title: Lipoxin A4 Attenuates Obesity-Induced Adipose Inflammation and Associated Liver and Kidney Disease.
abstract: The role of inflammation in obesity-related pathologies is well established. We investigated the therapeutic potential of LipoxinA4 (LXA4:5(S),6(R),15(S)-trihydroxy-7E,9E,11Z,13E,-eicosatetraenoic acid) and a synthetic 15(R)-Benzo-LXA4-analog as interventions in a 3-month high-fat diet (HFD; 60% fat)-induced obesity model. Obesity caused distinct pathologies, including impaired glucose tolerance, adipose inflammation, fatty liver, and chronic kidney disease (CKD). Lipoxins (LXs) attenuated obesity-induced CKD, reducing glomerular expansion, mesangial matrix, and urinary H2O2. Furthermore, LXA4 reduced liver weight, serum alanine-aminotransferase, and hepatic triglycerides. LXA4 decreased obesity-induced adipose inflammation, attenuating TNF-α and CD11c(+) M1-macrophages (MΦs), while restoring CD206(+) M2-MΦs and increasing Annexin-A1. LXs did not affect renal or hepatic MΦs, suggesting protection occurred via attenuation of adipose inflammation. LXs restored adipose expression of autophagy markers LC3-II and p62. LX-mediated protection was demonstrable in adiponectin(-/-) mice, suggesting that the mechanism was adiponectin independent. In conclusion, LXs protect against obesity-induced systemic disease, and these data support a novel therapeutic paradigm for treating obesity and associated pathologies.
authors.affiliation: Center for Renal Translational Medicine, Division of Nephrology-Hypertension, Department of Medicine, Institute for Metabolomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Veterans Affair, San Diego Healthcare System, Veterans Medical Research Foundation, San Diego, La Jolla, CA 92093, USA; Diabetes Complications Research Centre, UCD Conway Institute, School of Medicine, University College Dublin, Dublin 4, Ireland. Electronic address: kborgeson@ucsd.edu.
authors.forename: Emma
authors.initials: E
authors.lastname: Börgeson
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Andrew M F
authors.initials: AM
authors.lastname: Johnson
authors.affiliation: Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Yun Sok
authors.initials: YS
authors.lastname: Lee
authors.affiliation: Division of Biological Sciences and San Diego Center for Systems Biology, University of California, San Diego, La Jolla, CA 92093, USA; Institute of Reconstructive Neurobiology, LIFE&BRAIN, University Clinic Bonn, Sigmund-Freud Str. 25, 53127 Bonn, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Till
authors.affiliation: Department of Medicine, Division of Infectious Diseases, University of California, San Diego, La Jolla, CA 92093, USA.
authors.forename: Gulam Hussain
authors.initials: GH
authors.lastname: Syed
authors.affiliation: Centre for Synthesis and Chemical Biology, UCD Conway Institute, UCD School of Chemistry, University College Dublin, Dublin 4, Ireland.
authors.forename: Syed Tasadaque
authors.initials: ST
authors.lastname: Ali-Shah
authors.affiliation: Centre for Synthesis and Chemical Biology, UCD Conway Institute, UCD School of Chemistry, University College Dublin, Dublin 4, Ireland.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Guiry
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Jesmond
authors.initials: J
authors.lastname: Dalli
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Romain A
authors.initials: RA
authors.lastname: Colas
authors.affiliation: Center for Experimental Therapeutics and Reperfusion Injury, Department of Anesthesiology, Perioperative and Pain Medicine, Harvard Institutes of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Charles N
authors.initials: CN
authors.lastname: Serhan
authors.affiliation: Center for Renal Translational Medicine, Division of Nephrology-Hypertension, Department of Medicine, Institute for Metabolomic Medicine, University of California, San Diego, La Jolla, CA 92093, USA; Veterans Affair, San Diego Healthcare System, Veterans Medical Research Foundation, San Diego, La Jolla, CA 92093, USA.
authors.forename: Kumar
authors.initials: K
authors.lastname: Sharma
authors.affiliation: Diabetes Complications Research Centre, UCD Conway Institute, School of Medicine, University College Dublin, Dublin 4, Ireland.
authors.forename: Catherine
authors.initials: C
authors.lastname: Godson
mesh_terms: D000273:Adipose Tissue / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D001343:Autophagy / Q000187:drug effects; D007249:Inflammation / Q000150:complications* / Q000188:drug therapy* / Q000276:immunology / Q000473:pathology; D007668:Kidney / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D007674:Kidney Diseases / Q000150:complications* / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D044045:Lipoxins / Q000627:therapeutic use*; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008107:Liver Diseases / Q000150:complications* / Q000188:drug therapy / Q000276:immunology / Q000473:pathology; D008810:Mice, Inbred C57BL; D009765:Obesity / Q000150:complications* / Q000276:immunology
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D044045:Lipoxins; C040527:lipoxin A4