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Cell Metab. 2015 Jul 7;22(1):125-37. doi: 10.1016/j.cmet.2015.05.003. Epub 2015 Jun 4.

Lipoxin A4 Attenuates Obesity-Induced Adipose Inflammation and Associated Liver and Kidney Disease.

Author information

1
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.
2
Department of Medicine, Division of Endocrinology and Metabolism, University of California, San Diego, La Jolla, CA 92093, USA.
3
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.
4
Department of Medicine, Division of Infectious Diseases, University of California, San Diego, La Jolla, CA 92093, USA.
5
Centre for Synthesis and Chemical Biology, UCD Conway Institute, UCD School of Chemistry, University College Dublin, Dublin 4, Ireland.
6
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.
7
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.
8
Diabetes Complications Research Centre, UCD Conway Institute, School of Medicine, University College Dublin, Dublin 4, Ireland.

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.

PMID:
26052006
PMCID:
PMC4584026
DOI:
10.1016/j.cmet.2015.05.003
[Indexed for MEDLINE]
Free PMC Article

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