Essential Role for miR-196a in Brown Adipogenesis of White Fat Progenitor Cells

University of Cambridge, United Kingdom
PLoS Biology (Impact Factor: 9.34). 04/2012; 10(4):e1001314. DOI: 10.1371/journal.pbio.1001314
Source: PubMed


The recent discovery of functional brown adipocytes in adult humans illuminates the potential of these cells in the treatment of obesity and its associated diseases. In rodents, brown adipocyte-like cells are known to be recruited in white adipose tissue (WAT) by cold exposure or β-adrenergic stimulation, but the molecular machinery underlying this phenomenon is not fully understood. Here, we show that inducible brown adipogenesis is mediated by the microRNA miR-196a. We found that miR-196a suppresses the expression of the white-fat gene Hoxc8 post-transcriptionally during the brown adipogenesis of white fat progenitor cells. In mice, miR-196a is induced in the WAT-progenitor cells after cold exposure or β-adrenergic stimulation. The fat-specific forced expression of miR-196a in mice induces the recruitment of brown adipocyte-like cells in WAT. The miR-196a transgenic mice exhibit enhanced energy expenditure and resistance to obesity, indicating the induced brown adipocyte-like cells are metabolically functional. Mechanistically, Hoxc8 targets and represses C/EBPβ, a master switch of brown-fat gene program, in cooperation with histone deacetylase 3 (HDAC3) through the C/EBPβ 3' regulatory sequence. Thus, miR-196a induces functional brown adipocytes in WAT through the suppression of Hoxc8, which functions as a gatekeeper of the inducible brown adipogenesis. The miR-196a-Hoxc8-C/EBPβ signaling pathway may be a therapeutic target for inducing brown adipogenesis to combat obesity and type 2 diabetes.

Download full-text


Available from: Masaki Mori
  • Source
    • "Our data demonstrated that miR-196a overexpression enhanced adipocyte differentiation (Figure 5), without influencing cell proliferation (Figure 4). Consistently, ASO (antisense oligonucleotide) against miR-196a suppressed the expression of PPARγ in mouse SVF (stromal vascular fraction) cells followed by adipogenic induction[50]. However, our results are in disagreement with previous findings[22], which demonstrated that overexpression of miR-196a decreased hASC (human adipose tissue-derived mesenchymal stem cells) proliferation and enhanced osteogenic differentiation, without affecting adipogenic differentiation. "
    [Show abstract] [Hide abstract]
    ABSTRACT: MicroRNAs (miRNAs) are a class of small non-coding RNA molecules, which play important roles in animals by targeting mRNA transcripts for translational repression. Recent studies have demonstrated that miRNAs are involved in regulation of adipocyte development. The expression of miR-196a in different porcine tissues and developing fat tissues was detected, and gene ontology (GO) term enrichment was then used to predict the expression profiles and potential biological roles of miR-196a in swine. To further verify the roles of miR-196a in porcine adipocyte development, a recombinant adenovirus encoding miR-196a gene (Ad-miR-196a) was constructed and used to study the effect of miR-196a on preadipocyte proliferation and differentiation. Here, our data demonstrate that miR-196a displays a tissue-specific expression pattern and has comprehensive biological roles in swine, especially in adipose development. In addition, overexpression of miR-196a had no effect on preadipocyte proliferation, but induced preadipocyte differentiation by increasing expression of adipocyte specific markers, lipid accumulation and triglyceride content. These data represent the first demonstration of miR-196a expression profiles and roles in swine, thereby providing valuable insight into the functions of miR-196a in adipocyte biology.
    Preview · Article · Jan 2016 · Genes
  • Source
    • "Several micro- RNAs (miR), including miR-133, miR-193b, and miR-365, target PRDM16 and negatively regulate brown and beige adipocyte development in mice (Liu et al., 2013; Sun et al., 2011; Trajkovski et al., 2012; Yin et al., 2013). miR-196a activates C/EBP-b expression and induces beige adipocyte differentiation through repression of HoxC8, a negative regulator of C/EBP-b (Mori et al., 2012), whereas miR-155 represses CEBP-b expression and impairs brown adipocyte differentiation (Chen et al., 2013). Additionally, miR-378 and miR-30 activate brown or beige adipocyte differentiation by targeting repressors of BAT thermogenesis , such as phosphodiesterase1b (PDE1b) and receptorinteracting protein 140 (RIP140), respectively (Hu et al., 2015; Pan et al., 2014). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Since brown adipose tissue (BAT) dissipates energy through UCP1, BAT has garnered attention as a therapeutic intervention for obesity and metabolic diseases including type 2 diabetes. As we better understand the physiological roles of classical brown and beige adipocytes, it is becoming clear that BAT is not simply a heat-generating organ. Increased beige fat mass in response to a variety of external/internal cues is associated with significant improvements in glucose and lipid homeostasis that may not be entirely mediated by UCP1. We aim to discuss recent insights regarding the developmental lineages, molecular regulation, and new functions for brown and beige adipocytes.
    Full-text · Article · Oct 2015 · Cell metabolism
  • Source
    • "A recent study revealed the effect of miR-155 in controlling the development of brown and beige fat cells, through its targeting of C/EBPb [13]. In addition, it has been reported that overexpression of miR-196a induces the browning of inguinal-WAT (Ing-WAT) in mice [14]. However, to date, miRNA profile-based studies to investigate the murine BAT and WAT response to prolonged cold stimulation have not been reported. "
    [Show abstract] [Hide abstract]
    ABSTRACT: There are two classic adipose tissues in mammals, white adipose tissue (WAT) and brown adipose tissue (BAT). It has been well known that browning of WAT can be induced by cold exposure. In this study, to identify the novel cold responsive key miRNAs that are involved in browning, mice were housed at 6°C for 10 days, and deep sequencing of the miRNAs of WAT and BAT was performed. Our data showed that WAT and BAT displayed distinct expression profiles due to their different locations, morphology and biological function. A total of 27 BAT and 29 WAT DE (differentially expressed) miRNAs were identified in response to cold stimulation, respectively (fold change >2 and FDR (false discovery rate) <0.05), of which, 9 were overlapped in both adipose tissues. Furthermore, the potential target genes of the DE miRNAs from BAT and WAT were predicted computationally, and the KEGG pathway analysis revealed the enrichment pathways in cold stimulated adipose tissues. The expression pattern of miR-144-3p/Bmpr1b/Phlda1 and miR-146a-5p/Sphk2 were further measured by qPCR. Finally, we found that miR-146a-5p was significantly induced during the primary adipogenesis caused by BAT differentiation, whereas miR-144-3p was decreased. Our study identifies for the first time the novel miRNAs involved in browning of WAT by sequencing and expands the therapeutic approaches for combating metabolic diseases. Copyright © 2015. Published by Elsevier Inc.
    Full-text · Article · May 2015 · Biochemical and Biophysical Research Communications
Show more