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RELATED PAPERS |
1 Cellular and Molecular Metabolism Laboratory, School of Medical Sciences, RMIT University, Bundoora, Victoria, 3083, Australia
2 St Vincent's Institute and Department of Medicine, University of Melbourne, Fitzroy, Victoria, 3065, Australia
3 CSIRO Molecular Health Technologies, 343 Royal Parade, Parkville, Victoria, 3052, Australia
We investigated the role of fatty acid availability on AMPK signalling and fatty acid oxidation in skeletal muscle. Incubating L6 skeletal muscle myotubes with palmitate (a saturated fatty acid) or linoleate (a polyunsaturated fatty acid) increased AMPK activity by 56 and 38%, respectively, compared with untreated cells. Consistent with these changes, AMPK Thr172 and acetyl-CoA carboxylase ß Ser218 phosphorylation were increased in fatty acid treated cells. Pre-incubating cells with palmitate or linoleate increased subsequent fatty acid oxidation by 86 and 92%, respectively. The enhanced AMPK signalling occurred in the absence of detectable changes in free AMP and glycogen content. The activity of the upstream kinase LKB1 was decreased by fatty acid treatment indicating that AMPK activation was not a consequence of LKB1 activation. Instead, fatty acids enhanced LKB1 phosphorylation of AMPK. Fatty acids did not alter LKB1 activity when either synthetic peptide or AMPK 
(1–312) catalytic fragment was used as substrate indicating that the ß
subunits were required for the fatty acid activation. Infection of cells with a dominant-negative AMPK adenovirus reduced basal fatty acid oxidation and inhibited the stimulatory effects of fatty acid pretreatment on fatty acid oxidation. These results indicate that increasing fatty acid availability increases AMPK activity independent of changes in the cellular energy charge and support the view that fatty acids may modulate AMPK allosterically, making it a better substrate for LKB1.
(Received 9 February 2006;
accepted after revision 24 April 2006;
first published online 27 April 2006)
Corresponding author M. J. Watt: Street Vincent's Institute of Medical Research, 9 Princes Street, Fitzroy, Victoria, 3065, Australia. Email: mwatt{at}svi.edu.au
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