The miR-182-5p/FGF21/acetylcholine axis mediates the crosstalk between adipocytes and macrophages to promote beige fat thermogenesis
Wen Meng, Ting Xiao, Xiuci Liang, Jie Wen, Xinyi Peng, Jing Wang, Yi Zou, Jiahao Liu, Christie Bialowas, Hairong Luo, Yacheng Zhang, Bilian Liu, Jingjing Zhang, Fang Hu, Meilian Liu, Lily Q. Dong, Zhiguang Zhou, Feng Liu, Juli Bai
Wen Meng, Ting Xiao, Xiuci Liang, Jie Wen, Xinyi Peng, Jing Wang, Yi Zou, Jiahao Liu, Christie Bialowas, Hairong Luo, Yacheng Zhang, Bilian Liu, Jingjing Zhang, Fang Hu, Meilian Liu, Lily Q. Dong, Zhiguang Zhou, Feng Liu, Juli Bai
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Research Article Endocrinology Metabolism

The miR-182-5p/FGF21/acetylcholine axis mediates the crosstalk between adipocytes and macrophages to promote beige fat thermogenesis

Abstract

A dynamically regulated microenvironment, which is mediated by crosstalk between adipocytes and neighboring cells, is critical for adipose tissue homeostasis and function. However, information on key molecules and/or signaling pathways regulating the crosstalk remains limited. In this study, we identify adipocyte miRNA-182-5p (miR-182-5p) as a crucial antiobesity molecule that stimulated beige fat thermogenesis by promoting the crosstalk between adipocytes and macrophages. miR-182-5p was highly enriched in thermogenic adipocytes, and its expression was markedly stimulated by cold exposure in mice. In contrast, miR-182-5p expression was significantly reduced in adipose tissues of obese humans and mice. Knockout of miR-185-5p decreased cold-induced beige fat thermogenesis whereas overexpression of miR-185-5p increased beiging and thermogenesis in mice. Mechanistically, miR-182-5p promoted FGF21 expression and secretion in adipocytes by suppressing nuclear receptor subfamily 1 group D member 1 (Nr1d1) at 5′-UTR, which in turn stimulates acetylcholine synthesis and release in macrophages. Increased acetylcholine expression activated the nicotine acetylcholine receptor in adipocytes, which stimulated PKA signaling and consequent thermogenic gene expression. Our study reveals a key role of the miR-182-5p/FGF21/acetylcholine/acetylcholine receptor axis that mediates the crosstalk between adipocytes and macrophages to promote beige fat thermogenesis. Activation of the miR-182-5p–induced signaling pathway in adipose tissue may be an effective approach to ameliorate obesity and associated metabolic diseases.

Authors

Wen Meng, Ting Xiao, Xiuci Liang, Jie Wen, Xinyi Peng, Jing Wang, Yi Zou, Jiahao Liu, Christie Bialowas, Hairong Luo, Yacheng Zhang, Bilian Liu, Jingjing Zhang, Fang Hu, Meilian Liu, Lily Q. Dong, Zhiguang Zhou, Feng Liu, Juli Bai

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Figure 4

FGF21 mediates the promotive effect of miR-182-5p on UCP1 expression in adipocytes via a macrophage-dependent mechanism.

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FGF21 mediates the promotive effect of miR-182-5p on UCP1 expression in ...
(A) INOH pathway analysis of the RNA-Seq data from primary adipocytes overexpressing miR-182-5p (n = 3/group). (B) Heatmap analysis shows the relative expression levels of secretory genes. (C) The Venn diagram showing the strategy to identify thermogenesis-related secretory factors. Volcano plot depicting the gene expression differences between miR-182-5p intervention and control group. Upregulated genes were colored in red, and downregulated genes were colored in blue. (D) FGF21 mRNA and (E) protein levels in primary adipocytes overexpressing miR-182-5p mimic (182-mimic) or its negative control (nc-mimic) were determined by qRT-PCR (n = 3/group) or Western blot, respectively. (F) FGF21 mRNA and (G) protein levels in sWAT of miR-182-5p agomir- or nc-agomir–injected (fat pad) mice (n = 5–6/group) were determined by qRT-PCR or ELISA, respectively. (H) qRT-PCR analysis for FGF21 mRNA levels and (I) ELISA analysis for FGF21 protein concentration in sWAT of miR-182-5p+/–and WT control mice exposed to cold (n = 3–4/group). (J) PMs were treated with or without FGF21 (50 nM) for 48 hours, and conditioned medium (CM) of the cells was collected. Primary adipocytes were incubated with the FGF21-treated (+) or nontreated (-) CM or directly treated with FGF21 for 3 days. UCP1 expression in cells was determined by Western blot analysis (n = 3 biological replicates). 182-mimic or nc-mimic was overexpressed in primary white adipocytes isolated from FGF21KO and their control mice. The cells were cocultured with PMs for 3 days, and the mRNA levels of (K) Arg1 and (L) UCP1 were determined by qRT-PCR (n = 4/group). Data represent mean ± SEM. Significance determined by unpaired 2-tailed Student’s t test (D and F–I) and by 1-way ANOVA (K and L). *P < 0.05; **P < 0.01.