NFAT-133 increases glucose uptake in L6 myotubes by activating AMPK pathway

• Published in: European journal of pharmacology 2015-12, Vol.769, p.117-126
• Main Authors: Thakkar, Chandni S., Kate, Abhijeet S., Desai, Dattatraya C., Ghosh, Asit Ranjan, Kulkarni-Almeida, Asha A.
• Format: Article
• Language: English
• Subjects: Adenosine Monophosphate - metabolism; Adenosine Triphosphate - metabolism; AMP-Activated Protein Kinases - antagonists & inhibitors; AMP-Activated Protein Kinases - metabolism; AMP/ATP ratio; AMPK; Animals; Biological Transport - drug effects; Cell Line; Dose-Response Relationship, Drug; Enzyme Activation - drug effects; Glucose - metabolism; Glucose Transporter Type 4 - metabolism; Glucose uptake; GTPase-Activating Proteins - metabolism; Humans; Insulin - pharmacology; L6 myotubes; Membrane Potential, Mitochondrial - drug effects; Mice; Mitochondrial membrane potential; Muscle Fibers, Skeletal - cytology; Muscle Fibers, Skeletal - drug effects; Muscle Fibers, Skeletal - metabolism; NFAT-133; Pentanols - pharmacology; Pentanones - pharmacology; Phosphorylation - drug effects; Protein Kinase Inhibitors - pharmacology; Rats; Signal Transduction - drug effects; Time Factors
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2015.11.006

NFAT-133 is an aromatic compound with cinammyl alcohol moiety, isolated from streptomycetes strain PM0324667. We have earlier reported that NFAT-133 increases insulin stimulated glucose uptake in L6 myotubes using a PPARγ independent mechanism and reduces plasma or blood glucose levels in diabetic mice. Here we investigated the effects of NFAT-133 on cellular signaling pathways leading to glucose uptake in L6 myotubes. Our studies demonstrate that NFAT-133 increases glucose uptake in a dose- and time-dependent manner independent of the effects of insulin. Treatment with Akti-1/2, wortmannin and increasing concentrations of insulin had no effect on NFAT-133 mediated glucose uptake. NFAT-133 induced glucose uptake is completely mitigated by Compound C, an AMPK inhibitor. Further, the kinases upstream of AMPK activation namely; LKB-1 and CAMKKβ are not involved in NFAT-133 mediated AMPK activation nor does the compound NFAT-133 have any effect on AMPK enzyme activity. Further analysis confirmed that NFAT-133 indirectly activates AMPK by reducing the mitochondrial membrane potential and increasing the ratio of AMP:ATP.