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 4

The metabolic benefits of adipose-selective miR-34a deficiency are mediated by macrophages.

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The metabolic benefits of adipose-selective miR-34a deficiency are media...
Male adipose-specific miR-34a–KO mice or WT controls on HFD for 12 weeks were intraperitoneally injected with PBS-liposomes or clodronate-conjugated liposomes (CLOD-liposomes) for 4 weeks. (A) Representative flow cytometry dot plots showing F4/80+ total macrophages in SVFs of epiWAT from HFD-fed WT mice injected with PBS- or CLOD-liposomes for 4 weeks. (B) Representative images of immunohistological staining of F4/80 in epiWAT from WT and KO mice treated with PBS- or CLOD-liposomes. Scale bar: 40 μm. (C) Glucose tolerance test of HFD-fed WT and KO mice treated with PBS- or CLOD-liposomes (n = 8; *P < 0.05, **P < 0.01 compared with KO+PBS). (D) Area under the curve (AUC) of glucose tolerance test (n = 8). (E) Insulin tolerance test of mice (n = 8; *P < 0.05, **P < 0.01 compared with KO+PBS). (F) AUC of insulin tolerance test (n = 8). (G–L) Serum levels of insulin (G), TNF-α (H), IL-6 (I), IL-1β (J), MCP-1 (K), and adiponectin (L) determined with ELISA (n = 8). Data represent mean ± SEM. Differences were determined by ANOVA (C–L); *P < 0.05, **P < 0.01, ***P < 0.001.