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 3

Adipose miR-34a modulates infiltration and polarization of macrophages in mice with dietary obesity.

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Adipose miR-34a modulates infiltration and polarization of macrophages i...
(A and B) Representative images of immunohistological staining of F4/80 (A) and quantification of crown-like structures (CLSs; B) in epiWAT of WT or KO mice on HFD for 0, 8, and 16 weeks (n = 6). Scale bar: 40 μm. (C and D) Cells isolated from SVFs of epiWAT in KO and WT mice fed with HFD for 0, 8, and 16 weeks were subjected to flow cytometry analysis for percentage of F4/80+ total macrophages (C), M1 (CD11c+CD206–), and M2 (CD206+CD11c–) within the macrophage population (D) (n = 4–6). (E and F) Immunoblot analysis for the expression of iNOS and arginase 1 (Arg1) in epiWAT of mice on STC or HFD for 16 weeks (E), and densitometric analysis for their abundance relative to tubulin (F) (n = 6–8). (G) Real-time PCR analysis for the mRNA levels of the M1 and M2 markers in epiWAT of mice on STD or HFD 16 weeks (n = 6). Data represent mean values ± SEM. Differences between groups were determined by ANOVA (B–D, F, and G); *P < 0.05, **P < 0.01, ***P < 0.001. Gene levels were normalized to 18S RNA abundance.