Apolipoprotein AIV regulates CCK secretion and potentiates CCK-induced satiation

描述(申请人提供)：肥胖是一种全国性和全球性的流行病，限制能量摄入将是一种有效的治疗方法。载脂蛋白AIV(Apo AIV)和胆囊收缩素(CCK)都是小肠对膳食脂肪的反应而分泌的饱腹感信号，apo AIV和CCK在抑制摄食方面具有协同作用。然而，载脂蛋白AIV和CCK在哪里以及如何相互作用来抑制食物摄取仍然不清楚。CCK作用于迷走神经传入神经上的局部感受器，并向后脑发送令人满足的信息。最近，我们发现，外周载脂蛋白AIV需要一个完整的CCK系统来将饱腹感信号传递到后脑。此外，隔膜下选择性迷走神经去传入(SDA)可减轻腹膜内apo AIV对大鼠摄食的抑制和后脑神经元的激活。我们还发现，载脂蛋白AIV在体外和体内都能增加CCK的分泌。这些结果表明，CCK和apo AIV在控制摄食中的相互作用可能是通过相互依赖的分泌和/或迷走神经传入神经的联合激活来调节的。我们的中心假设是apo AIV增加了CCK的分泌以响应脂质，并且apo AIV也增强了CCK的作用。第一个具体目标将检验载脂蛋白AIV剂量依赖地增加CCK分泌量对饮食脂质的反应的假设。这将包括确定载脂蛋白AIV参与刺激G蛋白信号级联反应和对CCK分泌重要的环磷酸腺苷-蛋白激酶A(cAMP-PKA)通路。在特定的目标2中，我们将检验外周apo AIV通过直接作用于神经元或通过增强CCK对神经元的作用来增加迷走神经传入神经活动的假设。成功完成这项赠款申请将确定CCK和apo AIV在外周相互作用以增加迷走神经传入神经元激活并有助于限制膳食大小的生理和细胞机制。这将为产生影响食物摄入量和体重的药理方法提供一个新的概念。

DESCRIPTION (provided by applicant): Obesity is a national and global epidemic and limiting energy intake would be an effective treatment. Apolipoprotein AIV (apo AIV) and cholecystokinin (CCK) are each satiating signals secreted from the small intestine in response to dietary lipids, and the combination of apo AIV plus CCK has a synergistic effect on the suppression of food intake. However, where and how apo AIV and CCK interact to inhibit food intake remain unclear. CCK acts on local receptors on vagal afferent nerves and sends a satiating message to the hindbrain. Recently, we found that peripheral apo AIV requires an intact CCK system to relay satiating signals to the hindbrain. In addition, subdiaphragmatic selective vagal deafferentation (SDA) attenuates the inhibition of food intake as well as neuronal activation in the hindbrain induced by intraperitoneal (ip) apo AIV. We also found that apo AIV increases CCK secretion in vitro and in vivo. These findings suggest that the interaction of CCK and apo AIV in the control of food intake might be mediated via a co-dependent secretion and/or a combined activation of vagal afferent nerves. Our central hypothesis is that apo AIV increases CCK secretion in response to lipids, and that apo AIV also enhances CCK's action. The first specific aim will test the hypothesis that apo AIV dose-dependently increases the amount of CCK secreted in response to dietary lipids. This will include determining the involvement of apo AIV in stimulating G-protein signaling cascades and cyclic AMP-protein kinase A (cAMP-PKA) pathways important for CCK secretion. In Specific Aim 2, we will test the hypothesis that peripheral apo AIV increases vagal afferent nerve activity, either by acting directly on the neurons or else by potentiating CCK's action on them. Successful completion of this grant application will identify the physiological and cellular mechanisms by which CCK and apo AIV interact in the periphery to increase activation of vagal afferent neurons and contribute to limiting meal size. This will provide a novel concept for generating pharmacological approaches to influence food intake and body weight.