Lipoxin A(4) 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 LipoxinA(4) (LXA(4): 5(S), 6(R), 15(S)-trihydroxy-7E, 9E, 11Z, 13E,-eicosatetraenoic acid) and a synthetic 15(R)-Benzo-LXA(4)-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, LXA(4) reduced liver weight, serum alanine-aminotransferase, and hepatic triglycerides. LXA(4) decreased obesity-induced adipose inflammation, attenuating TNF-alpha and CD11c(+) M1-macrophages (M Phi s), while restoring CD206(+) M2-M Phi s and increasing Annexin-A1. LXs did not affect renal or hepatic M Phi s, 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