Apolipoprotein AIV regulates CCK secretion and potentiates CCK-induced satiation

载脂蛋白 AIV 调节 CCK 分泌并增强 CCK 诱导的饱腹感

• 批准号: 8583768
• 负责人: Chunmin C. Lo
• 金额: $ 7.93万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8583768
• 关键词: Afferent Neurons; Applications Grants; Atherosclerosis; Attenuated; Blood - brain barrier anatomy; Body Weight; Calcium; Cholecystokinin; Consumption; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Deafferentation procedure; Dependence; Developed Countries; Developing Countries; Diet; Dietary Fats; Dose; Eating; Energy Intake; Epidemic; Fasting; Fat-Restricted Diet; Fatty acid glycerol esters; Food; G-Protein-Coupled Receptors; GTP-Binding Proteins; Gene Expression; Goals; Homeostasis; In Vitro; Incidence; Institutes; Lead; Lipids; Mediating; Metabolic Diseases; Mus; Nerve; Neurons; Nodose Ganglion; Non-Insulin-Dependent Diabetes Mellitus; Obesity; Pathway interactions; Peripheral; Physiological; Plasma; Public Health; Receptor Gene; Relative (related person); Research; Satiation; Signal Transduction; Small Intestines; System; Testing; Transgenic Mice; Universities; Wild Type Mouse; afferent nerve; apolipoprotein A-IV; effective therapy; gastrointestinal system; hindbrain; in vivo; intraperitoneal; neuronal cell body; novel; public health relevance; receptor; research study; response

DESCRIPTION (provided by applicant): Obesity is a national and global epidemic and limiting energy intake would be an effective treatment. Apolipoprotein AIV (apo AIV) and cholecystokinin (CCK) are each satiating signals secreted from the small intestine in response to dietary lipids, and the combination of apo AIV plus CCK has a synergistic effect on the suppression of food intake. However, where and how apo AIV and CCK interact to inhibit food intake remain unclear. CCK acts on local receptors on vagal afferent nerves and sends a satiating message to the hindbrain. Recently, we found that peripheral apo AIV requires an intact CCK system to relay satiating signals to the hindbrain. In addition, subdiaphragmatic selective vagal deafferentation (SDA) attenuates the inhibition of food intake as well as neuronal activation in the hindbrain induced by intraperitoneal (ip) apo AIV. We also found that apo AIV increases CCK secretion in vitro and in vivo. These findings suggest that the interaction of CCK and apo AIV in the control of food intake might be mediated via a co-dependent secretion and/or a combined activation of vagal afferent nerves. Our central hypothesis is that apo AIV increases CCK secretion in response to lipids, and that apo AIV also enhances CCK's action. The first specific aim will test the hypothesis that apo AIV dose-dependently increases the amount of CCK secreted in response to dietary lipids. This will include determining the involvement of apo AIV in stimulating G-protein signaling cascades and cyclic AMP-protein kinase A (cAMP-PKA) pathways important for CCK secretion. In Specific Aim 2, we will test the hypothesis that peripheral apo AIV increases vagal afferent nerve activity, either by acting directly on the neurons or else by potentiating CCK's action on them. Successful completion of this grant application will identify the physiological and cellular mechanisms by which CCK and apo AIV interact in the periphery to increase activation of vagal afferent neurons and contribute to limiting meal size. This will provide a novel concept for generating pharmacological approaches to influence food intake and body weight.

描述（由申请人提供）：肥胖是一种全国性和全球性的流行病，限制能量摄入将是一种有效的治疗方法。载脂蛋白AIV（apo AIV）和胆囊收缩素（CCK）各自是响应于膳食脂质而从小肠分泌的饱腹信号，并且apo AIV与CCK的组合对抑制食物摄入具有协同作用。然而，载脂蛋白AIV和CCK在何处以及如何相互作用以抑制食物摄入仍不清楚。CCK作用于迷走传入神经上的局部受体，并向后脑发送饱足信息。最近，我们发现，外周载脂蛋白AIV需要一个完整的CCK系统中继饱足的信号到后脑。此外，蛛网膜下选择性迷走神经传入阻滞（SDA）减弱了由腹膜内（ip）apo AIV诱导的对摄食的抑制以及后脑中的神经元激活。我们还发现apo AIV在体外和体内增加CCK分泌。这些结果表明，CCK和载脂蛋白AIV在控制食物摄入的相互作用可能是通过共同依赖的分泌和/或迷走传入神经的联合激活介导的。我们的中心假设是，载脂蛋白AIV增加CCK分泌的脂质反应，载脂蛋白AIV也增强CCK的行动。第一个具体目标将检验载脂蛋白AIV剂量依赖性地增加响应于饮食脂质而分泌的CCK的量的假设。这将包括确定载脂蛋白AIV参与刺激G蛋白信号级联和环腺苷酸-蛋白激酶A（cAMP-PKA）途径对CCK分泌的重要性。在具体目标2中，我们将检验外周apo AIV通过直接作用于神经元或通过增强CCK对它们的作用来增加迷走传入神经活动的假设。成功完成这项资助申请将确定CCK和载脂蛋白AIV在外周相互作用以增加迷走传入神经元激活并有助于限制膳食量的生理和细胞机制。这将为产生影响食物摄入和体重的药理学方法提供新的概念。