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Adipocyte-derived Exosomal miRNAs: A Novel Mechanism for Obesity-Related Disease.

Ferrante SC, P Nadler E, Pillai DK, Hubal MJ, Wang Z, Wang JM, Gordish-Dressman H, Koeck E, Sevilla S, Wiles AA, Freishtat RJ (2014) Pediatr Res.  doi: 10.1038/pr.2014.202. [Epub ahead of print] Nature Publishing Group

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  Background:Obesity is frequently complicated by comorbid conditions, yet how excess adipose contributes is poorly understood. Although adipocytes in obese individuals induce systemic inflammation via secreted cytokines, another potential mediator has recently been identified (i.e.adipocyte-derived exosomes). We hypothesized that adipocyte-derived exosomes contain mediators capable of activating end-organ inflammatory and fibrotic signaling pathways.Methods:We developed techniques to quantify and characterize exosomes shed by adipocytes from 7 obese (age: 12-17.5 years, BMI: 33-50 kg/m2) and 5 lean (age: 11-19 years, BMI: 22-25 kg/m2) subjects.Results:Abundant exosomal miRNAs, but no mRNAs, were detected. Comparison of obese vs. lean visceral adipose donors detected 55 differentially-expressed miRNAs (p<0.05; fold change≥|1.2|). qRT-PCR confirmed downregulation of miR-148b (ratio = 0.2 (95% confidence interval = 0.1, 0.6)) and miR-4269 (0.3 (0.1, 0.8)), and upregulation of miR-23b (6.2 (2.2, 17.8)) and miR-4429 (3.8 (1.1 to 13.4)). Pathways analysis identified TGF-ß signaling and Wnt/ ß-catenin signaling among the top canonical pathways expected to be altered with visceral adiposity based on projected mRNA targets for the 55 differentially expressed miRNAs. A select mRNA target was validated in vitro.Conclusion:These data show that visceral adipocytes shed exosomal-mediators predicted to regulate key end-organ inflammatory and fibrotic signaling pathways.