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)是由小肠分泌的肠肽。 对饮食脂质的反应，每种都减少了食物的摄入量。CCK作用于十二指肠感觉的局部受体 神经并通过迷走神经向后脑发送信息，而apo AIV通过 通向大脑的未知路径。最近，我们发现联合应用apo的腹膜腔内给药。 AIV和CCK可以减少进食，这种相互作用激活了CCK1受体(CCK1R)。我们 研究还发现，隔膜下迷走神经切断(SDA)可减轻对食物摄取的抑制 通过外周CCK。相比之下，在SDA之后，IP apo AIV仍然减少食物摄入量，其效果是 增强版。我们的初步数据表明，apo AIV基因敲除小鼠对IP CCK比WT更敏感 并增加了CCK1R基因在NTS中的表达；CCK缺陷小鼠也没有 减少他们的食物摄入量，以应对IP apo AIV。这些发现表明：1)外周因素的交互作用 CCK和apo AIV通常可以减少进食；2)外周apo AIV需要NTS中CCK1R的活性；3) IP注射载脂蛋白AIV需要CCK来抑制食物摄取；4)外周APO AIV通过 迷走神经通路和非迷走神经通路。对CCK的反应中，饱足的效力通过维持在 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IP或脑室内(IVT)载脂蛋白AIV和IP/IVT CCK的相互作用 通过传入迷走神经减少进食，可能是在后脑。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，减少下丘脑的食物摄取。在这两个目标中， 我们假设特定的CCK受体介导了这种相互作用，并进一步假设 大脑黑素皮质素系统参与其中。在特定的目标3中，我们将检验给药CCK的假设 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(请参阅说明)：

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):