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      De Novo Lipogenesis Products and Endogenous Lipokines

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      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 references48

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          FAT SIGNALS - Lipases and Lipolysis in Lipid Metabolism and Signaling

          Lipolysis is defined as the catabolism of triacylglycerols stored in cellular lipid droplets. Recent discoveries of essential lipolytic enzymes and characterization of numerous regulatory proteins and mechanisms have fundamentally changed our perception of lipolysis and its impact on cellular metabolism. New findings that lipolytic products and intermediates participate in cellular signaling processes and that “lipolytic signaling” is particularly important in many nonadipose tissues unveil a previously underappreciated aspect of lipolysis, which may be relevant for human disease.
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            Identification of a lipokine, a lipid hormone linking adipose tissue to systemic metabolism.

            Dysregulation of lipid metabolism in individual tissues leads to systemic disruption of insulin action and glucose metabolism. Utilizing quantitative lipidomic analyses and mice deficient in adipose tissue lipid chaperones aP2 and mal1, we explored how metabolic alterations in adipose tissue are linked to whole-body metabolism through lipid signals. A robust increase in de novo lipogenesis rendered the adipose tissue of these mice resistant to the deleterious effects of dietary lipid exposure. Systemic lipid profiling also led to identification of C16:1n7-palmitoleate as an adipose tissue-derived lipid hormone that strongly stimulates muscle insulin action and suppresses hepatosteatosis. Our data reveal a lipid-mediated endocrine network and demonstrate that adipose tissue uses lipokines such as C16:1n7-palmitoleate to communicate with distant organs and regulate systemic metabolic homeostasis.
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              Novel Functional Sets of Lipid-Derived Mediators with Antiinflammatory Actions Generated from Omega-3 Fatty Acids via Cyclooxygenase 2–Nonsteroidal Antiinflammatory Drugs and Transcellular Processing

              Aspirin therapy inhibits prostaglandin biosynthesis without directly acting on lipoxygenases, yet via acetylation of cyclooxygenase 2 (COX-2) it leads to bioactive lipoxins (LXs) epimeric at carbon 15 (15-epi-LX, also termed aspirin-triggered LX [ATL]). Here, we report that inflammatory exudates from mice treated with ω-3 polyunsaturated fatty acid and aspirin (ASA) generate a novel array of bioactive lipid signals. Human endothelial cells with upregulated COX-2 treated with ASA converted C20:5 ω-3 to 18R-hydroxyeicosapentaenoic acid (HEPE) and 15R-HEPE. Each was used by polymorphonuclear leukocytes to generate separate classes of novel trihydroxy-containing mediators, including 5-series 15R-LX5 and 5,12,18R-triHEPE. These new compounds proved to be potent inhibitors of human polymorphonuclear leukocyte transendothelial migration and infiltration in vivo (ATL analogue > 5,12,18R-triHEPE > 18R-HEPE). Acetaminophen and indomethacin also permitted 18R-HEPE and 15R-HEPE generation with recombinant COX-2 as well as ω-5 and ω-9 oxygenations of other fatty acids that act on hematologic cells. These findings establish new transcellular routes for producing arrays of bioactive lipid mediators via COX-2–nonsteroidal antiinflammatory drug–dependent oxygenations and cell–cell interactions that impact microinflammation. The generation of these and related compounds provides a novel mechanism(s) for the therapeutic benefits of ω-3 dietary supplementation, which may be important in inflammation, neoplasia, and vascular diseases.
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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
                [1] 1Department of Genetics and Complex Diseases and Sabri Ülker Center, Harvard T.H. Chan School of Public Health, Boston, MA
                [2] 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
                53960885-a300-4b64-a36b-544498b25c60
                © 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.
                History
                : 22 February 2016
                : 24 March 2016
                Page count
                Figures: 1, Tables: 0, Equations: 0, References: 81, Pages: 8
                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
                Endocrinology & Diabetes

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