Lipocalin-2 (Lcn2) is an innate immune protein elevated by several orders of magnitude in various inflammatory conditions including aging and obesity. Recent studies have shown that Lcn2 is secreted by adipocytes in response to inflammation and is categorized as a new adipokine cross-linking innate immunity and metabolic disorders including obesity. However, the involvement of Lcn2 and its function during the progression of obesity is largely unknown. Recently, browning of white adipose tissue (WAT) has gained attention as a therapeutic strategy to combat obesity. Herein, we have shown that treatment of mature 3T3-L1 adipocytes with recombinant Lcn2 (rec-Lcn2) resulted in the up-regulation of thermogenic and beige/brown markers (UCP1, PRDM16, ZIC-1 and TBX1) and increased mitochondrial activity. Additionally, global Lcn2 genetic knockout (Lcn2KO) mice exhibited accelerated weight gain and visceral fat deposition with age, when compared to wild type (WT) mice. Taken together, both in vitro and in vivo studies suggest that Lcn2 is a naturally occurring adipokine, and may serve as an anti-obesity agent by upregulating the thermogenic markers resulting in the browning of WAT. Therefore, Lcn2 and its downstream signaling pathways could be a potential therapeutic target for obesity.