title: Adipocyte-derived exosomal miRNAs: a novel mechanism for obesity-related disease.
abstract: 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 seven obese (age: 12-17.5 y, BMI: 33-50 kg/m(2)) and five lean (age: 11-19 y, BMI: 22-25 kg/m(2)) 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 (1.1-13.4)). Pathways analysis identified TGF-β signaling and Wnt/β-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.
  
  
  CONCLUSIONS
  These data show that visceral adipocytes shed exosomal-mediators predicted to regulate key end-organ inflammatory and fibrotic signaling pathways.
authors.affiliation: Department of Integrative Systems Biology, Children's National Medical Center, Washington, DC.
authors.forename: Sarah C
authors.initials: SC
authors.lastname: Ferrante
authors.affiliation: 1] Department of Integrative Systems Biology, Children's National Medical Center, Washington, DC [2] Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Medical Center, Washington, DC [3] Division of Pediatric Surgery, Children's National Medical Center, Washington, DC.
authors.forename: Evan P
authors.initials: EP
authors.lastname: Nadler
authors.affiliation: 1] Department of Integrative Systems Biology, Children's National Medical Center, Washington, DC [2] Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC [3] Division of Pulmonary and Sleep Medicine, Children's National Medical Center, Washington, DC.
authors.forename: Dinesh K
authors.initials: DK
authors.lastname: Pillai
authors.affiliation: 1] Department of Integrative Systems Biology, Children's National Medical Center, Washington, DC [2] Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Medical Center, Washington, DC.
authors.forename: Monica J
authors.initials: MJ
authors.lastname: Hubal
authors.affiliation: Department of Integrative Systems Biology, Children's National Medical Center, Washington, DC.
authors.forename: Zuyi
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Integrative Systems Biology, Children's National Medical Center, Washington, DC.
authors.forename: Justin M
authors.initials: JM
authors.lastname: Wang
authors.affiliation: Department of Integrative Systems Biology, Children's National Medical Center, Washington, DC.
authors.forename: Heather
authors.initials: H
authors.lastname: Gordish-Dressman
authors.affiliation: Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Medical Center, Washington, DC.
authors.forename: Emily
authors.initials: E
authors.lastname: Koeck
authors.affiliation: Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's National Medical Center, Washington, DC.
authors.forename: Samantha
authors.initials: S
authors.lastname: Sevilla
authors.affiliation: Department of Integrative Systems Biology, Children's National Medical Center, Washington, DC.
authors.forename: Andrew A
authors.initials: AA
authors.lastname: Wiles
authors.affiliation: 1] Department of Integrative Systems Biology, Children's National Medical Center, Washington, DC [2] Department of Pediatrics, George Washington University School of Medicine and Health Sciences, Washington, DC [3] Division of Emergency Medicine Children's National Medical Center, Washington, DC.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Freishtat
mesh_terms: D017667:Adipocytes / Q000378:metabolism*; D000293:Adolescent; D002460:Cell Line; D055354:Exosomes / Q000737:chemistry*; D005786:Gene Expression Regulation / Q000502:physiology*; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000209:etiology*; D008264:Macrophages / Q000502:physiology; D035683:MicroRNAs / Q000009:adverse effects / Q000032:analysis*; D009765:Obesity / Q000150:complications* / Q000503:physiopathology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D035683:MicroRNAs