A rise in tissue-embedded macrophages displaying "M1-like" proinflammatory polarization is a hallmark of metabolic
inflammation during a high fat diet or
obesity. Here we show that bone marrow-derived macrophages (BMDM) from high fat-fed mice retain a memory of their dietary environment in vivo (displaying the elevated proinflammatory genes Cxcl1,
Il6, Tnf, Nos2) despite 7-day differentiation and proliferation ex vivo. Notably, 6-h incubation with
palmitoleate (PO) reversed the proinflammatory gene expression and
cytokine secretion seen in BMDM from high fat-fed mice. BMDM from low fat-fed mice exposed to
palmitate (PA) for 18 h ex vivo also showed elevated expression of proinflammatory genes (Cxcl1,
Il6, Tnf, Nos2, and Il12b) associated with M1 polarization. Conversely, PO treatment increased anti-inflammatory genes (Mrc1, Tgfb1,
Il10, Mgl2) and oxidative metabolism, characteristic of M2 macrophages. Therefore, saturated and
unsaturated fatty acids bring about opposite macrophage polarization states. Coincubation of BMDM with both
fatty acids counteracted the PA-induced Nos2 expression in a PO dose-dependent fashion. PO also prevented PA-induced IκBα degradation, RelA nuclear translocation, NO production, and
cytokine secretion. Mechanistically, PO exerted its anti-inflammatory function through
AMP-activated protein kinase as
AMP kinase knockout or inhibition by Compound C offset the PO-dependent prevention of PA-induced
inflammation. These results demonstrate a nutritional memory of BMDM ex vivo, highlight the plasticity of BMDM polarization in response to saturated and
unsaturated fatty acids, and identify the potential to reverse diet- and saturated fat-induced M1-like polarization by administering
palmitoleate. These findings could have applicability to reverse
obesity-linked
inflammation in metabolically relevant tissues.