The contributions of oxidative stress, oxidised lipoproteins and AMPK towards exercise-associated PPARγ signalling within human monocytic cells.
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% VO2max; 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.
Cardiff School of Health Sciences, Cardiff Metropolitan University , Cardiff , UK.
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NA
Davies
L
L
Watkeys
L
L
Butcher
S
S
Potter
M G
MG
Hughes
H
H
Moir
K
K
Morris
A W
AW
Thomas
R
R
Webb
D055372:AMP-Activated Protein Kinases / Q000097:blood*; D000328:Adult; D000975:Antioxidants / Q000008:administration & dosage; D002478:Cells, Cultured; D015331:Cohort Studies; D015444:Exercise / Q000502:physiology*; D006801:Humans; D008077:Lipoproteins, LDL / Q000097:blood* / Q000494:pharmacology; D008297:Male; D009000:Monocytes / Q000378:metabolism*; D018384:Oxidative Stress / Q000502:physiology; D047495:PPAR gamma / Q000097:blood*; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D014157:Transcription Factors / Q000097:blood
D000975:Antioxidants; D008077:Lipoproteins, LDL; D047495:PPAR gamma; C486497:PPARGC1A protein, human; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D017382:Reactive Oxygen Species; D014157:Transcription Factors; C099252:oxidized low density lipoprotein; D055372:AMP-Activated Protein Kinases; C526180:PRKAA1 protein, human
AMPK; PPARγ; antioxidant supplementation; exercise-associated oxidative stress; monocytes