Celastrol is a leptin-sensitizing agent with profound anti-obesity effects in diet-induced obese (DIO) mice. However, the genes and pathways that mediate celastrol-induced leptin sensitization have not been fully understood. By comparing the hypothalamic transcriptomes of celastrol and vehicle-treated DIO mice, we identified lipocalin-2 (Lcn2) as the gene most strongly upregulated by celastrol. LCN2 was previously suggested as an anorexigenic and anti-obesity agent. Celastrol increased LCN2 protein levels in hypothalamus, liver, fat, muscle, and bone marrow, as well as in the plasma. However, genetic deficiency of LCN2 altered neither the development of diet-induced obesity, nor the ability of celastrol to promote weight loss and improve obesity-associated dyshomeostasis. We conclude that LCN2 is dispensable for both high fat diet-induced obesity and its therapeutic reduction by celastrol.