Journal
JOURNAL OF BIOLOGICAL CHEMISTRY
Volume 290, Issue 27, Pages 16979-16988Publisher
ELSEVIER
DOI: 10.1074/jbc.M115.646992
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Funding
- Canadian Diabetes Association [OG-3-12-3838-AK]
- Canadian Institutes of Health Research [MOP-130493]
- Fondation pour la Recherche Medicale Grant Equipe FRM [DEQ20140329495]
- Banting and Best Diabetes Centre (BBDC)
- Research Training Centre from the Hospital for Sick Children
- BBDC
- SickKids Summer Research Program (SSuRe)
- French Ministry of Research
- Association Francaise contre les Myopathies
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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 I kappa B alpha 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.
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