Exercise-associated generation of PPAR ligands activates PPAR signaling events and upregulates genes related to lipid metabolism

The aim of the present study was to test the hypotheses that exercise is associated with generation of peroxisome proliferator-activated receptor-╬│ (PPAR╬│) ligands in the plasma and that this may activate PPAR╬│ 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 PPAR╬│ response element (PPRE)-luciferase reporter gene assays showed increased PPAR╬│ activity following standardized exercise bouts (Post/Pre = 1.23 ± 0.10 at week 0, P < 0.05), suggesting that PPAR╬│ ligands were generated during exercise. However, increases in PPAR╬│/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 PPAR╬│ ligand generation. In untrained individuals, specific transient increases in monocyte expression of PPAR╬│-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 PPAR╬│ 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 PPAR╬│-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 PPAR╬│ activation has been linked to beneficial antidiabetic effects (e.g., exercise-induced upregulation of monocytic PPAR╬│-controlled genes is associated with reverse cholesterol transport and anti-inflammatory effects). Thus, exercise-triggered monocyte PPAR╬│ activation may constitute an additional rationale for prescribing exercise to type 2 diabetes patients.