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

<div><p>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 <em>Hoxc8</em> 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 <em>C/EBPβ</em>, a master switch of brown-fat gene program, in cooperation with histone deacetylase 3 (HDAC3) through the <em>C/EBPβ</em> 3′ regulatory sequence. Thus, miR-196a induces functional brown adipocytes in WAT through the suppression of <em>Hoxc8</em>, which functions as a gatekeeper of the inducible brown adipogenesis. The miR-196a-<em>Hoxc8</em>-<em>C/EBPβ</em> signaling pathway may be a therapeutic target for inducing brown adipogenesis to combat obesity and type 2 diabetes.</p>