Food intake and energy metabolism regulated by apo AIV and CCK

描述（由申请人提供）： 载脂蛋白AIV（apo AIV）和胆囊收缩素（CCK）是响应于膳食脂质而从小肠分泌的肠道肽，并且各自减少食物摄入。CCK作用于十二指肠感觉神经上的局部受体，并通过迷走神经将信息发送到后脑，而apo AIV通过未知的大脑途径减少膳食量。最近，我们发现腹膜内（ip）给药的组合载脂蛋白AIV和胆囊收缩素相加减少膳食的大小和这种相互作用激活胆囊收缩素1受体（CCK 1 R）。我们还发现，蛛网膜下迷走神经传入（SDA）减弱外周CCK引起的摄食抑制。相比之下，ip apo AIV在SDA后仍然减少摄食量，并且效果增强。我们的初步数据表明，载脂蛋白AIV基因敲除小鼠是更敏感的ip CCK比野生型对照，并增加了基因表达的CCK 1 R，在NTS，此外，CCK缺陷小鼠不减少他们的食物摄入量，以响应ip载脂蛋白AIV。这些研究结果表明：1）外周CCK和apo AIV的相互作用通常减少膳食量; 2）外周apo AIV需要NTS中的CCK 1 R活性; 3）ip注射的apo AIV需要CCK抑制食物摄取;和4）外周apo AIV通过迷走和非迷走途径控制食物摄取。通过维持高脂饮食（HFD）降低了对CCK的饱足反应的效力。然而，HFD对apo AIV敏感性的影响尚不清楚。在具体目标1中，我们将检验ip或脑室内（ivt）apo AIV和ip/ivt CCK的相互作用通过传入迷走神经（可能在后脑内）减少进餐量的假设。在具体目标2中，我们将检验ip或ivt CCK和apo AIV相互作用以减少下丘脑食物摄入的假设。在这两个目标中，我们假设特定的CCK受体介导的相互作用，我们进一步假设，大脑黑皮质素系统参与。在具体目标3中，我们将检验以下假设：静脉注射而非腹腔注射CCK或apo AIV将恢复HFD诱导的肥胖动物的敏感性，并导致摄食抑制。 公共卫生相关性：

DESCRIPTION (provided by applicant): Apolipoprotein AIV (apo AIV) and cholecystokinin (CCK) are gut peptides secreted from the small intestine in response to dietary lipids, and each reduces food intake. CCK acts on local receptors on duodenal sensory nerves and sends a message to the hindbrain via the vagus nerve, whereas apo AIV reduces meal size via unknown pathways to the brain. Recently, we found that intraperitoneal (ip) administration of combined apo AIV and CCK additively reduces meal size and this interaction activates the CCK1 receptor (CCK1R). We also found that subdiaphragmatic vagal dafferentiation [sic] (SDA) attenuates the inhibition of food intake induced by perpheral [sic] CCK. In contrast, ip apo AIV still decreases food intake following SDA, and the effect is enhanced. Our preliminary data indicate that apo AIV knockout mice are more sensitive to ip CCK than WT controls and have increased gene expression of the CCK1R, in the NTS; also, CCK-deficient mice do not reduce their food intake in response to ip apo AIV. These findings suggest that: 1) interaction of peripheral CCK and apo AIV normally reduces meal size; 2) peripheral apo AIV requires activity at CCK1R in NTS; 3) ip-injected apo AIV requires CCK in inhibiting food intake; and 4) peripheral apo AIV controls food intake via vagal and non-vagal pathways. The potency of satiation in response to CCK is reduced by maintenance on a high-fat diet (HFD). However, the effect of a HFD on sensitivity to apo AIV is not known. In Specific Aim 1, we will test the hypothesis that the interaction of ip or intracerebroventricular (ivt) apo AIV and ip/ivt CCK reduce meal size via the afferent vagus, possibly within the hindbrain. In Specific Aim 2, we will test the hypothesis that ip or ivt CCK and apo AIV interact to reduce food intake in the hypothalamus. In both Aims, we hypothesize that specific CCK receptors mediate the interaction, and we further hypothesize that the brain melanocortin system is involved. In Specific Aim 3, we will test the hypothesis that administering CCK or apo AIV, ivt but not ip, will restore sensitivity in HFD-induced obese animals and result in an inhibition of food intake. PUBLIC HEALTH RELEVANCE: