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Adipocyte-secreted exosomal microRNA-34a inhibits M2 macrophage polarization to promote obesity-induced adipose inflammation
Yong Pan, … , Karen Siu Ling Lam, Aimin Xu
Yong Pan, … , Karen Siu Ling Lam, Aimin Xu
Published January 22, 2019
Citation Information: J Clin Invest. 2019;129(2):834-849. https://doi.org/10.1172/JCI123069.
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Research Article Inflammation Metabolism

Adipocyte-secreted exosomal microRNA-34a inhibits M2 macrophage polarization to promote obesity-induced adipose inflammation

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Abstract

Persistent, unresolved inflammation in adipose tissue is a major contributor to obesity-associated metabolic complications. However, the molecular links between lipid-overloaded adipocytes and inflammatory immune cells in obese adipose tissues remain elusive. Here we identified adipocyte-secreted microRNA-34a (miR-34a) as a key mediator through its paracrine actions on adipose-resident macrophages. The expression of miR-34a in adipose tissues was progressively increased with the development of dietary obesity. Adipose-selective or adipocyte-specific miR-34a–KO mice were resistant to obesity-induced glucose intolerance, insulin resistance, and systemic inflammation, and this was accompanied by a significant shift in polarization of adipose-resident macrophages from proinflammatory M1 to antiinflammatory M2 phenotype. Mechanistically, mature adipocyte-secreted exosomes transported miR-34a into macrophages, thereby suppressing M2 polarization by repressing the expression of Krüppel-like factor 4 (Klf4). The suppressive effects of miR-34a on M2 polarization and its stimulation of inflammatory responses were reversed by ectopic expression of Klf4 in both bone marrow–derived macrophages and adipose depots of obese mice. Furthermore, increased miR-34a expression in visceral fat of overweight/obese subjects correlated negatively with reduced Klf4 expression, but positively with the parameters of insulin resistance and metabolic inflammation. In summary, miR-34a was a key component of adipocyte-secreted exosomal vesicles that transmitted the signal of nutrient overload to the adipose-resident macrophages for exacerbation of obesity-induced systemic inflammation and metabolic dysregulation.

Authors

Yong Pan, Xiaoyan Hui, Ruby Lai Chong Hoo, Dewei Ye, Cyrus Yuk Cheung Chan, Tianshi Feng, Yu Wang, Karen Siu Ling Lam, Aimin Xu

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Figure 8

Schematic summary of the role of adipocyte-secreted exosomal miR-34a in obesity-induced alterations in macrophage polarization, adipose inflammation, and insulin resistance.

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Schematic summary of the role of adipocyte-secreted exosomal miR-34a in ...
Hypertrophic adipocytes in obese adipose tissue release exosomes, which carry miR-34a to adipose-resident macrophages, where it shifts macrophage polarization from M2 to M1 by downregulation of Klf4, thereby leading to induction of proinflammatory cytokines and local fibrosis and downregulation of adiponectin, thereby leading to systemic insulin resistance and glucose intolerance.
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