A miR-327–FGF10–FGFR2-mediated autocrine signaling mechanism controls white fat browning

Carina Fischer, Takahiro Seki, Sharon Lim, Masaki Nakamura, Patrik Andersson, Yunlong Yang, Jennifer Honek, Yangang Wang, Yanyan Gao, Fang Chen, Nilesh J. Samani, Jun Zhang, Masato Miyake, Seiichi Oyadomari, Akihiro Yasue, Xuri Li, Yun Zhang, Yizhi Liu and Yihai Cao ()
Additional contact information
Carina Fischer: Karolinska Institute
Takahiro Seki: Karolinska Institute
Sharon Lim: Karolinska Institute
Masaki Nakamura: Karolinska Institute
Patrik Andersson: Karolinska Institute
Yunlong Yang: Karolinska Institute
Jennifer Honek: Karolinska Institute
Yangang Wang: Affiliated Hospital of Qingdao University
Yanyan Gao: Affiliated Hospital of Qingdao University
Fang Chen: Hospital of Zhejiang Chinese Medicine University
Nilesh J. Samani: University of Leicester and NIHR Leicester Cardiovascular Biomedical Research Unit, Glenfield Hospital
Jun Zhang: Tokushima University
Masato Miyake: Tokushima University
Seiichi Oyadomari: Tokushima University
Akihiro Yasue: Tokushima University Graduate School
Xuri Li: Sun Yat-Sen University
Yun Zhang: Shandong University Qilu Hospital
Yizhi Liu: Sun Yat-Sen University
Yihai Cao: Karolinska Institute

Nature Communications, 2017, vol. 8, issue 1, 1-19

Abstract: Abstract Understanding the molecular mechanisms regulating beige adipocyte formation may lead to the development of new therapies to combat obesity. Here, we report a miRNA-based autocrine regulatory pathway that controls differentiation of preadipocytes into beige adipocytes. We identify miR-327 as one of the most downregulated miRNAs targeting growth factors in the stromal-vascular fraction (SVF) under conditions that promote white adipose tissue (WAT) browning in mice. Gain- and loss-of-function experiments reveal that miR-327 targets FGF10 to prevent beige adipocyte differentiation. Pharmacological and physiological β-adrenergic stimulation upregulates FGF10 levels and promotes preadipocyte differentiation into beige adipocytes. In vivo local delivery of miR-327 to WATs significantly compromises the beige phenotype and thermogenesis. Contrarily, systemic inhibition of miR-327 in mice induces browning and increases whole-body metabolic rate under thermoneutral conditions. Our data provide mechanistic insight into an autocrine regulatory signaling loop that regulates beige adipocyte formation and suggests that the miR-327–FGF10–FGFR2 signaling axis may be a therapeutic targets for treatment of obesity and metabolic diseases.

Date: 2017
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DOI: 10.1038/s41467-017-02158-z

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