Hyperleptinemia, visceral adiposity, and decreased glucose tolerance in mice with a targeted disruption of the histidine decarboxylase gene.
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.
Fülöp
András K
AK
Laboratory of Molecular Neuroendocrinology, Institute of Experimental Medicine, H-1083 Budapest, Hungary.
Földes
Anna
A
Buzás
Edit
E
Hegyi
Krisztina
K
Miklós
Ildikó H
IH
Romics
László
L
Kleiber
Monika
M
Nagy
András
A
Falus
András
A
Kovács
Krisztina J
KJ
D000273:Adipose Tissue / Q000473:pathology*; D002001:Adipose Tissue, Brown / Q000378:metabolism; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001835:Body Weight; D001921:Brain / Q000378:metabolism / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics; D004734:Energy Metabolism; D018149:Glucose Intolerance / Q000235:genetics*; D006632:Histamine / Q000378:metabolism; D006639:Histidine / Q000494:pharmacology; D006640:Histidine Decarboxylase / Q000172:deficiency / Q000235:genetics*; D006728:Hormones / Q000097:blood; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007473:Ion Channels; D020738:Leptin / Q000097:blood*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D024101:Mitochondrial Proteins; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D000071256:Uncoupling Protein 1; D014781:Viscera
D001786:Blood Glucose; D002352:Carrier Proteins; D006728:Hormones; D007328:Insulin; D007473:Ion Channels; D020738:Leptin; D008565:Membrane Proteins; D024101:Mitochondrial Proteins; D012333:RNA, Messenger; C000604372:Ucp1 protein, mouse; D000071256:Uncoupling Protein 1; D006639:Histidine; D006632:Histamine; D006640:Histidine Decarboxylase