Abstract
BMS309403 is a biphenyl azole inhibitor against fatty acid binding protein 4 (FABP4) and regarded as a lead compound for effective treatment of obesity related cardio-metabolic diseases. Here we discovered an off-target activity of BMS309403 in that it stimulates glucose uptake in C2C12 myotubes in a temporal and dose dependent manner via activation of AMP-activated protein kinase (AMPK) signaling pathway but independent of FABPs. Further analysis indicated that BMS309403 activates AMPK through increasing the ratio of intracellular AMP:ATP while decreasing mitochondrial membrane potential. These findings provide mechanistic insights on the action of BMS309403.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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AMP-Activated Protein Kinases / metabolism*
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Adenosine Monophosphate / metabolism
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Adenosine Triphosphate / metabolism
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Animals
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Biphenyl Compounds / pharmacology*
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Blotting, Western
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Cell Line
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Cytosol / metabolism
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Enzyme Activation / drug effects
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Fatty Acid Binding Protein 3
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Fatty Acid-Binding Proteins / metabolism
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Gene Knockdown Techniques
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Glucose / metabolism*
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Membrane Potential, Mitochondrial / drug effects
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Mice
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Muscle Fibers, Skeletal / drug effects
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Muscle Fibers, Skeletal / enzymology*
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Phosphorylation / drug effects
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Pyrazoles / pharmacology*
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Signal Transduction / drug effects
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Time Factors
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p38 Mitogen-Activated Protein Kinases / metabolism
Substances
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2-(2'-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)biphenyl-3-yloxy)acetic acid
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Biphenyl Compounds
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FABP3 protein, human
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Fatty Acid Binding Protein 3
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Fatty Acid-Binding Proteins
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Pyrazoles
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Adenosine Monophosphate
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Adenosine Triphosphate
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p38 Mitogen-Activated Protein Kinases
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AMP-Activated Protein Kinases
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Glucose