Sodium salicylate induces browning of white adipocytes via M2 macrophage polarization by HO-1 upregulation

Browning, a white to brown-like (beige) adipocyte conversion, offers a promising therapeutic strategy for the treatment of human obesity. In the present study, the effects of sodium salicylate, a nonsteroidal anti-inflammatory drug, on adipocyte browning were investigated. We found sodium salicylate altered the macrophage phenotype to M2 in RAW264.7 cells, mediated by up-regulation of heme oxygenase-1 (HO-1), and sodium salicylate-treated conditioned medium from macrophages (Sal-M2 CM) induced browning of fully differentiated 3T3-L1 adipocytes. Conversely, the conditioned medium obtained from macrophages when treated with sodium salicylate in the presence of either ZnPP (a HO-1 inhibitor) or HO-1 siRNA did not induce browning. In association with macrophage HO-1 induction by sodium salicylate, iron production also increased, and deferoxamine (an iron chelator) blunted the browning effects of Sal-M2 CM, suggesting that iron may play a role in the Sal-M2 CM-induced browning. The in vivo browning effects of sodium salicylate were confirmed in ob/ob mice, whereas in vivo macrophage depletion by clodronate as well as HO-1 blockade by either ZnPP or adeno-associated virus carrying HO-1 shRNA (AAV–HO–1 shRNA) attenuated the browning effects of sodium salicylate. These results reveal sodium salicylate induces browning in vitro and in vivo by up-regulating HO-1 thus promoting M2 polarization.