Selective leptin resistance within the brainstem of histamine deficient mice
Anna Földes, Veronika Márkus & Krisztina Kovács
Histamine is an important anorexic factor that suppresses food intake via hypothalamic H1 receptors and increases energy expenditure by stimulating lipolysis. Mice with targeted deletion of the key enzyme of histamine biosynthesis, histidine decarboxylase (HDC-KO), are unable to synthesize histamine. These animals display a metabolic phenotype with adult onset obesity, selective increase in visceral fat depots, impaired glucose tolerance and hyperleptinemia. To test the possibility that changes in the leptin-induced signal transduction pathways are responsible for leptin resistance in histamine deficient mice, we have analyzed phosphorylation of signal transducer and activator of transcription (STAT-3) a key component of leptin action in target cells. Adult male, wild type and HDC-KO animals were injected ip with leptin and phosphoSTAT-3 (Tyr 705) immunoreactivity was revealed 30 min after injection by conventional avidin-biotin-peroxydase histochemical reaction and the number of phosphoSTAT-3 cell nuclei was counted. Wild type mice display leptin-induced phosphoSTAT-3-ir in the arcuate-, dorsomedial- and ventromedial nuclei in the hypothalamus, in the midbrain as well as in the dorsal vagal complex (DVC) of the brainstem. In histamine deficient mice, the distribution of leptin-responsive neurons and the number of pSTAT-3 ir profiles within the hypothalamus was similar to those seen in wild type animals. In contrast, cells in the dorsal vagal complex of HDC-KO mice display significantly less phospho-STAT-3 -immunoreactivity than the wild type controls in response to exogenous leptin. These data suggest that leptin action in the brainstem, but not in hypothalamus, is specifically impaired in histamine-deficient mice. Defects in leptin signaling in neurons within the DVC may contribute in the pathogenesis of leptin-resistant obesity as well as in the inability of HDC-KO animals to mobilize their energy stores.