Lipid accumulation in macrophages interacts with microenvironment signals and accelerates diabetic
atherosclerosis. However, the molecular mechanisms by which macrophage metabolism interacts with microenvironment signals during
lipid accumulation are not clearly understood. Accordingly, an untargeted metabolomics approach was employed to characterize the metabolic reprogramming, and to identify potential regulatory targets related to
lipid accumulation in macrophages treated with
oleate, an important nutrient. The metabolomics approach revealed that multiple metabolic pathways were significantly disturbed in
oleate-treated macrophages. We discovered that
amino acids,
nucleosides,
lactate,
monoacylglycerols, total
free fatty acids (FFAs), and
triglycerides (TGs) accumulated in
oleate-treated macrophages, but these effects were effectively attenuated or even abolished by
resveratrol. Notably, 1-monooleoylglycerol and 2-monooleoylglycerol showed the largest fold changes in the levels among the differential metabolites. Subsequently, we found that
oleate triggered total FFA and TG accumulation in macrophages by accelerating FFA influx through the activation of Fatp1 expression, but this effect was attenuated by
resveratrol via the activation of PPARα and PPARγ signaling. We verified that the activation of PPARα and PPARγ by WY14643 and
pioglitazone, respectively, attenuated
oleate triggered total FFA and TG accumulation in macrophages by repressing FFA import via the suppression of Fatp1 expression. Furthermore, the inhibition of Fatp1 by
tumor necrosis factor α alleviated
oleate-induced total FFA and TG accumulation in macrophages. This study provided the first demonstration that accumulation of
amino acids,
nucleosides,
lactate,
monoacylglycerols, total FFAs, and TGs in
oleate-treated macrophages is effectively attenuated or even abolished by
resveratrol, and that the activation of PPARα and PPARγ attenuates
oleate-induced total FFA and TG accumulation via suppression of Fatp1 expression in macrophages. Therapeutic strategies aim to activate
PPAR signaling, and to repress FFA import and
triglyceride synthesis are promising approaches to reduce the risk of
obesity, diabetes and
atherosclerosis.