Hypothalamic neuronal histamine as a target of leptin in feeding behavior.

Abstract

Leptin, an ob gene product, has been shown to suppress food intake by regulating hypothalamic neuromodulators. The present study was designed to examine the involvement of brain histamine in leptin-induced feeding suppression. A bolus infusion of 1.0 microg 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 expression of histidine decarboxylase (HDC), a histamine-synthesizing enzyme, was observed in the hypothalamus after i3vt infusion of leptin. These results indicate that leptin increases histamine turnover by affecting the posttranscriptional process of HDC formation or histamine release per se. As expected, concomitant suppression in 24-h cumulative food intake was also observed after infusion of leptin. Systemic depletion of brain histamine levels by pretreatment with an intraperitoneal injection of 224 micromol/kg alpha-fluoromethylhistidine (FMH), a suicide inhibitor of HDC, attenuated the leptin-induced feeding suppression by 50.7% (P < 0.05). This attenuation of feeding suppression was mimicked by the i3vt infusion of 2.24 micromol/kg FMH before leptin treatment (P < 0.05). In addition, concentrations of hypothalamic 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 each 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 role for the hypothalamic histamine neurons in the central regulation of feeding behavior controlled by leptin.

Histamine in the brain: Beyond sleep and memory

“…1). A large body of literature links the histaminergic system with consumption of food, as a satiety signal: (a) intracerebroventricular injections of histamine suppress appetite, whereas depletion of histamine stimulates feeding [49]; (b) hypothalamic neuronal histamine has been implicated in the regulation of feeding behavior and body adiposity through activation of postsynaptic histamine H 1 -receptor (H 1 -R) in the ventromedial hypothalamic (VMH) and paraventricular (PVN) nucleus [50,51], two brain areas that secrete neuroactive peptides crucially involved in the regulation of feeding behavior [52]; (c) histaminergic neurons are the targets of leptin in the brain, and central administration of leptin increases histamine turnover in the hypothalamus [53,54]; (d) blockade of the histaminergic H 3 autoreceptor increases extracellular histamine levels in the hypothalamus and reduces food intake [55]. Indeed, antagonists of the H 3 receptors are being developed as anti obesity drugs [55,56].…”

Targeted Disruption of Histamine H1-Receptor Attenuates Regulatory Effects of Leptin on Feeding, Adiposity, and UCP Family in Mice

“…In addition, concentration or turnover rate of hypothalamic histamine was lowered in leptin-deficient ob/ob and leptin receptor-mutated db/db mice, but it was increased in diet-induced obese animals (11). Leptin regulates metabolic efficiency and exerts anorectic action (12)(13)(14) through its hypothalamic long-form receptors, in the VMH, the dorsomedial hypothalamus, the arcuate nucleus, and the ventral premammillary nucleus (15)(16)(17).…”

“…Leptin, an ob gene product (10), has been recently demonstrated to promote histamine turnover by affecting the posttranscriptional process of histidine decarboxylase formation or histamine release per se (11). In addition, concentration or turnover rate of hypothalamic histamine was lowered in leptin-deficient ob/ob and leptin receptor-mutated db/db mice, but it was increased in diet-induced obese animals (11).…”

Proline Decreases the Suppressive Effect of Histidine on Food Intake and Fat Accumulation

“…Hypothalamic neuronal histamine has anti-obesity effects such as suppressed food intake (2-6), increased lipolysis in white adipose tissue (WAT), and increased energy consumption through increased expression of uncoupling protein 1 (UCP1) in brown adipose tissue (BAT) (7)(8)(9). Histamine cannot cross the blood-brain barrier (BBB), which is in contrast to histidine, a precursor in the synthesis of histamine (10).…”