Food intake and energy metabolism regulated by apo AIV and CCK

apo AIV 和 CCK 调节食物摄入和能量代谢

• 批准号: 7840400
• 负责人: Chunmin C. Lo
• 金额: $ 11.53万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-15 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7840400
• 关键词: Address; Animals; Attenuated; Brain; Cholecystokinin; Cholecystokinin Receptor; Data; Diet; Dietary Fats; Dose; Eating; Energy Metabolism; Fatty acid glycerol esters; Gene Expression; Hypothalamic structure; Knockout Mice; Maintenance; Mediating; Mus; Obesity; Pathway interactions; Peptides; Peripheral; Reporting; Satiation; Small Intestines; System; Testing; Vagus nerve structure; afferent nerve; apolipoprotein A-IV; base; food consumption; hindbrain; intraperitoneal; public health relevance; receptor; research study; response

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:

描述（由申请人提供）： 载脂蛋白AIV (apo AIV) 和胆囊收缩素(CCK) 是小肠响应膳食脂质而分泌的肠肽，并且各自减少食物摄入量。 CCK 作用于十二指肠感觉神经上的局部受体，并通过迷走神经向后脑发送信息，而 apo AIV 通过未知的大脑途径减少膳食量。最近，我们发现腹腔内 (ip) 联合使用 apo AIV 和 CCK 可进一步减少膳食量，并且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[原文如此]（SDA）减弱了外周CCK引起的食物摄入抑制。相比之下，ip apo AIV在SDA之后仍然减少食物摄入，并且效果增强。我们的初步数据表明，apo AIV 敲除小鼠比 WT 对照对 ip CCK 更敏感，并且 NTS 中 CCK1R 的基因表达增加；此外，CCK 缺陷小鼠不会因腹腔注射 apo AIV 而减少食物摄入量。这些发现表明：1) 外周 CCK 和 apo AIV 的相互作用通常会减少膳食量； 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 通过迷走神经和非迷走神经途径控制食物摄入。维持高脂肪饮食 (HFD) 会降低对 CCK 的饱足感反应能力。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，我们将测试以下假设：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，我们将检验 ip 或 ivt CCK 和 apo AIV 相互作用以减少下丘脑食物摄入量的假设。在这两个目标中，我们假设特定的 CCK 受体介导相互作用，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，我们将测试以下假设：静脉注射 (ivt) 但腹腔注射 (ip) 施用 CCK 或 apo AIV 将恢复 HFD 诱导的肥胖动物的敏感性并导致食物摄入受到抑制。 公共卫生相关性：