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The present study aimed to examine roles of histamine neurons in leptin signaling pathways and leptin resistant states. H1-receptor knockout (H1KO) mice showed no change in daily food intake, adiposity, growth curve, basal expression of hypothalamic neuropeptides, uncoupling proteins (UCPs) or ob gene. However, H1KO mice fed with high fat diet increased fat deposition and ob gene expression more excessively. Leptin-induced feeding suppression was attenuated in H1KO mice. Chronic leptin treatment decreased visceral fat and up-regulated UCPs expression in brown and white fat. These effects of leptin were attenuated in pair-fed H1KO mice. Chronic histamine or histidine treatment decreased body weight, body fat deposition, and serum glucose and insulin in diet-induced obese, ob/ob and db/db mice. Activation of histamine neurons suppressed ob gene expression in the fat tissue together with elevation of seurm leptin and UCPs mRNA. These actions of neuronal histamine were attenuated in the double knockout mice, i.e., db/db mice with H1KO. Taken together, H1KO mice, a novel leptin resistant model, elucidate essential roles of H1-R in energy intake and expenditure as a down-stream-signaling message of leptin actions in the brain. The anti-obesity and anti-diabetic effects of histamine neurons provide a new insight into therapeutic strategies on human obesity and diabetes with leptin resistance.
