title: Exercise-associated generation of PPARγ ligands activates PPARγ signaling events and upregulates genes related to lipid metabolism.
abstract: The aim of the present study was to test the hypotheses that exercise is associated with generation of peroxisome proliferator-activated receptor-γ (PPARγ) ligands in the plasma and that this may activate PPARγ signaling within circulating monocytes, thus providing a mechanism to underpin the exercise-induced antiatherogenic benefits observed in previous studies. A cohort of healthy individuals undertook an 8-wk exercise-training program; samples were obtained before (Pre) and after (Post) standardized submaximal exercise bouts (45 min of cycling at 70% of maximal O(2) uptake, determined at baseline) at weeks 0, 4, and 8. Addition of plasma samples to PPARγ response element (PPRE)-luciferase reporter gene assays showed increased PPARγ activity following standardized exercise bouts (Post/Pre = 1.23 ± 0.10 at week 0, P < 0.05), suggesting that PPARγ ligands were generated during exercise. However, increases in PPARγ/PPRE-luciferase activity in response to the same standardized exercise bout were blunted during the training program (Post/Pre = 1.18 ± 0.14 and 1.10 ± 0.10 at weeks 4 and 8, respectively, P > 0.05 for both), suggesting that the relative intensity of the exercise may affect PPARγ ligand generation. In untrained individuals, specific transient increases in monocyte expression of PPARγ-regulated genes were observed within 1.5-3 h of exercise (1.7 ± 0.4, 2.6 ± 0.4, and 1.4 ± 0.1 fold for CD36, liver X receptor-α, and ATP-binding cassette subfamily A member 1, respectively, P < 0.05), with expression returning to basal levels within 24 h. In contrast, by the end of the exercise program, expression at the protein level of PPARγ target genes had undergone sustained increases that were not associated with an individual exercise bout (e.g., week 8 Pre/week 0 Pre = 2.79 ± 0.61 for CD36, P < 0.05). Exercise is known to upregulate PPARγ-controlled genes to induce beneficial effects in skeletal muscle (e.g., mitochondrial biogenesis and aerobic respiration). We suggest that parallel exercise-induced benefits may occur in monocytes, as monocyte PPARγ activation has been linked to beneficial antidiabetic effects (e.g., exercise-induced upregulation of monocytic PPARγ-controlled genes is associated with reverse cholesterol transport and anti-inflammatory effects). Thus, exercise-triggered monocyte PPARγ activation may constitute an additional rationale for prescribing exercise to type 2 diabetes patients.
authors.affiliation: Cardiff School of Health Sciences, UWIC, Cardiff CF5 2YB, UK. rwebb@uwic.ac.uk
authors.forename: A W
authors.initials: AW
authors.lastname: Thomas
authors.forename: N A
authors.initials: NA
authors.lastname: Davies
authors.forename: H
authors.initials: H
authors.lastname: Moir
authors.forename: L
authors.initials: L
authors.lastname: Watkeys
authors.forename: J S
authors.initials: JS
authors.lastname: Ruffino
authors.forename: S A
authors.initials: SA
authors.lastname: Isa
authors.forename: L R
authors.initials: LR
authors.lastname: Butcher
authors.forename: M G
authors.initials: MG
authors.lastname: Hughes
authors.forename: K
authors.initials: K
authors.lastname: Morris
authors.forename: R
authors.initials: R
authors.lastname: Webb
mesh_terms: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000328:Adult; D018955:CD36 Antigens / Q000235:genetics / Q000378:metabolism; D002461:Cell Line, Transformed; D015331:Cohort Studies; D015444:Exercise / Q000502:physiology*; D057809:HEK293 Cells; D006801:Humans; D007071:Immunoglobulin A, Secretory / Q000235:genetics / Q000378:metabolism; D008024:Ligands; D050356:Lipid Metabolism / Q000235:genetics*; D000071518:Liver X Receptors; D009000:Monocytes / Q000378:metabolism / Q000502:physiology; D057093:Orphan Nuclear Receptors / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation
chemical_list: D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D018955:CD36 Antigens; D007071:Immunoglobulin A, Secretory; D008024:Ligands; D000071518:Liver X Receptors; C000605213:NR1H3 protein, human; D057093:Orphan Nuclear Receptors; D047495:PPAR gamma