BMS309403 stimulates glucose uptake in myotubes through activation of AMP-activated protein kinase

PLoS One. 2012;7(8):e44570. doi: 10.1371/journal.pone.0044570. Epub 2012 Aug 31.

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

  • Research Support, Non-U.S. Gov't

MeSH terms

  • AMP-Activated Protein Kinases / metabolism*
  • Adenosine Monophosphate / metabolism
  • Adenosine Triphosphate / metabolism
  • Animals
  • Biphenyl Compounds / pharmacology*
  • Blotting, Western
  • Cell Line
  • Cytosol / metabolism
  • Enzyme Activation / drug effects
  • Fatty Acid Binding Protein 3
  • Fatty Acid-Binding Proteins / metabolism
  • Gene Knockdown Techniques
  • Glucose / metabolism*
  • Membrane Potential, Mitochondrial / drug effects
  • Mice
  • Muscle Fibers, Skeletal / drug effects
  • Muscle Fibers, Skeletal / enzymology*
  • Phosphorylation / drug effects
  • Pyrazoles / pharmacology*
  • Signal Transduction / drug effects
  • Time Factors
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • 2-(2'-(5-ethyl-3,4-diphenyl-1H-pyrazol-1-yl)biphenyl-3-yloxy)acetic acid
  • Biphenyl Compounds
  • FABP3 protein, human
  • Fatty Acid Binding Protein 3
  • Fatty Acid-Binding Proteins
  • Pyrazoles
  • Adenosine Monophosphate
  • Adenosine Triphosphate
  • p38 Mitogen-Activated Protein Kinases
  • AMP-Activated Protein Kinases
  • Glucose