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      De Novo Lipogenesis Products and Endogenous Lipokines

      1 , 1 , , 1 , 2

      Diabetes

      American Diabetes Association

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          Abstract

          Recent studies have shown that in addition to their traditionally recognized functions as building blocks, energy stores, or hazardous intermediates, lipids also have the ability to act as signaling molecules with potent effects on systemic metabolism and metabolic diseases. This Perspective highlights this somewhat less apparent biology of lipids, especially focusing on de novo lipogenesis as a process that gives rise to key messenger molecules mediating interorgan communication. Elucidating the mechanisms of lipid-dependent coordination of metabolism promises invaluable insights into the understanding of metabolic diseases and may contribute to the development of a new generation of preventative and therapeutic approaches.

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          Most cited references 79

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          Pro-resolving lipid mediators are leads for resolution physiology.

          Advances in our understanding of the mechanisms that bring about the resolution of acute inflammation have uncovered a new genus of pro-resolving lipid mediators that include the lipoxin, resolvin, protectin and maresin families, collectively called specialized pro-resolving mediators. Synthetic versions of these mediators have potent bioactions when administered in vivo. In animal experiments, the mediators evoke anti-inflammatory and novel pro-resolving mechanisms, and enhance microbial clearance. Although they have been identified in inflammation resolution, specialized pro-resolving mediators are conserved structures that also function in host defence, pain, organ protection and tissue remodelling. This Review covers the mechanisms of specialized pro-resolving mediators and omega-3 essential fatty acid pathways that could help us to understand their physiological functions.
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            GPR120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects.

            Omega-3 fatty acids (omega-3 FAs), DHA and EPA, exert anti-inflammatory effects, but the mechanisms are poorly understood. Here, we show that the G protein-coupled receptor 120 (GPR120) functions as an omega-3 FA receptor/sensor. Stimulation of GPR120 with omega-3 FAs or a chemical agonist causes broad anti-inflammatory effects in monocytic RAW 264.7 cells and in primary intraperitoneal macrophages. All of these effects are abrogated by GPR120 knockdown. Since chronic macrophage-mediated tissue inflammation is a key mechanism for insulin resistance in obesity, we fed obese WT and GPR120 knockout mice a high-fat diet with or without omega-3 FA supplementation. The omega-3 FA treatment inhibited inflammation and enhanced systemic insulin sensitivity in WT mice, but was without effect in GPR120 knockout mice. In conclusion, GPR120 is a functional omega-3 FA receptor/sensor and mediates potent insulin sensitizing and antidiabetic effects in vivo by repressing macrophage-induced tissue inflammation. Copyright 2010 Elsevier Inc. All rights reserved.
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              Resolvins

              Aspirin (ASA) is unique among current therapies because it acetylates cyclooxygenase (COX)-2 enabling the biosynthesis of R-containing precursors of endogenous antiinflammatory mediators. Here, we report that lipidomic analysis of exudates obtained in the resolution phase from mice treated with ASA and docosahexaenoic acid (DHA) (C22:6) produce a novel family of bioactive 17R-hydroxy-containing di- and tri-hydroxy-docosanoids termed resolvins. Murine brain treated with aspirin produced endogenous 17R-hydroxydocosahexaenoic acid as did human microglial cells. Human COX-2 converted DHA to 13-hydroxy-DHA that switched with ASA to 17R-HDHA that also proved a major route in hypoxic endothelial cells. Human neutrophils transformed COX-2-ASA–derived 17R-hydroxy-DHA into two sets of novel di- and trihydroxy products; one initiated via oxygenation at carbon 7 and the other at carbon 4. These compounds inhibited (IC50 ∼50 pM) microglial cell cytokine expression and in vivo dermal inflammation and peritonitis at ng doses, reducing 40–80% leukocytic exudates. These results indicate that exudates, vascular, leukocytes and neural cells treated with aspirin convert DHA to novel 17R-hydroxy series of docosanoids that are potent regulators. These biosynthetic pathways utilize omega-3 DHA and EPA during multicellular events in resolution to produce a family of protective compounds, i.e., resolvins, that enhance proresolution status.
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                Author and article information

                Journal
                Diabetes
                Diabetes
                diabetes
                diabetes
                Diabetes
                Diabetes
                American Diabetes Association
                0012-1797
                1939-327X
                July 2016
                12 June 2016
                : 65
                : 7
                : 1800-1807
                Affiliations
                1Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA
                2Broad Institute of MIT and Harvard, Cambridge, MA
                Author notes
                Corresponding author: Gökhan S. Hotamisligil, ghotamis@ 123456hsph.harvard.edu .
                Article
                0251
                10.2337/db16-0251
                4915584
                27288005
                © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 81, Pages: 8
                Product
                Funding
                Funded by: National Institute of Diabetes and Digestive and Kidney Diseases http://dx.doi.org/10.13039/100000062
                Award ID: DK-052539
                Funded by: National Heart, Lung, and Blood Institute http://dx.doi.org/10.13039/100000050
                Award ID: HL-125753
                Funded by: National Institute of Allergy and Infectious Diseases http://dx.doi.org/10.13039/100000060
                Award ID: AI-116901
                Funded by: JDRF http://dx.doi.org/10.13039/100008664
                Award ID: 2-SRA-2016-147-Q-R
                Funded by: Union Chemique Belge
                Funded by: Servier
                Categories
                Diabetes Symposium: Bioactive Lipids and Nonpeptide Mediators of Metabolism

                Endocrinology & Diabetes

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