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

描述(申请人提供)：饱腹感激素，如胰高血糖素样肽-1(GLP1)是在进食时分泌的，并激活神经过程，随后抑制食物摄取。虽然GLP1的饱腹感效应已经被知道超过15年了，但调节这种效应的机制还没有明确的定义。这一点意义重大，因为一些基于GLP1的2型糖尿病疗法显示出适度的减肥效果。因此，了解GLP1如何调节食物摄入量可能会导致设计具有更好减肥效果的治疗干预措施。根据我们的初步数据，我们假设中枢GLP1受体(GLP1R)介导的厌食效应与下丘脑信号蛋白整合在一起，下丘脑信号蛋白对循环葡萄糖的变化做出反应。下丘脑GLP1受体(GLP1R)的激活抑制了细胞能量感受器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，我们推测这也是GLP1抑制摄食的一个机制。我们还发现，GLP1R激动剂Exendin-4(EX4)对下丘脑细胞系中AMPK的抑制作用仅随着葡萄糖浓度的增加而发生。EX4还以一种依赖于葡萄糖浓度的方式刺激葡萄糖的吸收和代谢。由于糖代谢增加抑制AMPK，我们假设中枢GLP1R激活抑制AMPK，随后通过刺激中枢葡萄糖代谢减少食物摄入量。支持这一假设的是，我们发现抑制大脑中的糖酵解可以阻断厌食剂 EX4的效果。与葡萄糖的作用相比，中央注射果糖可减弱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，促进中枢GLP1抵抗。这可以部分解释我们的观察结果，即喂食蔗糖饮食的小鼠与只提供葡萄糖的等卡路里淀粉饮食的小鼠相比，吃得更多。基于果糖摄入量增加与肥胖流行之间的关联，这也具有临床意义，特别是在儿童中。由于GLP1R在下丘脑的多个核团中表达，第一个目的是确定介导GLP1R激动剂厌食效应的下丘脑区。第二个目标是将GLP1R的下丘脑核特异性调节与药物结合起来，这些药物的目标过程我们假设是GLP1R的下游-葡萄糖代谢和AMPK活性。最终目的是评估饮食中的果糖是否是饱腹感的抑制因素。 由中枢GLP1R激活介导。这项应用的长期目标是阐明调节摄食行为的多个方面的机制。确定中央GLP1R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干扰的部位和治疗干预的目标。

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.