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: 8687647
• 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/8687647
• 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）都是小肠响应膳食脂质而分泌的饱腹信号，载脂蛋白AIV和CCK联合使用具有协同抑制食物摄入的作用。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的局部受体，向后脑发送饱腹信息。最近，我们发现外周载脂蛋白AIV需要一个完整的CCK系统来将饱腹信号传递到后脑。此外，膈下选择性迷走神经分化（SDA）减弱了由腹腔内（ip）载脂蛋白AIV诱导的食物摄入抑制和后脑神经元激活。我们还发现载脂蛋白AIV在体内和体外都能增加CCK的分泌。这些发现表明，CCK和apo AIV在控制食物摄入中的相互作用可能是通过迷走传入神经的共同依赖分泌和/或联合激活来介导的。我们的中心假设是载脂蛋白AIV增加CCK分泌以响应脂质，并且载脂蛋白AIV也增强CCK的作用。第一个具体目标是测试载脂蛋白AIV剂量依赖性增加CCK分泌量的假设，以响应膳食脂质。这将包括确定载脂蛋白AIV参与刺激g蛋白信号级联反应和环amp蛋白激酶A （cAMP-PKA）通路对CCK分泌的重要作用。在特异性目标2中，我们将验证外周载脂蛋白AIV通过直接作用于神经元或通过增强CCK对神经元的作用来增加迷走传入神经活动的假设。这项拨款申请的成功完成将确定CCK和载脂蛋白AIV在外周相互作用以增加迷走神经传入神经元的激活并有助于限制食物大小的生理和细胞机制。这将为产生影响食物摄入和体重的药理学方法提供一个新的概念。