Hypothalamic Neuronal Histamine in Genetically Obese Animals: Its Implication of Leptin Action in the Brain

Abstract

Leptin regulates feeding behavior and energy metabolism by affecting hypothalamic neuromodulators. The present study was designed to examine hypothalamic neuronal histamine, a recently identified mediator of leptin signaling in the brain, in genetic obese animals. Concentrations of hypothalamic histamine and tele-methylhistamine (t-MH), a major histamine metabolite, were significantly lower in obese (ob/ob) and diabetic (db/db) mice, and Zucker fatty (fa/fa) rats, leptin-deficient and leptin-receptor defective animals, respectively, relative to lean littermates (P < 0.05 for each). A bolus infusion of leptin (1.0 microg) into the lateral ventricle (ilvt) significantly elevated the turnover rate of hypothalamic neuronal histamine, as assessed by pargyline-induced accumulation of t-MH, in ob/ob mice compared with phosphate-buffered saline (PBS) infusions (P < 0.05). However, this same treatment did not affect hypothalamic histamine turnover in db/db mice. In agouti yellow (A(y)/a) mice, animals defective in pro-opiomelanocortin (POMC) signaling, normal levels of histamine, and t-MH were seen in the hypothalamus at 4 weeks of age when obesity had not yet developed. These amine levels in A(y)/a mice showed no change until 16 weeks of age, although the mice were remarkably obese by this time. Infusions of corticotropin releasing hormone (CRH), one of neuropeptide related to leptin signaling, into the third ventricle (i3vt) increased histamine turnover in the hypothalamus of Wistar King A rats (P < 0.05 versus PBS infusion). Infusion of neuropeptide Y (NPY) or alpha-melanocyte stimulating hormone (MSH), a POMC-derived peptide failed to increase histamine turnover. These results indicate that lowered activity of hypothalamic neuronal histamine in ob/ob and db/db mice, and fa/fa rats may be due to insufficiency of leptin action in the brains of these animals. These results also suggest that disruption of POMC signaling in A(y)/a mice may not impact on neuronal histamine. Moreover, CRH but neither POMC-derived peptide nor NPY may act as a signal to neuronal histamine downstream of the leptin signaling pathway.

Simultaneous fluorometric measurement of histamine and tele-methylhistamine levels in rodent brain by high-performance liquid chromatography

“…The method consists of HPLC postcolumn OPA derivatization coupled with a prior SPE procedure and shows reliable sensitivity, selectivity, and reproducibility. We observed altered histaminergic activities in H3 receptor knockout mice and obese Zucker rats, as reported previously [24,25], validating the current assay system. The simultaneous detection system described here is quite convenient and useful to address physiological and pharmacological roles of the central histaminergic systems.…”

Food Intake and Reward Mechanisms in Patients with Schizophrenia: Implications for Metabolic Disturbances and Treatment with Second-Generation Antipsychotic Agents

“…Orexin and melanin concentrating hormone (MCH) from neurons in the lateral hypothalamus (LH) stimulate the orexigenic networks; ventromedial nucleus exerts an opposite effect via histaminergic mechanisms (Mercer et al, 1994;Sakata et al, 1997). Histamine also has an important role in catabolic processes by mediating the effects of leptin (Masaki et al, 2004) that promotes histamine release (Itateyama et al, 2003). Other important anorexigenic factors include serotonin (via 5HT 1b , 5HT 2A , and 5HT 2C receptors) and corticotropin-releasing hormone (CRH; Kalra et al, 1999;Makarenko et al, 2002;Muller et al, 2004), whereas orexigenic processes are favored by endogenous opiate peptides (Morley, 1987;Horvath et al, 1992;Kalra et al, 1999) and glucocorticoids (Kalra et al, 1999).…”

Histamine in the brain: Beyond sleep and memory

“…In some aspect, the histaminergic and endocannabinoid systems seem to be regulated in an opposing fashion: for instance, systemic administration of leptin that signals to the hypothalamus the nutritional state and reduces food intake, facilitates histamine release from the hypothalamus [72], whereas it downregulates endocannabinoids levels in the same region [73]. Furthermore, concentrations of hypothalamic histamine and tele-methylhistamine, a major histamine metabolite, are significantly lower in obese (ob/ob) and diabetic (db/db) mice, and fatty ( fa/ fa) rats, leptin-deficient and leptin-receptor defective animals, respectively, relative to lean littermates [54]. On the other hand, defective leptin signalling is associated with elevated hypothalamic levels of enocannabinoids in obese db/ db and ob/ob mice and Zucker rats.…”

“…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].…”