Excessive adiposity in obese individuals is accompanied by low-level inflammation, which is regarded as the mechanistic link between obesity and related cardiovascular and diabetic complications. Improvement of the inflammatory components accompanying diabetes and metabolic syndrome is a current goal. Co-ligands of PPARα and Γ, combining the metabolic- and anti-inflammatory properties of α and Γ agonists, are one therapeutic option. Adipose tissue production of MCP-1 orchestrates monocyte-macrophage recruitment into inflamed adipose tissue. We therefore investigated whether the dual agonist ALE, in comparison to selective agonists for PPARα and Γ, fenofibrate(FENO) and rosiglitazone(RSG) respectively, regulates MCP-1 expression in fully differentiated human Simpson-Golabi-Behmel syndrome adipocytes (SGBS cells) and human umbilical vein endothelial cells (HUVEC), and explored underlying mechanisms.
Methods: SGBS cells and HUVEC were treated with 0.01-1000 nmol/L ALE and RSG or 5-50 μmol/L FENO for 24 h before stimulation with 10 ng/mL TNFα. Conditioned media were then tested for MCP-1 release by ELISA, while in parallel, MCP-1 mRNA expression was investigated by q-PCR, the activation of NF-κB by transactivation assay, and the activation status of p38 mitogen-activated protein (MAP) kinase, Jun N-terminal kinase (JNK) and p44/42 extracellular-signal-regulated kinase (ERK1/2) were assessed by Western analysis using antibodies recognizing the phosphorylated (activated) forms of each kinases.
Results: MCP-1 release, in both SGBS cells and HUVEC increased significantly after stimulation with TNFα for 24 h (P<0.01). In SGBS cells, but not in HUVEC, ALE, RSG and FENO reduced TNFα-induced MCP-1 release in a concentration dependent manner, with a maximal inhibitory concentration, at 10 and 125 nmol/L for ALE and RSG respectively (P<0.01) and 50 μmol/L (P<0.01) for FENO. At the same concentrations ALE also reduced MCP-1 mRNA expression by 40% (P<0.05 versus TNFα). At 10 nmol/L ALE minimally inhibited TNFα-induced activation of NF-κB, but significantly reduced the activation of p38 MAP kinase and JNK.
Conclusions: ALE, at concentrations as low as 10 nmol/L, which ensure the half-maximal activation of both PPARα and PPARΓ, selectively reduces the expression of MCP-1 in mature adipocytes. Such effect seems to be mediated, at least in part, by the interference with the activation of p38 MAP kinase. Overall, these data suggest that ALE may benefit diabetic and obese patients suppressing, in a highly cellular-selective fashion, the contribution of adipose tissue to systemic and perivascular inflammation.