Ishizuka Tomoko, Hatano Kouta, Murotani Tomotaka, Yamatodani Atsushi
Molecular Research Center for Child Mental Development, Faculty of Medicine, Osaka University, Suita, Osaka, Japan.
Behav Brain Res. 2008 Apr 9;188(2):250-4. doi: 10.1016/j.bbr.2007.11.001. Epub 2007 Nov 13.
Leptin is a key signal linking peripheral adiposity levels to the regulation of energy homeostasis in the brain. The injection of leptin decreases body weight and food intake in lean rodents; however, in a rodent model of high fat diet-induced obesity (DIO), the exogenous leptin cannot improve adiposity. This ineffectiveness is known as leptin resistance, and the factors downstream of leptin signaling have received attention as viable targets in the treatment of obesity. We previously reported that the histaminergic system is one of the targets of leptin. In the present study, the effect of an H(3)-receptor inverse agonist on hypothalamic histamine release and energy intake was investigated in normal and DIO mice. Leptin (1.3 mg/kg, i.p.) significantly increased hypothalamic histamine release and reduced 12 h-energy intake in normal mice, but had no such effects in DIO mice. In contrast, clobenpropit (5 mg/kg, i.p.), an H(3)-inverse agonist, elicited a significant increase in histamine release in both types of mice. Clobenpropit did not reduce 12 h-energy intake; however, it decreased 3 h-energy intake in both types of mice. These results suggest that lack of the activation of the histaminergic system partly contributes to obesity in DIO mice and direct activation of the histaminergic system circumvents leptin resistance.
瘦素是一种关键信号，可将外周脂肪水平与大脑中的能量稳态调节联系起来。在瘦型啮齿动物中注射瘦素可降低体重和食物摄入量；然而，在高脂饮食诱导的肥胖（DIO）啮齿动物模型中，外源性瘦素并不能改善肥胖状况。这种无效性被称为瘦素抵抗，瘦素信号下游的因素作为肥胖治疗的可行靶点受到了关注。我们之前报道过组胺能系统是瘦素的靶点之一。在本研究中，研究了H(3)受体反向激动剂对正常和DIO小鼠下丘脑组胺释放及能量摄入的影响。瘦素（1.3毫克/千克，腹腔注射）可显著增加正常小鼠下丘脑组胺释放并减少12小时能量摄入，但对DIO小鼠无此作用。相比之下，H(3)反向激动剂氯苯丙醇胺（5毫克/千克，腹腔注射）可使两种类型小鼠的组胺释放显著增加。氯苯丙醇胺并未降低12小时能量摄入；然而，它降低了两种类型小鼠的3小时能量摄入。这些结果表明，组胺能系统激活的缺乏部分导致了DIO小鼠的肥胖，组胺能系统的直接激活可规避瘦素抵抗。
