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.

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    • "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). "
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    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.
    Cell metabolism 10/2015; 22(4):546-559. DOI:10.1016/j.cmet.2015.09.007 · 17.57 Impact Factor
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    • "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. "
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    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.
    Biochemical and Biophysical Research Communications 05/2015; 463(3). DOI:10.1016/j.bbrc.2015.05.014 · 2.30 Impact Factor
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    • "In a cell line RAW264.7 an osteoclast precursor, miRNA-223 was found to play a role in osteoclast differentiation. PU.1, a transcription factor induced by M-CSF, stimulates the expression of miRNA-223, which in turn downregulates the NFI-A levels required for upregulating macrophage colony-stimulating factor receptor (M-CSFR) [7, 65, 78, 79]. PU.1 selectively regulates genes during osteoclast differentiation. "
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    ABSTRACT: Increased life expectancy and the need for long-term antiretroviral therapy have brought new challenges to the clinical management of HIV-infected individuals. The prevalence of osteoporosis and fractures is increased in HIV-infected patients; thus optimal strategies for risk management and treatment in this group of patients need to be defined. Prevention of bone loss is an important component of HIV care as the HIV population grows older. Understanding the mechanisms by which HIV infection affects bone biology leading to osteoporosis is crucial to delineate potential adjuvant treatments. This review focuses on HIV-induced osteoporosis within the context of microRNAs (miRNAs) by reviewing first basic concepts of bone biology as well as current knowledge of the role of miRNAs in bone development. Evidence that HIV-associated osteoporosis is in part independent of therapies employed to treat HIV (HAART) is supported by cross-sectional and longitudinal studies and is the focus of this review.
    Journal of Osteoporosis 10/2013; 2013(3):571418. DOI:10.1155/2013/571418
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