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Hyperleptinemia, Visceral Adiposity, and Decreased Glucose Tolerance in Mice with a Targeted Disruption of the Histidine Decarboxylase Gene

Laboratory of Molecular Neuroendocrinology (A.Fö., I.H.M., K.J.K.), Institute of Experimental Medicine, H-1083 Budapest, Hungary; Department of Genetics, Cell, and Immunobiology (A.K.F., E.B., K.H., A.Fa.) and 3rd Department of Internal Medicine (L.R., M.K.), Semmelweis University, H-1089 Budapest, Hungary; Samuel Lunenfeld Research Institute (A.N.), Mount Sinai Hospital, Toronto, Canada M5G 1X5; and Molecular Immunology Research Group (A.Fa.), Hungarian Academy of Sciences, H-1089 Budapest, Hungary

Address all correspondence and requests for reprints to: Krisztina J. Kovács, Ph.D., Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, Szigony u. 43, H-1083 Budapest, Hungary. E-mail: kovacs{at}koki.hu.

Histamine has been referred to as an anorexic factor that decreases appetite and fat accumulation and affects feeding behavior. Tuberomammillary histaminergic neurons have been implicated in central mediation of peripheral metabolic signals such as leptin, and centrally released histamine inhibits ob gene expression. Here we have characterized the metabolic phenotype of mice that completely lack the ability to produce histamine because of 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 presumably are due to the impaired regulatory loop between leptin and hypothalamic histamine that results in orexigenic dominance through decreased energy expenditure, attenuated ability to induce uncoupling protein-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.

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