miR-133a Regulates Adipocyte Browning In Vivo

<div><p>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 <i>Prdm16</i>. 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, <i>Prdm16</i> and brown adipogenesis. More importantly, double knockout of <i>miR-133a1</i> and <i>miR-133a2</i> in mice leads to elevations of the brown and thermogenic gene programs in SAT. Even 75% deletion of miR-133a (<i>a1^−/−a2^+/−</i>) genes results in browning of SAT, manifested by the appearance of numerous multilocular UCP1-expressing adipocytes within SAT. Additionally, compared to wildtype mice, <i>miR-133a1^−/−a2^+/−</i> 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.</p>