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

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 7

Dysregulated miR-34a/KLF4 axis in adipose tissues is associated with inflammation and insulin resistance in overweight/obese Chinese subjects.

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Dysregulated miR-34a/KLF4 axis in adipose tissues is associated with inf...
(A) Real-time PCR analysis for the expression levels of miR-34a in visceral adipose tissue (VAT) and subcutaneous white adipose tissue (scWAT) from 29 lean and 24 overweight/obese individuals undergoing elective abdominal surgery for benign, noninfective gynecological conditions. (B) Gene expression of Klf4. (C) Correlation between miR-34a and KLF4 levels in visceral fat of these study subjects. (D and E) The association between miR-34a and the mRNA abundance of TNFA (D) and IL6 (E) in visceral fat. (F and G) Correlation between the insulin resistance index (HOMA-IR) and the expression level of miR-34a (F) or KLF4 (G) in the visceral fat. Data represent mean ± SEM. Differences were determined by ANOVA (A) or Student’s t test (B), and correlation was assessed by nonparametric Spearman’s test (C–G); *P < 0.05, ***P < 0.001. MiR-34a expression was normalized to sno202 levels, and gene abundance of Klf4, TNFA, and IL6 were normalized to 18S RNA abundance.