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

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. [Display omitted] •Lipoxins attenuated high-fat diet-induced liver and kidney disease•LXA4 attenuated adipose inflammation, promoting a macrophage M1-to-M2 switch•LXA4 restored obesity-induced attenuation of autophagy markers LC3-II and p62•LXA4-mediated protection was adiponectin independent, but restored Annexin-A1 Börgeson et al. investigated the role of anti-inflammatory lipid mediators in obesity. LipoxinA4 and a synthetic lipoxin analog protected against obesity-induced kidney and liver disease. Lipoxins mediated protection by decreasing adipose inflammation and promoting a macrophage M1-to-M2 switch. Lipoxin-mediated protection was adiponectin independent, but correlated with restored adipose Annexin-A1 levels.