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)是小肠对膳食脂肪的反应而分泌的肠肽，它们都减少了食物的摄入量。CCK作用于十二指肠感觉神经上的局部受体，通过迷走神经向后脑发送信息，而载脂蛋白AIV通过未知的途径到达大脑，从而减少进食。最近，我们发现，联合应用载脂蛋白AIV和CCK(腹膜腔内注射)可额外减少进食量，这种相互作用可激活CCK1受体(CCK1R)。我们还发现，隔膜下迷走神经分化[SIC](SDA)可减弱外周[SIC]CCK对食物摄取的抑制。相比之下，ip apo AIV仍可减少SDA后的摄食量，且效果增强。我们的初步数据表明，与WT对照相比，apo AIV基因敲除小鼠对IP CCK更敏感，并增加了NTS中CCK1R的基因表达；此外，CCK缺陷小鼠并不减少对IP apo AIV的摄食量。这些发现表明：1)外周APO AIV与CCK的相互作用通常会减少进食；2)外周APO AIV需要NTS中CCK1R的活性；3)IP注射apo AIV需要CCK抑制食物摄取；4)外周APO AIV通过迷走神经和非迷走神经途径控制食物摄取。维持高脂饮食(HFD)会降低饱腹感对CCK的反应能力。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，我们将检验这样一种假设，即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(可能是在后脑内)减少了食物的大小。在特定的目标2中，我们将测试IP或IVT CCK和apo AIV相互作用以减少下丘脑摄食量的假设。在这两个目标中，我们假设特定的CCK受体介导了相互作用，并进一步假设大脑黑素皮质素系统参与其中。在具体目标3中，我们将检验这样一种假设，即使用CCK或apo AIV、IVT而不是IP，可以恢复HFD诱导的肥胖动物的敏感性，并导致食物摄取受到抑制。 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: