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

Abstract

Histamine neurons are widely distributed in the brain and suppress food intake through the histamine H 1 receptor (H 1 -R) in the hypothalamus. To examine the role of neuronal histamine in leptin signaling pathways, we investigated the effects of H 1 -R knockout (H1KO) mice on both food intake and mRNA expressions of uncoupling proteins (UCPs) as regulated by leptin, and concomitantly on basal changes in both expression of hypothalamic neuropeptides and diet-induced fat deposition in adipose tissues. H1KO mice showed no change in daily food intake, growth curve, body weight, or adiposity. Reflecting no specificity in these parameters, H1KO mice induced no basal changes in mRNA expression of hypothalamic neuropeptides, ob gene, or peripheral UCPs. Loading H1KO mice with a high-fat diet accelerated fat deposition and ob gene expression compared with the controls. Leptin-induced feeding suppression was partially attenuated in H1KO mice, indicating involvement of histamine neurons in feeding regulation as a downstream signal of leptin. Upregulation of fat UCP mRNA and reduction of body fat induced by central infusion of leptin were attenuated in the H1KO mice. These results show that H1KO mice are a novel leptin-resistant model and that H 1 -R is a key receptor for downstream signaling of leptin in the brain that contributes to regulation of feeding, fat deposition, and UCP mRNA expression. Diabetes 50:385-391, 2001 H istamine neurons originating from the tuberomammillary nucleus of the posterior hypothalamus project diffusely in the brain to regulate energy homeostasis (1,2). Neuronal histamine has been shown to suppress food intake through histamine H 1 -receptors (H 1 -Rs) in the ventromedial hypothalamus (VMH) and the paraventricular nucleus (PVN) (3,4). It also alters thermoregulation (5). Energy deficiency in the brain, i.e., neural glucoprivation, activates histamine neurons in the hypothalamus (6) and augments glycogenolysis in the brain (7). Histamine neurons stimulate the sympathetic nervous system to increase lipolysis in the adipose tissue (8,9).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). Leptin regulates metabolic efficiency and exerts anorectic action (12-14) through its hypothalamic long-form receptors, in the VMH, the dorsomedial hypothalamus, the arcuate nucleus, and the ventral premammillary nucleus (15-17). The VMH, the PVN, and the arcuate nucleus are known as controlling centers of appetite and receive projections from histamine neurons (3,4,18,19).From the viewpoint of energy metabolism, the uncoupling protein (UCP) family plays an essential role in energy homeostasis (20)(21)(22). Gene expression of these proteins is regulated by...

Therapeutic potential of histamine H3 receptor agonist for the treatment of obesity and diabetes mellitus

“…Elevation of histamine levels in the brain, by either direct administration of histamine or systemic administration of its precursor, histidine, results in appetite suppression, and a number of pharmacological studies have suggested the involvement of H1 receptors (5,8,13,(15)(16)(17)(18). This finding was confirmed by this study, which shows that inhibition of histamine release by ␣-FMH increased appetite slightly at 4 h and significantly at 12 h. In contrast, comparable inhibition of histamine release by imetit resulted in appetite suppression, suggesting that imetit decreases appetite independently of histaminergic tone modulation.…”

“…Intracerebroventricular administration of histamine consistently decreases appetite in several species (4). Mice with genes disrupted for histamine H1 receptor or histidine decarboxylase (HDC), a ratelimiting enzyme for histamine synthesis, are prone to becoming obese on a high-fat diet or at advanced age (5)(6)(7)(8). Furthermore, several antipsychotic drugs with high affinities for H1 receptors are known to cause weight gain in rodents and humans (9).…”

Atypical antipsychotic-induced metabolic side effects: insights from receptor-binding profiles

“…This finding has subsequently been confirmed by others, [53][54][55] and is consistent with data demonstrating that histamine H 1 receptor antagonism promotes feeding in rodents and that H 1 knockout mice are prone to weight gain. [55][56][57] Recently, Kim et al 55 showed that atypical orexigenic antipsychotics selectively and potently stimulate hypothalamic adenosine monophosphate-activated protein kinase (AMP kinase), an enzyme involved in regulating food intake, 58 while reversing the actions of leptin, an anorexigenic hormone. This effect is mediated through the histamine H 1 receptor: clozapine augmentation of AMP kinase was abolished in H 1 knockout mice and the orexigenic potencies of various atypical antipsychotics were found to correlate with their affinity for the H 1 receptor, with olanzapine and clozapine having the highest affinities in animal models.…”

Ameliorating antipsychotic-induced weight gain by betahistine: Mechanisms and clinical implications

“…It has been reported that H 1 R antagonists play a crucial role in increasing appetite and obesity development [12,53], which were also observed in H 1 R knockout (KO) mice [51,54].…”