Targeted disruption of histamine H1-receptor attenuates regulatory effects of leptin on feeding, adiposity, and UCP family in mice
Targeted disruption of histamine H1-receptor attenuates regulatory effects of leptin on feeding, adiposity, and UCP family in mice
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DOI：
10.2337/diabetes.50.2.385
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发表时间：
2001-02-01
期刊：
影响因子：
7.7
通讯作者：
Sakata, T
中科院分区：
文献类型：
--
作者：
Masaki, T;Yoshimatsu, H;Sakata, T
组胺神经元广泛分布于大脑，通过下丘脑的组胺H-1受体(H-1-R)抑制食物摄取。为了探讨神经元组胺在瘦素信号通路中的作用，我们研究了H-1-R基因敲除小鼠(H-1-R基因敲除小鼠)对瘦素调节的摄食量和解偶联蛋白(UCPs)基因表达的影响，以及下丘脑神经肽表达和饮食诱导脂肪组织脂肪沉积的基础变化。H1KO小鼠在每日摄食量、生长曲线、体重或肥胖方面没有变化。H1KO小鼠在这些参数中没有特异性，没有诱导下丘脑神经肽、基因或外周UCPs的mRNA表达的基础变化。与对照组相比，摄入高脂饮食的H1KO小鼠脂肪沉积和ob基因表达加速。在H1KO小鼠中，瘦素诱导的摄食抑制被部分减弱，这表明组胺神经元作为瘦素的下游信号参与了摄食调节。中枢注射瘦素可抑制H1KO小鼠脂肪UCP基因表达上调和体脂减少。这些结果表明，H1KO小鼠是一种新的瘦素抵抗模型，H-1-R是大脑中瘦素下游信号的关键受体，有助于调节摄食、脂肪沉积和UCP mRNA的表达。
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, of, 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.