title: Palmitoleate Reverses High Fat-induced Proinflammatory Macrophage Polarization via AMP-activated Protein Kinase (AMPK).
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.
authors.affiliation: 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.
authors.forename: Kenny L
authors.initials: KL
authors.lastname: Chan
authors.affiliation: From the Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
authors.forename: Nicolas J
authors.initials: NJ
authors.lastname: Pillon
authors.affiliation: From the Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
authors.forename: Darshan M
authors.initials: DM
authors.lastname: Sivaloganathan
authors.affiliation: From the Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
authors.forename: Sheila R
authors.initials: SR
authors.lastname: Costford
authors.affiliation: From the Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario M5G 0A4, Canada.
authors.forename: Zhi
authors.initials: Z
authors.lastname: Liu
authors.affiliation: the Centre de Génétique et de Physiologie Moléculaire et Cellulaire, Université Claude Bernard Lyon 1, Villeurbanne 69622, France.
authors.forename: Marine
authors.initials: M
authors.lastname: Théret
authors.affiliation: the Centre de Génétique et de Physiologie Moléculaire et Cellulaire, Université Claude Bernard Lyon 1, Villeurbanne 69622, France.
authors.forename: Benedicte
authors.initials: B
authors.lastname: Chazaud
authors.affiliation: 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.
authors.forename: Amira
authors.initials: A
authors.lastname: Klip
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000235:genetics / Q000276:immunology*; D000818:Animals; D016764:Cell Polarity; D059305:Diet, High-Fat / Q000009:adverse effects; D004041:Dietary Fats / Q000009:adverse effects / Q000378:metabolism; D005229:Fatty Acids, Monounsaturated / Q000737:chemistry / Q000276:immunology* / Q000378:metabolism; D006801:Humans; D008264:Macrophages / Q000166:cytology / Q000276:immunology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009765:Obesity / Q000201:enzymology* / Q000235:genetics / Q000276:immunology* / Q000378:metabolism
chemical_list: D004041:Dietary Fats; D005229:Fatty Acids, Monounsaturated; C008757:palmitoleic acid; D055372:AMP-Activated Protein Kinases
keywords: AMP-activated kinase (AMPK); fatty acid; inflammation; macrophage; obesity