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 February 1, 2019; First published January 22, 2019
Citation Information: J Clin Invest. 2019;129(2):834-849. https://doi.org/10.1172/JCI123069.
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Categories: Research Article Inflammation Metabolism

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

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 2

Adipose tissue–specific ablation of miR-34a protects mice from obesity-induced glucose intolerance and insulin resistance.

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Adipose tissue–specific ablation of miR-34a protects mice from obesity-i...
(A) Representative photos of adipose-specific miR-34a–KO mice and their WT miR-34afl/fl littermates fed with either STC or HFD for 16 weeks. (B) Dynamic changes in body weight of WT and KO mice during 16 weeks of STC or HFD feeding (n = 6–8). (C and D) Fat mass of whole body (C) and individual tissues (D) (n = 6–8). (E) Glucose tolerance test after mice were fed with HFD for 0, 4, 8, and 16 weeks (n = 6–8). (F) Serum concentrations of fed insulin in mice on HFD for 0, 4, 8, and 16 weeks (n = 6–8). (G) Insulin tolerance test after mice were fed with HFD for 0, 4, 8, and 16 weeks (n = 6–8). (H and I) The KO mice or WT littermates on STC or HFD for 16 weeks were injected intraperitoneally with insulin (2 IU/kg body weight) for 10 minutes. (H) Immunoblot analyses of epiWAT samples using antibodies against phospho-AKT (p-AKT-S473), total AKT, and tubulin. (I) Densitometry analysis for the p-AKT/AKT ratio (n = 4–5). Data represent mean ± SEM. Differences between WT and KO mice were determined by ANOVA (B–G and I); *P < 0.05, **P < 0.01, ***P < 0.001.