title: NFAT-133 increases glucose uptake in L6 myotubes by activating AMPK pathway.
abstract: 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.
authors.affiliation: Screening-Metabolic Disorders Translational Unit, Piramal Enterprises Limited, 1A-Nirlon Complex, Off Western Express Highway, Goregaon (East), Mumbai 400063, Maharashtra, India.
authors.forename: Chandni S
authors.initials: CS
authors.lastname: Thakkar
authors.affiliation: Department of Natural Products, Piramal Enterprises Limited, 1A-Nirlon Complex, Off Western Express Highway, Goregaon (East), Mumbai 400063, Maharashtra, India.
authors.forename: Abhijeet S
authors.initials: AS
authors.lastname: Kate
authors.affiliation: Department of Medicinal Chemistry, Piramal Enterprises Limited, 1A-Nirlon Complex, Off Western Express Highway, Goregaon (East), Mumbai 400063, Maharashtra, India.
authors.forename: Dattatraya C
authors.initials: DC
authors.lastname: Desai
authors.affiliation: Centre for Infectious Diseases & Control, School of BioSciences and Technology, VIT University, Vellore 632014, Tamil Nadu, India.
authors.forename: Asit Ranjan
authors.initials: AR
authors.lastname: Ghosh
authors.affiliation: Screening-Metabolic Disorders Translational Unit, Piramal Enterprises Limited, 1A-Nirlon Complex, Off Western Express Highway, Goregaon (East), Mumbai 400063, Maharashtra, India. Electronic address: asha_almeida@yahoo.co.in.
authors.forename: Asha A
authors.initials: AA
authors.lastname: Kulkarni-Almeida
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D000249:Adenosine Monophosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001692:Biological Transport / Q000187:drug effects; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D020690:GTPase-Activating Proteins / Q000378:metabolism; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D051379:Mice; D018485:Muscle Fibers, Skeletal / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D000439:Pentanols / Q000494:pharmacology*; D010422:Pentanones / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects*; D013997:Time Factors
chemical_list: D020690:GTPase-Activating Proteins; D051275:Glucose Transporter Type 4; D007328:Insulin; C094349:NFAT 133; D000439:Pentanols; D010422:Pentanones; D047428:Protein Kinase Inhibitors; C533101:TBC1D4 protein, rat; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D055372:AMP-Activated Protein Kinases; D005947:Glucose
keywords: AMP/ATP ratio; AMPK; Glucose uptake; L6 myotubes; Mitochondrial membrane potential; NFAT-133