Enhanced activation of cellular AMPK by dual-small molecule treatment: AICAR and A769662
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Enhanced activation of cellular AMPK by dual-small molecule treatment : AICAR and A769662. / Ducommun, Serge; Ford, Rebecca J.; Bultot, Laurent; Deak, Maria; Bertrand, Luc; Kemp, Bruce E.; Steinberg, Gregory R.; Sakamoto, Kei.
In: American Journal of Physiology - Endocrinology and Metabolism, Vol. 306, No. 6, 15.03.2014, p. E688-E696.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Enhanced activation of cellular AMPK by dual-small molecule treatment
T2 - AICAR and A769662
AU - Ducommun, Serge
AU - Ford, Rebecca J.
AU - Bultot, Laurent
AU - Deak, Maria
AU - Bertrand, Luc
AU - Kemp, Bruce E.
AU - Steinberg, Gregory R.
AU - Sakamoto, Kei
PY - 2014/3/15
Y1 - 2014/3/15
N2 - AMP-activated protein kinase (AMPK) is a key cellular energy sensor and regulator of metabolic homeostasis. Activation of AMPK provides beneficial outcomes in fighting against metabolic disorders such as insulin resistance and type 2 diabetes. Currently, there is no allosteric AMPK activator available for the treatment of metabolic diseases, and limited compounds are available to robustly stimulate cellular/tissue AMPK in a specific manner. Here we investigated whether simultaneous administration of two different pharmacological AMPK activators, which bind and act on different sites, would result in an additive or synergistic effect on AMPK and its downstream signaling and physiological events in intact cells. We observed that cotreating primary hepatocytes with the AMP mimetic 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) and a low dose (1 μM) of the allosteric activator A769662 produced a synergistic effect on AMPK Thr172 phosphorylation and catalytic activity, which was associated with a more profound increase/decrease in phosphorylation of downstream AMPK targets and inhibition of hepatic lipogenesis compared with single-compound treatment. Mechanistically, we found that cotreatment does not stimulate LKB1, upstream kinase for AMPK, but it protects against dephosphorylation of Thr172 phosphorylation by protein phosphatase PP2Cα in an additive manner in a cell-free assay. Collectively, we demonstrate that AICAR sensitizes the effect of A769662 and promotes AMPK activity and its downstream events. The study demonstrates the feasibility of promoting AMPK activity by using two activators with distinct modes of action in order to achieve a greater activation of AMPK and downstream signaling.
AB - AMP-activated protein kinase (AMPK) is a key cellular energy sensor and regulator of metabolic homeostasis. Activation of AMPK provides beneficial outcomes in fighting against metabolic disorders such as insulin resistance and type 2 diabetes. Currently, there is no allosteric AMPK activator available for the treatment of metabolic diseases, and limited compounds are available to robustly stimulate cellular/tissue AMPK in a specific manner. Here we investigated whether simultaneous administration of two different pharmacological AMPK activators, which bind and act on different sites, would result in an additive or synergistic effect on AMPK and its downstream signaling and physiological events in intact cells. We observed that cotreating primary hepatocytes with the AMP mimetic 5-aminoimidazole-4-carboxamide-1-β-D-ribofuranoside (AICAR) and a low dose (1 μM) of the allosteric activator A769662 produced a synergistic effect on AMPK Thr172 phosphorylation and catalytic activity, which was associated with a more profound increase/decrease in phosphorylation of downstream AMPK targets and inhibition of hepatic lipogenesis compared with single-compound treatment. Mechanistically, we found that cotreatment does not stimulate LKB1, upstream kinase for AMPK, but it protects against dephosphorylation of Thr172 phosphorylation by protein phosphatase PP2Cα in an additive manner in a cell-free assay. Collectively, we demonstrate that AICAR sensitizes the effect of A769662 and promotes AMPK activity and its downstream events. The study demonstrates the feasibility of promoting AMPK activity by using two activators with distinct modes of action in order to achieve a greater activation of AMPK and downstream signaling.
KW - 5-aminoimidazole- 4-carboxamide-1-ß-D-ribofuranoside
KW - A769662
KW - AMP-activated protein kinase
KW - Lipogenesis
KW - LKB1
UR - http://www.scopus.com/inward/record.url?scp=84900537112&partnerID=8YFLogxK
U2 - 10.1152/ajpendo.00672.2013
DO - 10.1152/ajpendo.00672.2013
M3 - Journal article
C2 - 24425763
AN - SCOPUS:84900537112
VL - 306
SP - E688-E696
JO - A J P: Endocrinology and Metabolism (Online)
JF - A J P: Endocrinology and Metabolism (Online)
SN - 1522-1555
IS - 6
ER -
ID: 239215547