Adipocyte-derived exosomal miRNAs: a novel mechanism for obesity-related disease

Abstract

BackgroundObesity 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.MethodsWe 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.ResultsAbundant 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-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.ConclusionThese data show that visceral adipocytes shed exosomal-mediators predicted to regulate key end-organ inflammatory and fibrotic signaling pathways.

A High-Fat Diet Promotes Mammary Gland Myofibroblast Differentiation through MicroRNA 140 Downregulation

“…Adipocytes from obese individuals actively shed miRNAcontaining exosomes (35), which may affect signaling in nearby cells. We have previously shown that exosomes secreted by preadipocytes contain high levels of miR-140 and that treatment with shikonin can induce high levels of miR-140 in preadipocyte exosomes (23).…”

The Role of Bone Marrow Microenvironment in Governing the Balance between Osteoblastogenesis and Adipogenesis

“…Exosomes are membrane vesicles that carry a cargo of proteins, lipids and nuclear acids, which may differ based on adipogenic stages and/or under pathological conditions [120,121,122]. Adipocyte-secreted exosomes are demonstrated to contain specific transcripts (such as adiponectin [123] and aP2 [124]) and miRNAs [119,99], which are transported into recipient cells and are involved in modulating gene expression as well as energy metabolism.…”

“…Adipocyte-secreted exosomes are demonstrated to contain specific transcripts (such as adiponectin [123] and aP2 [124]) and miRNAs [119,99], which are transported into recipient cells and are involved in modulating gene expression as well as energy metabolism. Several studies demonstrated that adipocyte derived exosomes mediate cell-cell communication that might play a role in controlling lipogenesis and cell size [121], obesity related disease [120] and nonalcoholic fatty liver disease [125]. It is possible that exosomes from bone marrow adipose tissue under osteoporotic conditions carry different cargo to affect the osteoblastic/adipocytic fate of bone marrow MSCs.…”

Adipocyte Exosomes Promote Melanoma Aggressiveness through Fatty Acid Oxidation: A Novel Mechanism Linking Obesity and Cancer

“…Few studies have focused on ad-exos in obesity, although their function and content are modified. For instance, they are implicated in insulin resistance (11) and their miRNAs mediate inflammation and fibrosis (12).…”