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The delta 6 desaturase knock out mouse reveals that immunomodulatory effects of essential n-6 and n-3 polyunsaturated fatty acids are both independent of and dependent upon conversion.
J Nutr Biochem. 2016 06; 32:29-38.JN

Abstract

Typically fatty acids (FA) exert differential immunomodulatory effects with n-3 [α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] and n-6 [linoleic acid (LA) and arachidonic acid (AA)] exerting anti- and pro-inflammatory effects, respectively. This over-simplified interpretation is confounded by a failure to account for conversion of the parent FA (LA and ALA) to longer-chain bioactive products (AA and EPA/DHA, respectively), thereby precluding discernment of the immunomodulatory potential of specific FA. Therefore, we utilized the Δ6-desaturase model, wherein knockout mice (D6KO) lack the Fads2 gene encoding for the rate-limiting enzyme that initiates FA metabolism, thereby providing a model to determine specific FA immunomodulatory effects. Wild-type (WT) and D6KO mice were fed one of four isocaloric diets differing in FA source (9weeks): corn oil (LA-enriched), arachidonic acid single cell oil (AA-enriched), flaxseed oil (ALA-enriched) or menhaden fish oil (EPA/DHA-enriched). Splenic mononuclear cell cytokine production in response to lipopolysaccharide (LPS), T-cell receptor (TCR) and anti-CD40 stimulation was determined. Following LPS stimulation, AA was more bioactive compared to LA, by increasing inflammatory cytokine production of IL-6 (1.2-fold) and TNFα (1.3-fold). Further, LPS-stimulated IFNγ production in LA-fed D6KO mice was reduced 5-fold compared to LA-fed WT mice, indicating that conversion of LA to AA was necessary for cytokine production. Conversely, ALA exerted an independent immunomodulatory effect from EPA/DHA and all n-3 FA increased LPS-stimulated IL-10 production versus LA and AA. These data definitively identify specific immunomodulatory effects of individual FA and challenge the simplified view of the immunomodulatory effects of n-3 and n-6 FA.

Authors+Show Affiliations

Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1; Guelph Food Research Centre, Agriculture Agri-Food Canada, Guelph, ON, Canada, N1G 5C9.Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1.Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1.Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1.Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1.Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1.Department of Food Science and Human Nutrition, University of Illinois at Urbana-Champaign, Urbana, IL, USA, 61801.Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1; Guelph Food Research Centre, Agriculture Agri-Food Canada, Guelph, ON, Canada, N1G 5C9.Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1. Electronic address: davidma@uoguelph.ca.Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, ON, Canada, N1G 2W1. Electronic address: lrobinso@uoguelph.ca.

Pub Type(s)

Comparative Study
Journal Article

Language

eng

PubMed ID

27142734

Citation

Monk, Jennifer M., et al. "The Delta 6 Desaturase Knock Out Mouse Reveals That Immunomodulatory Effects of Essential N-6 and N-3 Polyunsaturated Fatty Acids Are Both Independent of and Dependent Upon Conversion." The Journal of Nutritional Biochemistry, vol. 32, 2016, pp. 29-38.
Monk JM, Liddle DM, Cohen DJ, et al. The delta 6 desaturase knock out mouse reveals that immunomodulatory effects of essential n-6 and n-3 polyunsaturated fatty acids are both independent of and dependent upon conversion. J Nutr Biochem. 2016;32:29-38.
Monk, J. M., Liddle, D. M., Cohen, D. J., Tsang, D. H., Hillyer, L. M., Abdelmagid, S. A., Nakamura, M. T., Power, K. A., Ma, D. W., & Robinson, L. E. (2016). The delta 6 desaturase knock out mouse reveals that immunomodulatory effects of essential n-6 and n-3 polyunsaturated fatty acids are both independent of and dependent upon conversion. The Journal of Nutritional Biochemistry, 32, 29-38. https://doi.org/10.1016/j.jnutbio.2016.01.004
Monk JM, et al. The Delta 6 Desaturase Knock Out Mouse Reveals That Immunomodulatory Effects of Essential N-6 and N-3 Polyunsaturated Fatty Acids Are Both Independent of and Dependent Upon Conversion. J Nutr Biochem. 2016;32:29-38. PubMed PMID: 27142734.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - The delta 6 desaturase knock out mouse reveals that immunomodulatory effects of essential n-6 and n-3 polyunsaturated fatty acids are both independent of and dependent upon conversion. AU - Monk,Jennifer M, AU - Liddle,Danyelle M, AU - Cohen,Daniel J A, AU - Tsang,Denis H, AU - Hillyer,Lyn M, AU - Abdelmagid,Salma A, AU - Nakamura,Manabu T, AU - Power,Krista A, AU - Ma,David W L, AU - Robinson,Lindsay E, Y1 - 2016/03/02/ PY - 2015/06/22/received PY - 2015/12/14/revised PY - 2016/01/21/accepted PY - 2016/5/5/entrez PY - 2016/5/5/pubmed PY - 2017/10/11/medline KW - Cytokines KW - Fatty acid desaturase 2 KW - Fatty acid metabolism KW - Inflammation KW - Polyunsaturated fatty acid SP - 29 EP - 38 JF - The Journal of nutritional biochemistry JO - J. Nutr. Biochem. VL - 32 N2 - Typically fatty acids (FA) exert differential immunomodulatory effects with n-3 [α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)] and n-6 [linoleic acid (LA) and arachidonic acid (AA)] exerting anti- and pro-inflammatory effects, respectively. This over-simplified interpretation is confounded by a failure to account for conversion of the parent FA (LA and ALA) to longer-chain bioactive products (AA and EPA/DHA, respectively), thereby precluding discernment of the immunomodulatory potential of specific FA. Therefore, we utilized the Δ6-desaturase model, wherein knockout mice (D6KO) lack the Fads2 gene encoding for the rate-limiting enzyme that initiates FA metabolism, thereby providing a model to determine specific FA immunomodulatory effects. Wild-type (WT) and D6KO mice were fed one of four isocaloric diets differing in FA source (9weeks): corn oil (LA-enriched), arachidonic acid single cell oil (AA-enriched), flaxseed oil (ALA-enriched) or menhaden fish oil (EPA/DHA-enriched). Splenic mononuclear cell cytokine production in response to lipopolysaccharide (LPS), T-cell receptor (TCR) and anti-CD40 stimulation was determined. Following LPS stimulation, AA was more bioactive compared to LA, by increasing inflammatory cytokine production of IL-6 (1.2-fold) and TNFα (1.3-fold). Further, LPS-stimulated IFNγ production in LA-fed D6KO mice was reduced 5-fold compared to LA-fed WT mice, indicating that conversion of LA to AA was necessary for cytokine production. Conversely, ALA exerted an independent immunomodulatory effect from EPA/DHA and all n-3 FA increased LPS-stimulated IL-10 production versus LA and AA. These data definitively identify specific immunomodulatory effects of individual FA and challenge the simplified view of the immunomodulatory effects of n-3 and n-6 FA. SN - 1873-4847 UR - https://www.unboundmedicine.com/medline/citation/27142734/The_delta_6_desaturase_knock_out_mouse_reveals_that_immunomodulatory_effects_of_essential_n_6_and_n_3_polyunsaturated_fatty_acids_are_both_independent_of_and_dependent_upon_conversion_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S0955-2863(16)00035-8 DB - PRIME DP - Unbound Medicine ER -