MCP-1 release was significantly decreased by 26%(p < 0.01) in 24 h DNP (30 渭mol/L)-treated adipocytes compared to control cells. In contrast, secreted VEGF120 lacking a heparin-binding domain was markedly increased 2.0-fold (p < 0.01). CHOP content in these cells also were augmented (p < 0.01), but no significant increase of endogenous oxidative stress was observed. Treatment with thapsigargin, which can induce exogenous endoplasmic reticulum (ER) stress, clearly attenuated MCP-1 release (p < 0.01), but exhibited no effects on VEGF120 secretion. On the other hand, exogenous H2O2 amplified both MCP-1 and VEGF120 secretion (p < 0.05). In addition, under chronic activation of AMPK by AICAR, MCP-1 release was significantly diminished (p < 0.05) but VEGF120 secretion was increased (p < 0.01). JNK phosphorylation in mature adipocytes was decreased by treatment with either DNP or AICAR (p < 0.01). Enhanced VEGF120 secretion with either DNP or AICAR was markedly suppressed by PI3K inhibitor (p < 0.01).
Thus, induced mitochondrial uncoupling in adipocytes can reduce MCP-1 release through induction of endogenous ER stress and by reduced JNK activities via chronic activation of AMPK. Under this condition, VEGF120 secretion was increased through PI3K-dependent pathways, which were chronically activated by AMPK, and not through ER stress. Because the decrease of MCP-1 secretion under mitochondrial uncoupling might attenuate chronic low-grade inflammation by suppressing macrophages recruitment to adipose tissue, clarification of the mechanism might reveal novel therapeutic targets for ameliorating obesity-associated insulin resistance in metabolic syndrome and type 2 diabetes.