Regulation of Food Intake via the Glucagon-Like Peptide-1 Receptor

通过胰高血糖素样肽-1 受体调节食物摄入

• 批准号: 9579802
• 负责人: Julio E Ayala
• 金额: $ 23.05万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-10-09 至 2019-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9579802
• 关键词: Regulation; Food; Intake; via; Glucagon

DESCRIPTION (provided by applicant): Satiety hormones such as glucagon-like peptide-1 (Glp1) are secreted in response to feeding and activate neural processes that subsequently suppress food intake. While the satiety effects of Glp1 have been known for over 15 years, the mechanism mediating this effect is not clearly defined. This is significant since some Glp1-based therapies for type 2 diabetes display modest weight loss effects. Understanding how Glp1 regulates food intake may, therefore, lead to the design of therapeutic interventions with improved efficacy for weight loss. Based on our preliminary data, we hypothesize that the anorectic effect mediated via the central Glp1 receptor (Glp1r) is integrated with hypothalamic signaling proteins that respond to changes in circulating glucose. Activation of the hypothalamic Glp1 receptor (Glp1r) inhibits the cellular energy sensor AMP-activated protein kinase (AMPK). Considering that the anorectic effects of leptin, insulin and glucose are mediated in part by inhibition of hypothalamic AMPK, we hypothesize that this is also a mechanism by which Glp1 suppresses food intake. We also show that inhibition of AMPK by the Glp1r agonist Exendin-4 (Ex4) in hypothalamic cell lines occurs only with increasing glucose concentration. Ex4 also stimulates glucose uptake and metabolism in a glucose concentration-dependent manner. Since increased glucose metabolism inhibits AMPK, we hypothesize that central Glp1r activation inhibits AMPK and subsequently reduces food intake by stimulating central glucose metabolism. Supporting this hypothesis, we show that inhibition of glycolysis in the brain blocks the anorectic effect of Ex4. Contrasting the effects of glucose, central administration of fructose attenuates the anorectic effect of Ex4. Fructose activates hypothalamic AMPK. This suggests that by activating hypothalamic AMPK fructose can "short-circuit" the Glp1r signaling pathway and promote central Glp1 resistance. This could partially explain our observation that mice fed a sucrose diet, which provides fructose and glucose, eat more compared to mice fed an isocaloric starch diet that only provides glucose. This also has clinical implications based on the association between increased fructose consumption and the obesity epidemic, particularly in children. Since the Glp1r is expressed in multiple hypothalamic nuclei, the first aim is to identiy hypothalamic regions mediating the anorectic effect of Glp1r agonists. The second aim will combine hypothalamic nuclei- specific modulation of the Glp1r with pharmacological agents that target processes we hypothesize are downstream of the Glp1r - glucose metabolism and AMPK activity. The final aim will assess whether dietary fructose is an inhibitor of the satiety effects mediated by central Glp1r activation. The long-term goal of this application is to elucidate the mechanisms that regulate multiple aspects of feeding behavior. Defining the mechanisms by which the central Glp1r regulates food intake will identify key control points that could be sites for disruption by obesogenic factors and targets for therapeutic intervention.

描述（由申请人提供）：响应于喂养和激活随后抑制食物摄入的神经过程，分泌诸如胰高血糖素样肽-1（GLP1）之类的饱腹激素。虽然GLP1的饱腹感效果已知15年以上，但介导这种效果的机制尚未明确定义。这很重要，因为一些基于GLP1的2型糖尿病的疗法表现出适度的减肥效果。因此，了解GLP1如何调节食物摄入可能会导致设计治疗干预措施，并提高了减肥功效。根据我们的初步数据，我们假设通过中央GLP1受体（GLP1R）介导的厌食效应与下丘脑信号蛋白集成，这些蛋白会响应循环葡萄糖的变化。下丘脑GLP1受体（GLP1R）的激活抑制了细胞能传感器AMP激活的蛋白激酶（AMPK）。考虑到瘦素，胰岛素和葡萄糖的厌食作用部分是通过抑制下丘脑AMPK介导的，我们假设这也是GLP1抑制食物摄入量的机制。我们还表明，下丘脑细胞系中GLP1R激动剂Exendin-4（EX4）对AMPK的抑制作用仅随着葡萄糖浓度的增加而发生。 EX4还以葡萄糖浓度依赖性方式刺激葡萄糖摄取和代谢。由于增加的葡萄糖代谢抑制了AMPK，因此我们假设中央GLP1R激活抑制AMPK，随后通过刺激中央葡萄糖代谢来降低食物摄入。支持这一假设，我们表明抑制大脑中的糖酵解会阻塞厌食症 EX4的效果。 与葡萄糖的作用相反，果糖的中央给药会减弱EX4的厌食作用。果糖激活下丘脑AMPK。这表明，通过激活下丘脑AMPK果糖可以“短路” GLP1R信号通路并促进中央GLP1电阻。这可以部分解释我们的观察结果，即喂养蔗糖饮食（提供果糖和葡萄糖）的小鼠与喂养仅提供葡萄糖的等量平衡淀粉饮食的小鼠相比多吃。这也基于果糖消耗量增加与肥胖症流行（尤其是在儿童中）之间的关联，也具有临床意义。 由于GLP1R在多个下丘脑核中表达，因此第一个目的是鉴定下丘脑区域介导GLP1R激动剂的厌食作用。第二个目的将结合下丘脑核 - 特定于GLP1R的调节与我们假设的靶向过程的药理学剂是GLP1R-葡萄糖代谢和AMPK活性的下游。最终目标将评估饮食果糖是否是饱腹感的抑制剂 由中央GLP1R激活介导。 该应用的长期目标是阐明调节喂养行为多个方面的机制。定义中央GLP1R调节食物摄入的机制将确定可能是肥胖因子和治疗干预措施的靶标的关键控制点。