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

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/m2) and five lean (age: 11–19 y, 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 (1.1−13.4)). 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.Conclusion:These data show that visceral adipocytes shed exosomal-mediators predicted to regulate key end-organ inflammatory and fibrotic signaling pathways.

[1]  Miho Suzuki,et al.  IL-6/IL-6 receptor system and its role in physiological and pathological conditions. , 2012, Clinical science.

[2]  E. Hoffman,et al.  Asthmatic airway epithelium is intrinsically inflammatory and mitotically dyssynchronous. , 2011, American journal of respiratory cell and molecular biology.

[3]  M. Hristov,et al.  Delivery of MicroRNA-126 by Apoptotic Bodies Induces CXCL12-Dependent Vascular Protection , 2009, Science Signaling.

[4]  A. Poliakov,et al.  Adipose Tissue Exosome-Like Vesicles Mediate Activation of Macrophage-Induced Insulin Resistance , 2009, Diabetes.

[5]  L. Wood,et al.  Airway and systemic inflammation in obese children with asthma , 2013, European Respiratory Journal.

[6]  H. Hillege,et al.  Obesity and target organ damage: the kidney , 2002, International Journal of Obesity.

[7]  B. Hinz.  Formation and function of the myofibroblast during tissue repair. , 2007, The Journal of investigative dermatology.

[8]  K. Clément,et al.  Human adipose tissue macrophages: m1 and m2 cell surface markers in subcutaneous and omental depots and after weight loss. , 2009, The Journal of clinical endocrinology and metabolism.

[9]  W. Phipatanakul,et al.  Airway and Systemic Inflammation in Obese Children With Asthma , 2014, Pediatrics.

[10]  D. Pisetsky,et al.  The Role of Microparticles in Inflammation and Thrombosis , 2007, Scandinavian journal of immunology.

[11]  G. Raposo,et al.  Exosomes: endosomal-derived vesicles shipping extracellular messages. , 2004, Current opinion in cell biology.

[12]  H. Sul,et al.  Pref-1, a preadipocyte secreted factor that inhibits adipogenesis. , 2006, The Journal of nutrition.

[13]  Jaswinder K. Sethi.  Activatin' Human Adipose Progenitors in Obesity , 2010, Diabetes.

[14]  L. Tartaglia,et al.  Chronic inflammation in fat plays a crucial role in the development of obesity-related insulin resistance. , 2003, The Journal of clinical investigation.

[15]  C. Tomkiewicz,et al.  Expression of macrophage‐selective markers in human and rodent adipocytes , 2005, FEBS letters.

[16]  J. Zavadil,et al.  TGF-beta and epithelial-to-mesenchymal transitions. , 2005, Oncogene.

[17]  C. McCulloch,et al.  Integrity of cell-cell contacts is a critical regulator of TGF-beta 1-induced epithelial-to-myofibroblast transition: role for beta-catenin. , 2004, The American journal of pathology.

[18]  Ciro Tetta,et al.  Exosome/microvesicle-mediated epigenetic reprogramming of cells. , 2011, American journal of cancer research.

[19]  Isao Usui,et al.  Regulatory Mechanisms for Adipose Tissue M1 and M2 Macrophages in Diet-Induced Obese Mice , 2009, Diabetes.

[20]  Oliver Distler,et al.  Activation of canonical Wnt signalling is required for TGF-β-mediated fibrosis , 2012, Nature Communications.

[21]  A. Poliakov,et al.  Induction of myeloid‐derived suppressor cells by tumor exosomes , 2009, International journal of cancer.

[22]  T. Funahashi,et al.  Visceral adiposity as a target for the management of the metabolic syndrome , 2012, Annals of medicine.

[23]  A. Madan,et al.  Transforming growth factor beta1 release by human adipose tissue is enhanced in obesity. , 2005, Metabolism: clinical and experimental.

[24]  Ana Kozomara,et al.  miRBase: integrating microRNA annotation and deep-sequencing data , 2010, Nucleic Acids Res..

[25]  Carey N Lumeng,et al.  Inflammatory links between obesity and metabolic disease. , 2011, The Journal of clinical investigation.

[26]  P. Jong,et al.  PREVEND STUDY GROUP OBESITY AND TARGET ORGAN DAMAGE: THE KIDNEY , 2002 .

[27]  C. McCulloch,et al.  Integrity of cell-cell contacts is a critical regulator of TGF-beta 1-induced epithelial-to-myofibroblast transition: role for beta-catenin. , 2004, The American journal of pathology.

[28]  J. Lötvall,et al.  Isolation and Characterization of RNA-Containing Exosomes , 2012, Journal of visualized experiments : JoVE.

[29]  C. Peterson,et al.  Adipose tissue macrophages in insulin resistant subjects are 1 associated with collagen VI, fibrosis and demonstrate 2 alternative activation , 2010 .

[30]  S. Kuang,et al.  Fatty acid binding protein 4 expression marks a population of adipocyte progenitors in white and brown adipose tissues , 2013, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[31]  J. Lötvall,et al.  Human saliva, plasma and breast milk exosomes contain RNA: uptake by macrophages , 2011, Journal of Translational Medicine.

[32]  Philipp E. Scherer,et al.  Visceral Fat Adipokine Secretion Is Associated With Systemic Inflammation in Obese Humans , 2007, Diabetes.

[33]  S. Mathivanan,et al.  Exosomes: extracellular organelles important in intercellular communication. , 2010, Journal of proteomics.

[34]  N. Kawada,et al.  Inflammation and fibrogenesis in steatohepatitis , 2012, Journal of Gastroenterology.

[35]  Alex E. Lash,et al.  Gene Expression Omnibus: NCBI gene expression and hybridization array data repository , 2002, Nucleic Acids Res..

[36]  K. Clément,et al.  Macrophage-secreted factors impair human adipogenesis: involvement of proinflammatory state in preadipocytes. , 2007, Endocrinology.

[37]  M. Jensen,et al.  Weight and type 2 diabetes after bariatric surgery: systematic review and meta-analysis. , 2009, The American journal of medicine.

[38]  Jean-Daniel Zucker,et al.  Fibrosis in Human Adipose Tissue: Composition, Distribution, and Link With Lipid Metabolism and Fat Mass Loss , 2010, Diabetes.

[39]  S. Ichiyama,et al.  Enhancement of tumoricidal activity of alveolar macrophages via CD40-CD40 ligand interaction. , 1999, The American journal of physiology.

[40]  C. Nguyên,et al.  Inhibition of Wnt/β-catenin/CREB binding protein (CBP) signaling reverses pulmonary fibrosis , 2010, Proceedings of the National Academy of Sciences.

[41]  J. Santibañez,et al.  TGF-β/TGF-β receptor system and its role in physiological and pathological conditions. , 2011, Clinical science.

[42]  Luigi Biancone,et al.  Exosomes/microvesicles as a mechanism of cell-to-cell communication. , 2010, Kidney international.