Benzimidazole derivative small-molecule 991 enhances AMPK activity and glucose uptake induced by AICAR or contraction in skeletal muscle

AMP-activated protein kinase (AMPK) plays diverse roles and coordinates complex metabolic pathways for maintenance of energy homeostasis. This could be explained by the fact that AMPK exists as multiple heterotrimer complexes comprising a catalytic α-subunit (α1 and α2) and regulatory β (β1 and β2)- and (1, 2, 3)-subunits, which are uniquely distributed across different cell types. There has been keen interest in developing specific and isoform-selective AMPK-activating drugs for therapeutic use and also as research tools. Moreover, establishing ways of enhancing cellular AMPK activity would be beneficial for both purposes. Here, we investigated if a recently described potent AMPK activator called 991, in combination with the commonly used activator 5-aminoimidazole-4-carboxamide riboside or contraction, further enhances AMPK activity and glucose transport in mouse skeletal muscle ex vivo. Given that the 3-subunit is exclusively expressed in skeletal muscle and has been implicated in contraction-induced glucose transport, we measured the activity of AMPK3 as well as ubiquitously expressed 1-containing complexes. We initially validated the specificity of the antibodies for the assessment of isoform-specific AMPK activity using AMPK-deficient mouse models. We observed that a low dose of 991 (5 μM) stimulated a modest or negligible activity of both 1- and 3-containing AMPK complexes. Strikingly, dual treatment with 991 and 5-aminoimidazole-4-c...

Source: AJP: Endocrinology and Metabolism - September 30, 2016 Category: Endocrinology Authors: Bultot, L., Jensen, T. E., Lai, Y.-C., Madsen, A. L. B., Collodet, C., Kviklyte, S., Deak, M., Yavari, A., Foretz, M., Ghaffari, S., Bellahcene, M., Ashrafian, H., Rider, M. H., Richter, E. A., Sakamoto, K. Tags: Articles Source Type: research