Histamine has been referred to as an anorexic factor that decreases appetite, fat accumulation and affects feeding behavior. Tuberomammillary histaminergic neurons have been implicated in central mediation of peripheral metabolic signals such as leptin, while centrally released histamine inhibits ob gene expression. Here, we have characterized the metabolic phenotype of mice that completely lack the ability to produce histamine due to targeted disruption of the key enzyme in histamine biosynthesis (histidine decarboxylase, HDC). Histochemical analyses confirmed the lack of HDC mRNA, histamine-immunoreactivity and histaminergic innervation throughout the brain of gene knockout mouse. Aged histamine deficient (HDC^-) mice are characterized by visceral adiposity, increased amount of brown adipose tissue, impaired glucose tolerance, hyperinsulinemia and hyperleptinemia. Histamine deficient animals are not hyperphagic but gain more weight and are calorically more efficient than wild-type controls. These metabolic changes are presumably due to the impaired regulatory loop between leptin and hypothalamic histamine that results in orexigenic dominance through decreased energy expenditure, attenuated ability to induce UCP-1 mRNA in the brown adipose tissue and defect in mobilizing energy stores. Our results further support the role of histamine in regulation of energy homeostasis.