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

University of Cambridge, United Kingdom
PLoS Biology (Impact Factor: 11.77). 04/2012; 10(4):e1001314. DOI: 10.1371/journal.pbio.1001314
Source: PubMed

ABSTRACT 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, Aug 17, 2015
1 Follower
  • Source
    • "The recent discovery of functional brown fat in adult humans has greatly evoked the interest in better understanding the mechanisms regulating brown fat differentiation [2] [16]. In addition to various signaling molecules and transcription factors, recent studies have indicated that miRNAs, including the miR-193b-365 cluster , miR-196a, miR-133 and miR-155, also play key roles in regulating brown adipocyte differentiation [6] [7] [8] [9]. miR-106b and miR-93 pertain to the miR-106b-25 cluster and are co-located on chromosome 7 [17]. "
    [Show abstract] [Hide abstract]
    ABSTRACT: microRNAs (miRNAs) have been reported to play an essential role in the regulation of brown adipocyte adipogenesis. In the present study, we investigated the role of the miR-106b-93 cluster in the differentiation of brown adipocytes. We found that knockdown of miR-106b and miR-93 significantly induced the expression of brown fat-specific genes and promoted the accumulation of lipid-droplet in differentiating brown adipocytes. In addition, ectopic expression of miR-106b and miR-93 suppressed the mRNA level of Ucp1, a selective hallmark of brown adipocytes. Furthermore, the expression levels of miR-106b and miR-93 are higher in brown adipose tissues of high fat diet-induced obese mice compared to control mice. Taken together, our results identify miR-106b and miR-93 as negative regulators of brown adipocyte differentiation and the miR-106b-93 cluster may play an important role in regulating energy homeostasis.
    Biochemical and Biophysical Research Communications 08/2013; 438(4). DOI:10.1016/j.bbrc.2013.08.016 · 2.28 Impact Factor
  • Source
    • "as a consequence of ''browning'' (increased expression of uncoupling protein 1) of WAT [11] microRNA miR-196a, causes brown adipogenesis of white fat progenitor cells by suppressing the expression of a white-fat gene, the transcription factor Hoxc8. Consistently, overexpression of miR-196a in mice is associated to enhanced energy expenditure and resistance to obesity [12] TRPV4, a member of a family of ion channels, negatively regulates PGC-1a and the thermogenic gene program. Mice lacking this protein exhibit elevated thermogenesis and are protected against diet induced obesity and metabolic derangements [13] pharmacological inhibition of class I histone deacetylases transcriptionally reprograms WAT toward a phenotype more similar to brown fat (induction of PGC-1a and uncoupling protein 1). "
    European Journal of Lipid Science and Technology 11/2012; 114(11). DOI:10.1002/ejlt.201200344 · 2.03 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: The main parenchymal cells of the adipose organ are adipocytes. White adipocytes store energy, whereas brown adipocytes dissipate energy for thermogenesis. These two cell types with opposing functions can both originate from endothelial cells, and co-exist in the multiple fat depots of the adipose organ - a feature that I propose is crucial for this organ's plasticity. This poster review provides an overview of the adipose organ, describing its anatomy, cytology, physiological function and histopathology in obesity. It also highlights the remarkable plasticity of the adipose organ, explaining theories of adipocyte transdifferentiation during chronic cold exposure, physical exercise or lactation, as well as in obesity. White-to-brown adipocyte transdifferentiation is of particular medical relevance, because animal data indicate that higher amounts of brown adipose tissue are positively associated with resistance to obesity and its co-morbidities, and that 'browning' of the adipose organ curbs these disorders.
    Disease Models and Mechanisms 09/2012; 5(5):588-94. DOI:10.1242/dmm.009662 · 5.54 Impact Factor
Show more