Brown adipose tissue (BAT) is specialized for energy expenditure, but the signaling pathways that regulate BAT metabolism and activity are incompletely understood. Interferon (IFN) signaling is a sophisticated defense mechanism to counteract viral infection. IFNs and interferon-stimulated genes (ISGs) are reported to exert profound effects on adipocytes. IFN-alpha inducible protein 27 (Ifi27/ISG12a) is a BAT-enriched gene, yet no any studies on its roles in BAT have been reported. Here, we show that Ifi27 protein localizes to mitochondria and the expression of Ifi27 can be induced by beta 3-adrenergic activation in adipose tissues. Knockdown of Ifi27 leads to reduced expression of key enzymes of tricarboxylic acid cycle (TCA), the subunits of electron transport chain (ETC) and uncoupling protein 1 (Ucp1) in brown and beige adipocytes. Moreover, the browning of subcutaneous white fat induced by beta 3-adrenergic agonist is also dramatically blocked. Ectopic expression of Ifi27 in brown adipocytes has the opposite effects. Together, these data indicate that Ifi27 regulates mitochondrial function and browning in adipocytes. (C) 2018 Elsevier Inc. All rights reserved.