Hypothalamic neuronal histamine as a target of leptin in feeding behavior

Leptin, an ob gene product, has been shown to suppress food intake by regul ating hypothalamic neuromodulators. The present study was designed to exami ne the involvement of brain histamine in leptin-induced feeding suppression . A bolus infusion of 1.0 mu g leptin into the rat third cerebroventricle ( i3vt) elevated the turnover rate of hypothalamic neuronal histamine (P < 0. 05) as assessed by pargyline-induced accumulation of tele-methylhistamine ( t-MH), a major metabolite of histamine. No remarkable change in the mRNA ex pression of histidine decarboxylase (HDC), a histamine-synthesizing enzyme, was observed in the hypothalamus after i3vt infusion of leptin. These resu lts indicate that leptin increases histamine turnover by affecting the post transcriptional process of HDC formation or histamine release per se. As ex pected, concomitant suppression in 24-h cumulative food intake was also obs erved after infusion of leptin. Systemic depletion of brain histamine level s by pretreatment with an intraperitoneal injection of 224 mu mol/kg alpha- fluoromethylhistidine (FMH), a suicide inhibitor of HDC, attenuated the lep tin-induced feeding suppression by 50.7% (P < 0.05). This attenuation of fe eding suppression was mimicked by the i3vt infusion of 2.24 pmol/kg FMH bef ore leptin treatment (P < 0.05). In addition, concentrations of hypothalami c histamine and t-MH were lowered in diabetic (db/db) mice, which are known to be deficient in leptin receptors (P < 0.05 vs, lean littermates for eac h amine), although the amine levels were higher in diet-induced obese rats (P < 0.05 for each amine). Leptin-deficient obese mice (ob/ob) showed lower histamine turnover (P < 0.05 vs. lean littermates), which recovered after leptin infusion. Thus, a growing body of results points to an important rol e for the hypothalamic histamine neurons in the central regulation of feedi ng behavior controlled by leptin.