Abstract 5469: PPARδ Agonist Decreases Inflammatory Burden of Abdominal Fat by Reducing Adipose Macrophage Levels and Chemotaxis in Humans
The peroxisome proliferator activated receptor PPARδ plays an important role in fatty acid metabolism in skeletal muscle. In vitro data suggests that the PPARδ agonist (GW501516) releases sequestered anti-inflammatory cofactors, while preclinical studies reveal a reduction in the inflammatory milieu of adipose tissue. The influence of PPARδ on human adipose tissue inflammation in vivo has not been investigated.
Methods: Sixty-eight overweight and obese male individuals without diabetes (BMI ≥27/≤ 43, waist ≥ 95 cm, TG ≥100/≤400 mg/dL, LDLc ≥80mg/dL) were evaluated for serum proteins and lipid/lipoproteins, as well as subcutaneous abdominal adipose tissue protein and gene expression microarray. Subsequently, GW501516 was administered for 3 months to a random sub-cohort of these individuals (n=16) and compared for similar measures to placebo control (n=20). Mixed-model analysis was used to assess the treatment effects by comparing post-treatment measurements to pretreatment measurements within each subject. Adipose measures were correlated using Spearman Rank correlations, with both baseline data and percent change from baseline data.
Results: In the 68 subjects (BMI mean 30, HDLc 43mg/dL±12, TG 166mg/dL±60) adipose macrophage count (HAM56 staining) correlated positively to adipose-secreted cytokines (GM-CSF, INF-gamma, IL12, and IL6 [P<0.04] and gene expression of MCP-1 mRNA [P<0.05], plus serum inflammatory markers sICAM, sVCAM, and monocyte I protein A1 [MIP-A1], P<0.04). Compared with baseline, GW501516 treatment decreased adipose macrophage cell count (−26% [95%CI −55%, 0%]), adipose secreted MIPA1 (−42% [−64%, 7%]) and RT-PCR based CD68 and CD163. Analyses for biochemical pathways (Ingenuity program) for over 100 PPARδ-altered genes (predominantly demonstrating reduced expression) revealed associations with immune cell infiltration and migration.
Conclusions: Macrophage presence in human adipose tissue identifies an inflammatory environment within adipose and serum in obese subjects. A PPARδ agonist decreases inflammation in adipose, most likely by decreasing tissue infiltration. Such nuclear receptors may concurrently control organism-wide energetics and tissue bed exposure to inflammatory scavenger cells.