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

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          Abstract

          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.

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          Author and article information

          Journal
          J. Biol. Chem.
          The Journal of biological chemistry
          1083-351X
          0021-9258
          Jul 3 2015
          : 290
          : 27
          Affiliations
          [1 ] From the Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada, the Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada, and.
          [2 ] From the Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
          [3 ] the Centre de Génétique et de Physiologie Moléculaire et Cellulaire, Université Claude Bernard Lyon 1, Villeurbanne 69622, France.
          [4 ] From the Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada, the Department of Physiology, University of Toronto, Toronto, Ontario M5S 1A8, Canada, and amira@sickkids.ca.
          Article
          M115.646992
          10.1074/jbc.M115.646992
          4505442
          25987561
          © 2015 by The American Society for Biochemistry and Molecular Biology, Inc.

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