potently suppressed AICAR-stimulated glucose transport in both the extensor digitorum longus (EDL) and soleus muscle. This was despite only a modest lowering of AICAR-stimulated AMPK activation measured as ACC2 Ser212, while ULK1/2 Ser555 phosphorylation was prevented. Insulin-stimulated glucose transport was also potently inhibited by SBI-0206965 in soleus. No major changes were observed on insulin-stimulated cell signaling. No general effect of SBI-0206965 on intracellular membrane morphology was observed by transmission electron microscopy. As insulin is known to neither activate AMPK nor require AMPK to stimulate glucose transport, and insulin inhibits ULK1/2 activity, these data strongly suggest that SBI-0206965 has a non-specific off-target inhibitory effect on muscle glucose transport. Thus, SBI-0206965 is not a specific inhibitor of the AMPK/ULK-signaling axis in skeletal muscle, and data generated with this inhibitor must be interpreted with caution.
AB - The small molecule kinase inhibitor SBI-0206965 was originally described as a specific inhibitor of ULK1/2. More recently, it was reported to effectively inhibit AMPK and several studies now report its use as an AMPK inhibitor. Currently, we investigated the specificity of SBI-0206965 in incubated mouse skeletal muscle, measuring the effect on analog 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR)-stimulated AMPK-dependent glucose transport and insulin-stimulated AMPK-independent glucose uptake. Pre-treatment with 10 µM SBI-0206965 for 50 min potently suppressed AICAR-stimulated glucose transport in both the extensor digitorum longus (EDL) and soleus muscle. This was despite only a modest lowering of AICAR-stimulated AMPK activation measured as ACC2 Ser212, while ULK1/2 Ser555 phosphorylation was prevented. Insulin-stimulated glucose transport was also potently inhibited by SBI-0206965 in soleus. No major changes were observed on insulin-stimulated cell signaling. No general effect of SBI-0206965 on intracellular membrane morphology was observed by transmission electron microscopy. As insulin is known to neither activate AMPK nor require AMPK to stimulate glucose transport, and insulin inhibits ULK1/2 activity, these data strongly suggest that SBI-0206965 has a non-specific off-target inhibitory effect on muscle glucose transport. Thus, SBI-0206965 is not a specific inhibitor of the AMPK/ULK-signaling axis in skeletal muscle, and data generated with this inhibitor must be interpreted with caution.
KW - Faculty of Science
KW - AMPK
KW - ULK1/2
KW - Skeletal muscle
KW - Kinase inhibitor
KW - SBI-0206965
U2 - 10.3390/ijms21072344
DO - 10.3390/ijms21072344
M3 - Journal article
C2 - 32231045
VL - 21
JO - International Journal of Molecular Sciences (Online)
JF - International Journal of Molecular Sciences (Online)
SN - 1661-6596
IS - 7
M1 - 2344
ER -
ID: 241041113