The contributions of oxidative stress, oxidised lipoproteins and AMPK towards exercise-associated PPARγ signalling within human monocytic cells
Hughes, Michael G.
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Peroxisome proliferator-activated receptor gamma (PPARγ) is known to be activated via exercise-associated transient increases in oxidative stress. However, the precise mechanism(s) triggering PPARγ activation in monocytes during/following exercise remain to be confirmed. Here, two cohorts of five healthy male individuals undertook exercise bouts (cycling; 70% O2max; 45 min) in the presence/absence of dietary antioxidant supplementation (vitamins C (1000 mg/day) and E (400IU/day) for four weeks before exercise); monocytic 5’ adenosine monophosphate-activated protein kinase (AMPK)/PPARγ co-activator-1alpha (PGC-1α)/PPARγ signalling was investigated in samples obtained before exercise and up to 24 h after exercise, while THP-1 cells were cultured as an in vitro monocyte model. In THP-1 cells, AMPKα1 was phosphorylated within 1h of menadione (15 μM)-triggered increases in [reactive oxygen species (ROS)]cyto, an effect which was followed by upregulation of PPARγ and several of its target genes (PGC-1α, liver X receptor alpha [LXRα] and ATP-binding cassette subfamily A, member 1 [ABCA1]; 24–72 h), with these effects being blunted by co-administration of vitamin C (62.5 μM). Conversely, treatment with oxidised low-density lipoprotein (oxLDL) (1 μg/mL; 24–72 h), but not non-oxidised LDL, upregulated the above PPARγ-regulated genes without affecting AMPKα1 phosphorylation. In vivo, dietary antioxidant supplementation (which is known to prevent exercise-triggered increases in oxLDL levels) blunted exercise-associated upregulation of the above PPARγ-regulated genes, but had no effect on exercise-associated transient [ROS]cyto increases, or on AMPK phosphorylation. These data suggest that exercise-associated PPARγ signalling effects appear, at least in monocytes, to be mediated by increased generation of PPARγ ligands via oxidation of lipoproteins (following exercise-associated transient increases in oxidative stress), rather than via [ROS]cyto-mediated AMPK activation. These findings may be of clinical relevance, as PPARγ activation in monocytes is associated with beneficial effects related to type-2 diabetes and its cardiovascular complications.
Free Radical Research
Davies, N.A., Watkeys, L., Butcher, L., Potter, S., Hughes, M.G., Moir, H., Morris, K., Thomas, A.W. and Webb, R., (2015) 'The contributions of oxidative stress, oxidised lipoproteins and AMPK towards exercise-associated PPARγ signalling within human monocytic cells', Free radical research, 49(1), pp.45-56.
This article was published in Free Radical Research on 12 November 2014 (online), available at http://dx.doi.org/10.3109/10715762.2014.978311
Nia Anne Davies was the recipient of a NISCHR Welsh Office Research and Development PhD studentship (2009–2013).
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