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

描述（由申请人提供）：饱食激素如胰高血糖素样肽-1（Glp 1）响应进食而分泌，并激活随后抑制食物摄入的神经过程。虽然Glp 1的饱腹感效应已经被发现超过15年，但介导这种效应的机制尚未明确定义。这是重要的，因为一些基于Glp 1的2型糖尿病治疗显示出适度的减肥效果。因此，了解Glp 1如何调节食物摄入可能会导致设计具有改善减肥功效的治疗干预措施。基于我们的初步数据，我们假设，通过中央Glp 1受体（Glp 1 r）介导的厌食作用是整合与下丘脑信号蛋白，响应循环葡萄糖的变化。下丘脑Glp 1受体（Glp 1 r）的激活抑制细胞能量传感器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Glp 1抑制食物摄入的机制。我们还表明，AMPK的Glp 1 r激动剂Exendin-4（Ex 4）在下丘脑细胞系中的抑制只发生在葡萄糖浓度增加。Ex 4还以葡萄糖浓度依赖性方式刺激葡萄糖摄取和代谢。由于葡萄糖代谢增加抑制AMPK，我们假设，中央Glp 1 r激活抑制AMPK，随后通过刺激中央葡萄糖代谢减少食物摄入。支持这一假设，我们表明，抑制糖酵解在大脑阻断厌食症 Ex 4的效果。 与葡萄糖的作用相反，果糖的中枢给药减弱了Ex 4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”Glp 1 r信号通路，促进中枢Glp 1抗性。这可以部分解释我们的观察结果，即喂食蔗糖饮食（提供果糖和葡萄糖）的小鼠比喂食仅提供葡萄糖的等热量淀粉饮食的小鼠吃得更多。这也有临床意义的基础上增加果糖消费和肥胖症的流行，特别是在儿童之间的关联。 由于Glp 1 r在多个下丘脑核团中表达，因此第一个目的是鉴定介导Glp 1 r激动剂的厌食作用的下丘脑区域。第二个目标将结合联合收割机下丘脑核特异性调节Glp 1 r与药理学试剂，我们假设靶向过程是Glp 1 r-葡萄糖代谢和AMPK活性的下游。最终的目标是评估饮食中的果糖是否是饱腹感的抑制剂 由中央Glp 1 r激活介导。 本申请的长期目标是阐明调节摄食行为多个方面的机制。定义中央Glp 1 r调节食物摄入的机制将确定关键控制点，这些控制点可能是肥胖因素和治疗干预目标的干扰位点。

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.