Histamine neurons are widely distributed in the brain and suppress food intake through the histamine H₁ receptor (H₁-R) in the hypothalamus. To examine the role of neuronal histamine in leptin signaling pathways, we investigated the effects of H₁-R knockout (H1KO) mice on both food intake and mRNA expressions of uncoupling proteins(UCPs) as regulated by leptin, and concomitantly on basal changes in both expression of hypothalamic neuropeptides and diet-induced fat deposition in adipose tissues. H1KO mice showed no change in daily food intake, growth curve, body weight, or adiposity. Reflecting no specificity in these parameters, H1KO mice induced no basal changes in mRNA expression of hypothalamic neuropeptides, ob gene, or peripheral UCPs. Loading H1KO mice with a high-fat diet accelerated fat deposition and ob gene expression compared with the controls. Leptin-induced feeding suppression was partially attenuated in H1KO mice, indicating involvement of histamine neurons in feeding regulation as a downstream signal of leptin. Upregulation of fat UCP mRNA and reduction of body fat induced by central infusion of leptin were attenuated in the H1KO mice. These results show that H1KO mice are a novel leptin-resistant model and that H₁-R is a key receptor for downstream signaling of leptin in the brain that contributes to regulation of feeding, fat deposition, and UCP mRNA expression.