MiR-133a Regulates Adipocyte Browning In Vivo

Weiyi Liu,Hang Yin,Shihuan Kuang,Xin Yang,Ning Liu,Pengpeng Bi,Michael A Rudnicki,Yong-Xu Wang,Tizhong Shan,Shingo Kajimura

doi:10.1371/journal.pgen.1003626

Abstract

Prdm16 determines the bidirectional fate switch of skeletal muscle/brown adipose tissue (BAT) and regulates the thermogenic gene program of subcutaneous white adipose tissue (SAT) in mice. Here we show that miR-133a, a microRNA that is expressed in both BAT and SATs, directly targets the 3′ UTR of Prdm16. The expression of miR-133a dramatically decreases along the commitment and differentiation of brown preadipocytes, accompanied by the upregulation of Prdm16. Overexpression of miR-133a in BAT and SAT cells significantly inhibits, and conversely inhibition of miR-133a upregulates, Prdm16 and brown adipogenesis. More importantly, double knockout of miR-133a1 and miR-133a2 in mice leads to elevations of the brown and thermogenic gene programs in SAT. Even 75% deletion of miR-133a (a1−/−a2+/−) genes results in browning of SAT, manifested by the appearance of numerous multilocular UCP1-expressing adipocytes within SAT. Additionally, compared to wildtype mice, miR-133a1−/−a2+/− mice exhibit increased insulin sensitivity and glucose tolerance, and activate the thermogenic gene program more robustly upon cold exposure. These results together elucidate a crucial role of miR-133a in the regulation of adipocyte browning in vivo.

Highlights

Adipose tissues are classified as brown (BAT) and white (WAT), and an intermediate category of ‘‘brite’’ or ‘‘beige’’ adipocytes exist within subcutaneous WAT [1,2]
Recent studies indicate that white adipose is plastic and contains an intermediate type of adaptive adipocytes that have the energy-dissipating properties of brown adipocytes
Our results suggest that miR133a represents a potential drug target against obesity and Type2 diabetes

Summary

Introduction

Adipose tissues are classified as brown (BAT) and white (WAT), and an intermediate category of ‘‘brite’’ or ‘‘beige’’ adipocytes exist within subcutaneous WAT [1,2]. The signaling pathway that determines the developmental commitment and differentiation of brown and beige adipocytes is crucial for understanding the process and importance of adipose browning. Prdm is a critical regulator of brown adipocyte development and determines the thermogenic gene program in SAT. Downregulation of Prdm in brown adipocytes promotes their fate switch to myoblasts [3]. Ectopic overexpression of Prdm and its co-activator C/EBPb in myoblasts or fibroblasts transdifferentiated them into brown adipocytes [3,4]. Overexpression of Prdm in the stromal vascular fraction (SVF) cells of SAT led to the browning of white adipocytes [5]

Methods

Results

Discussion

Conclusion