A miR-327\u2013FGF10\u2013FGFR2-mediated autocrine signaling mechanism controls white fat browning

Carina Fischer,Patrik Andersson,Sharon Lim,Masaki Nakamura,Yihai Cao,Yanyan Gao,Yunlong Yang,Jennifer Honek,Akihiro Yasue,Yangang Wang,Seiichi Oyadomari,Yun Zhang,Xuri Li,Nilesh J Samani,Masato Miyake,Jun Zhang,Takahiro Seki,Fang Chen,Yizhi Liu

doi:10.1038/s41467-017-02158-z

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.

Highlights

Understanding the molecular mechanisms regulating beige adipocyte formation may lead to the development of new therapies to combat obesity
We chose a mouse white adipose tissue (WAT) browning model for the following reasons: (1) During browning of WAT, there is a significant expansion of the vascular component; (2) differentiation of preadipocyte to beige adipocyte is one of the key processes of adipocyte browning[28]; (3) thermogenesis can be accurately measured; and (4) the effect of therapeutic interventions can be assessed
Immunohistochemical analysis showed that CL-treated mitochondria had enriched COX4+ staining in subcutaneous WAT (scWAT) and visceral WAT (visWAT), indicating an increased number of mitochondria in these white adipose depots (Fig. 1a, d)

Summary

Introduction

Understanding the molecular mechanisms regulating beige adipocyte formation may lead to the development of new therapies to combat obesity. 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. Β3-adrenoceptor agonists, diet, drugs, and many other stimuli are able to activate brown adipose tissue (BAT) and to induce WAT browning[8] Depending on their anatomical location, different WAT depots possess intrinsic properties that define their ability to remain white or become beige adipocytes[9, 10]. MicroRNAs (miRNAs) are short non-coding RNA molecules that regulate protein expression through post-transcriptional mechanisms[18] They often act as repressors of protein production by controlling the mRNA levels and inhibiting translation of their targets within a cell. FGF10 expression is enriched in the stromal-vascular fraction (SVF) of WAT where adipocyte progenitors reside[27]

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