Food intake and energy metabolism regulated by apo AIV and CCK

载脂蛋白 AIV (apo AIV) 和胆囊收缩素 (CCK) 是小肠分泌的肠肽。 对膳食脂质的反应，并且各自减少食物摄入量。 CCK 作用于十二指肠感觉局部受体 神经并通过迷走神经向后脑发送信息，而 apo AIV 通过减少膳食量 通往大脑的未知途径。最近，我们发现联合apo腹腔内（ip）给药 AIV 和 CCK 会进一步减少膳食量，这种相互作用会激活 CCK1 受体 (CCK1R)。我们 还发现膈下迷走神经传导（SDA）减弱了食物摄入引起的抑制 通过外设CCK。相比之下，ip apo AIV 在 SDA 之后仍然减少食物摄入，效果是 增强。我们的初步数据表明，apo AIV 敲除小鼠对 ip CCK 比 WT 更敏感 NTS 中 CCK1R 的控制并增加了 CCK1R 的基因表达；此外，CCK 缺陷小鼠不 减少食物摄入量以应对 ip apo AIV。这些发现表明：1）外周的相互作用 CCK 和 apo AIV 通常会减少膳食量； 2) 外周apo AIV需要NTS中CCK1R的活性； 3） 腹腔注射apo AIV需要CCK来抑制食物摄入； 4) 外周apo AIV通过以下方式控制食物摄入： 迷走神经和非迷走神经通路。维持 CCK 会降低饱腹感的效力 高脂肪饮食（HFD）。然而，HFD 对载脂蛋白 AIV 敏感性的影响尚不清楚。在具体目标 1 中， 我们将检验以下假设：ip 或脑室内 (ivt) apo AIV 与 ip/ivt CCK 的相互作用 通过传入迷走神经（可能在后脑内）减少膳食量。在具体目标 2 中，我们将测试 假设 ip 或 ivt CCK 和 apo AIV 相互作用以减少下丘脑的食物摄入。在这两个目标中， 我们假设特定的 CCK 受体介导这种相互作用，并且我们进一步假设 大脑黑皮质素系统参与其中。在具体目标 3 中，我们将检验以下假设：施用 CCK 或apo AIV，ivt但不是ip，将恢复HFD诱导的肥胖动物的敏感性并导致抑制 食物摄入量。 相关性（参见说明）：

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 (SDA) attenuates the inhibition of food intake induced by perpheral 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. RELEVANCE (See instructions):