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The Mir-182-5P/FGF21/Acetylcholine Axis Mediates the Crosstalk Between Adipocytes and Macrophages to Promote Beige Fat Thermogenesis

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The Mir-182-5P/FGF21/Acetylcholine Axis Mediates the Crosstalk Between Adipocytes and Macrophages to Promote Beige Fat Thermogenesis The miR-182-5p/FGF21/acetylcholine axis mediates the crosstalk between adipocytes and macrophages to promote beige fat thermogenesis Wen Meng, … , Feng Liu, Juli Bai JCI Insight. 2021. https://doi.org/10.1172/jci.insight.150249. Research In-Press Preview Endocrinology Metabolism Graphical abstract Find the latest version: https://jci.me/150249/pdf The miR-182-5p/FGF21/acetylcholine axis mediates the crosstalk between adipocytes and macrophages to promote beige fat thermogenesis Wen Meng 1,#, Ting Xiao1,#, Xiuci Liang1, Jie Wen1,2 , Xinyi Peng1,2, Jing Wang1, Yi Zou3, Jiahao Liu1, Christie Bialowas4, Hairong Luo1, Yacheng Zhang1,5, Bilian Liu1, Jingjing Zhang1, Fang Hu1, Meilian Liu1,6, Lily Q. Dong7, Zhiguang Zhou1, Feng Liu1,2,* and Juli Bai1,2,* 1National Clinical Research Center for Metabolic Diseases, Metabolic Syndrome Research Center, and Department of Metabolism and Endocrinology, The Second Xiangya Hospital of Central South University, Changsha 410011, Hunan, China. Departments of 2Pharmacology, 3Greehey Children’s Cancer Research Institute, and 7Cell Systems & Anatomy, University of Texas Health at San Antonio, San Antonio, Texas, USA 4Division of Plastic Surgery, Department of Surgery, Albany Medical Center, Albany, NY 12208-3403 5Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Xinjiang Medical University, Urumqi, Xinjiang, China 6Department of Biochemistry and Molecular Biology, University of New Mexico Health Sciences Center, Albuquerque, New Mexico, USA *Corresponding author: E-mail: [email protected] or [email protected] Mailing address: Department of Pharmacology, University of Texas Health San Antonio, 7703 Floyd Curl Drive, San Antonio, Texas, 78229. Juli Bai Phone: 210-567-4526; Email: [email protected]; Feng Liu: 210-567-3097; Email: [email protected] #These authors contribute equally to the work Running title: miR-182-mediated immune regulation of beige fat development Word Count: 7314 words. Number of Figures: 6 Number of Tables: 0 1 1 Abstract 2 A dynamically regulated microenvironment, which is mediated by crosstalks between adipocytes 3 and neighboring cells, is critical for adipose tissue homeostasis and function. However, information on 4 key molecules and/or signaling pathways regulating the crosstalks remains limited. In this study, we 5 identify adipocyte miR-182-5p as a crucial anti-obesity molecule that stimulates beige fat thermogenesis 6 by promoting the crosstalk between adipocytes and macrophages. miR-182-5p is highly enriched in 7 thermogenic adipocytes and its expression is markedly stimulated by cold exposure in mice. In contrast, 8 miR-182-5p expression is significantly reduced in adipose tissues of obese humans and mice. Knockout 9 of miR-185-5p decreased cold-induced beige fat thermogenesis whereas overexpression of miR-185-5p 10 increased beiging and thermogenesis in mice. Mechanistically, miR-182-5p promotes FGF21 expression 11 and secretion in adipocytes by suppressing Nr1d1 at 5'UTR, which in turn stimulates acetylcholine 12 synthesis and release in macrophages. Increased acetylcholine expression activates the nicotine 13 acetylcholine receptor in adipocytes, which stimulates PKA signaling and consequent thermogenic gene 14 expression. Our study reveals a key role of the miR-182-5p/FGF21/acetylcholine/acetylcholine receptor 15 axis that mediates the crosstalk between adipocytes and macrophages to promote beige fat 16 thermogenesis. Activation of the miR-182-5p-induced signaling pathway in adipose tissue may be an 17 effective approach to ameliorate obesity and associated metabolic diseases. 2 18 Introduction 19 Excess expansion of white adipose tissue (WAT) due to positive energy balance and/or defects in 20 thermogenesis in beige fat and brown adipose tissue (BAT) are associated with obesity and various 21 metabolic diseases such as inflammation, insulin resistance, and type 2 diabetes (1, 2). Adipose tissue 22 microenvironment (ATME), which is modulated by signaling pathway crosstalks between adipocytes 23 and neighboring cells such as resident or infiltrated macrophages, have a great impact on adipose tissue 24 function and systemic metabolic homeostasis (3, 4). However, the precise mechanisms by which 25 adipocytes crosstalk to macrophages in adipose tissue remain to be further elucidated. 26 FGF21, which is mainly produced in the liver and to a lesser extent in adipose tissue, muscle and 27 pancreas, has various metabolic beneficial effects such as reducing adiposity and hepatic triglyceride 28 content, promoting thermogenesis and energy expenditure, and improving insulin sensitivity (5). 29 Various studies have demonstrated that the physiological roles of FGF21 are mediated by its endocrine, 30 autocrine, and/or paracrine actions. FGF21 deficient mice exhibited decreased cold-induced thermogenic 31 gene expression in WAT but not BAT (6). It has also been found that adipose- but not liver-derived 32 FGF21 may regulate beige fat thermogenesis through a paracrine action (6, 7). However, how adipose 33 FGF21 is regulated to exerts its paracrine action and induce beige cell thermogenesis remains elusive. 34 MicroRNAs (miRNAs) are endogenous, noncoding small RNAs that post transcriptionally regulate 35 gene expression and have been shown to have important roles in numerous disease processes (8). In 36 adipose tissues, miRNAs play an important role in regulating the pathways that control a range of 37 processes including adipocyte differentiation, insulin signaling and glucose homeostasis (8). Recent 38 studies have demonstrated that some miRNA directly target and regulate thermogenic genes of brown 39 adipocyte development and the beiging of white adipocytes(9-11). Among adipose expressed miRNA, 40 miR-182-5p is highly enriched in differentiated brown adipocytes compared to non-differentiated cells 3 41 (12). However, whether and how miR-182-5p is involved in regulating beiging progress of WAT is 42 largely unknown. 43 In the current study, we show that adipose miR-182-5p levels are negatively associated with obesity 44 in mice and humans. Adipose miR-182-5p expression is induced by cold exposure in mice and its 45 deficiency suppresses cold-induced expression of genes involved in mitochondrial biogenesis and 46 thermogenesis. On the other hand, overexpression of miR-182-5p in adipose tissue promoted beiging of 47 white adipose tissue and thermogenesis, improved energy homeostasis and resisted diet-induced obesity. 48 By inhibiting Nr1d1, adipose miR-182-5p increases FGF21 expression and secretion, which in turn 49 stimulates the production and secretion of acetylcholine in macrophages. Acetylcholine potentiates 50 nAChR-mediated activation of the PKA signaling pathway in adipocytes and thus increased 51 thermogenic gene expression. Our study identifies a novel miR-182-5p/FGF21/acetylcholine/PKA 52 signaling circuit that mediates the crosstalk between adipocytes and adipose tissue-resident macrophages 53 to promote beige fat development and counteract overnutrition-induced obesity. Thus, up-regulation of 54 the miR-182-5p/FGF21/acetylcholine /PKA axis may be an effective approach to ameliorate obesity- 55 induced metabolic diseases. 56 57 58 Results 59 miR-182-5p expression in WAT is negatively correlated with obesity in mice and humans but is 60 stimulated by cold exposure in mice 61 To determine the potential role of miR-182-5p is beiging process, we exposed mice to cold. We 62 found that cold exposure greatly increased miR-182-5p levels in both sWAT (Figure 1A) and BAT 4 63 (Figure 1B) of mice. Interestingly, miR-182-5p had a much greater response to cold exposure in sWAT 64 (~100-fold changes) than in BAT (~3-fold changes), suggesting that miR-182-5p may have a major 65 function in regulating beige fat thermogenesis. miR-182-5p expression levels were significantly reduced 66 in sWAT of HFD-fed mice (Figure 1C) and ob/ob mice (Figure 1D) compared to their respective control 67 mice. The expression of miR-182-5p in sWAT was also negatively correlated with BMI in humans 68 (Figures 1E and 1F). These data suggest that miR-182-5p down-regulation may contribute to diet- 69 induced obesity. 70 miR-182-5p promotes beiging of white adipose tissue and energy expenditure in mice 71 Next, we investigated whether miR-182-5p deficiency affects cold-induced thermogenic gene 72 expression in mice. Because some of the homozygous miR-182-5p knockout mice were born with 73 defects such as shorter tails and lacking ears, which may complicate the interpretation of the data, we 74 used heterozygous miR-182-5p knockout mice (miR-182-5p+/-) in our study, which showed a significant 75 decrease in miR-182-5p levels in both sWAT (Figure S1A) and BAT (Figure S1B) compared to their 76 control mice but did not show any detectable growth, morphological, and metabolic defects under 77 normal housing condition. While miR-182-5p deficiency in mice had no effect on cold exposure- 78 induced Ucp1 gene expression in BAT (Figure S1C), it greatly suppressed cold-induced protein 79 expression of key regulators of beige fat thermogenesis such as UCP1, PGC1α, and CEBPβ in sWAT 80 (Figure 2A), as well as the formation of multilocular brown-like adipocytes (Figure 2B). Consistent with 81 these results, miR-182-5p+/- mice displayed a significant reduction in norepinephrine (NE)-induced 82 oxygen consumption (Figure 2C) and impaired cold tolerance at 4 ℃ (Figure S1D) compared to control 83 littermates. In addition, the miR-182-5p+/- mice gained more body weight on HFD at room temperature 84 (Figure S1E), probably due to impaired beige fat thermogenesis. Taken together, these results suggest 85 that miRNA-182-5p is an important regulator of energy expenditure. 5 86 To further determine the potential role of adipose miR-182-5p in regulating beige fat development 87 and thermogenesis in vivo, we established a fat pad injection technique using a modified procedure as 88 described (13, 14). Subcutaneous fat pad injection of miR-182-5p agomir, a synthetic double-stranded 89 miRNA that mimics endogenous miR-182-5p, significantly increased miR-182-5p level in sWAT 90 (Figure S1F) but not in BAT and eWAT (Figures S1G and S1H), demonstrating the specificity of the 91 injection.
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