Palmitoleate Reverses High Fat-induced Proinflammatory Macrophage Polarization via AMP-activated Protein Kinase (AMPK)

Abstract A rise in tissue-embedded macrophages displaying "M1-like" pro-inflammatory polarization is a hallmark of metabolic inflammation during high fat diet or obesity. Here we show that bone marrow-derived macrophages (BMDM) from high fat-fed mice retain memory of their dietary environment in vivo (displaying elevated pro-inflammatory genes Cxcl1, Il6, Tnf, Nos2), in spite of 7-days differentiation and proliferation ex vivo. Notably, 6 h incubation with palmitoleate (PO) reversed the pro-inflammatory 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 pro-inflammatory genes (Cxcl1, Il6, Tnf, Nos2, Il12b) associated with M1 polarization. Conversely, PO treatment increased anti-inflammatory genes (Mrc1, Tgfb1, Il10, Mgl2), and oxidative metabolism, characteristic of M2 macrophages. Thus, saturated and unsaturated fatty acids bring about opposite macrophage polarization states. Co-incubation of BMDM with both fatty acids counteracted the PA-induced Nos2 expression in a PO dose-dependent fashion. PO also prevented the PA-induced IκBα degradation, RelA nuclear translocation, NO production and cytokine secretion. Mechanistically, PO exerted its anti-inflammatory function through AMPK, as AMPK inhibition by Compound C offset the PO-dependent prevention of PA-induced IκBα degradation, Nos2 expression and NO production. 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.