Sutton Gregory M, Patterson Laurel M, Berthoud Hans-Rudolf
Neurobiology of Nutrition Laboratory, Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, Louisiana 70808, USA.
J Neurosci. 2004 Nov 10;24(45):10240-7. doi: 10.1523/JNEUROSCI.2764-04.2004.
Increased food intake is a major factor in the development of obesity, and the control of meal size is a valid approach to reduce food intake in humans. Meal termination, or satiety, is thought to be organized within the caudal brainstem where direct signals from the food handling alimentary canal and long-term signals from the forebrain converge in the solitary nucleus. Cholecystokinin (CCK) released from the gut after ingestion of food has been strongly implicated in nucleus tractus solitarius (NTS)-mediated satiation, but the exact cellular and intracellular signaling events are not understood. Using Western blotting and immunohistochemistry with phosphospecific antibodies, we demonstrate here that peripheral administration of CCK in rats leads to rapid activation of the extracellular signal-regulated kinase (ERK) signaling cascade in NTS neurons and that blockade of ERK signaling with microinfusion of a selective mitogen-activated ERK kinase inhibitor into the fourth ventricle attenuates the capacity of CCK to suppress food intake. In addition, we show that CCK-induced activation of ERK results in phosphorylation of the voltage-dependent potassium channel Kv4.2 and the nuclear transcription factor CREB (cAMP response element-binding protein). The results demonstrate that ERK signaling is necessary for exogenous CCK to suppress food intake in deprived rats and suggest that this pathway may also be involved in natural satiation and the period of satiety between meals through coupling of ERK activation to both cytosolic and nuclear effector mechanisms that have the potential to confer acute and long-term changes in neuronal functioning.
食物摄入量增加是肥胖发生的一个主要因素，控制进餐量是减少人类食物摄入量的一种有效方法。进餐终止，即饱腹感，被认为是在延髓尾部组织的，来自食物处理消化道的直接信号和来自前脑的长期信号在孤束核汇聚。进食后从肠道释放的胆囊收缩素（CCK）与孤束核（NTS）介导的饱腹感密切相关，但确切的细胞和细胞内信号转导事件尚不清楚。我们使用蛋白质免疫印迹法和磷酸化特异性抗体免疫组织化学方法，在此证明在大鼠外周给予CCK会导致NTS神经元中细胞外信号调节激酶（ERK）信号级联的快速激活，并且通过向第四脑室微量注射选择性丝裂原活化ERK激酶抑制剂来阻断ERK信号，会减弱CCK抑制食物摄入的能力。此外，我们表明CCK诱导的ERK激活会导致电压依赖性钾通道Kv4.2和核转录因子CREB（cAMP反应元件结合蛋白）的磷酸化。结果表明，ERK信号对于外源性CCK抑制饥饿大鼠的食物摄入是必需的，并表明该途径可能还通过将ERK激活与细胞溶质和核效应机制偶联，参与自然饱腹感和餐间饱腹感期，这些机制有可能使神经元功能发生急性和长期变化。
