GLP-1 analogue effects on food cues, stress, motivation for highly palatable foods, and weight

摘要 美国处于全球肥胖症流行的前沿。要了解驱动机制 肥胖增加，R01-DK099039项目的第一个周期开发并验证了一个新的实验室 在HP食物提示和压力环境的背景下过量食用高度可口(HP)食物的模型 其中之一与体重增加和肥胖风险有关。研究结果支持与体重指数相关的适应 皮质醇、Ghrelin、胰岛素敏感性、HP食物渴求和饥饿均可预测HP在食物零食中暴饮暴食 在实验室实验中测试(FST)，值得注意的是，这些测量还前瞻性地预测体重增加 在纵向两年的结果期内。最近的数据表明，胰高血糖素样肽-1(GLP-1)可以调节 应激生物学及其对代谢的影响。Jastreboff博士领导的初步工作表明GLP-1 模拟(GLP-1a)治疗减少了实验室和现实世界中的渴望、饥饿和食物摄入量 布景。因此，在这一竞争更新中，我们提出了一种多PI实验疗法方法， GLP-1a，Semagluide，在当前项目中开发的独特的预测性实验室模型中测试 假设GLP-1a治疗将减弱Hp食物提示和应激诱导的食物动机和摄入量 肥胖还能改善新陈代谢和压力反应，这样的变化将预测体重结果。一个 使用GLP-1a的随机、双盲、安慰剂对照的12周男性和女性研究(N=96) 肥胖(BMI 30-39.9 kg/m2)被建议在实验室实验中验证上述总体假设 以及为期12周的治疗期，以评估现实世界的结果。具体目标是：1)检查效果 GLP-1a与PBO治疗对食物渴望、饥饿、食物提示和应激诱导的FST摄入和进食的比较 FST中的地形；2)评估GLP-1a与PBO治疗对每周食物渴望和食物的影响 在12周的治疗期间，在真实世界环境中的卡路里摄入量；以及3)检查 GLP-1a对HP食物的代谢和应激反应(Ghrelin、皮质醇和胰岛素抵抗)的治疗 食物渴求与FST摄入的实验室实验模型。探索性目标将GLP-1a 实验室结果的变化可以预测体重结果，以及性别、慢性疾病等特定因素 压力、饮食紊乱、饮食和体力活动都会影响结果。利用一种新的实验疗法 方法，该项目的下一阶段将应用当前周期经过验证的实验室模型来确定 更大的HP食物渴望、摄入量和体重增加的过程，以测试GLP-1a 类似物对肥胖有显著的体重效应。积极的发现不仅将告知GLP-1a如何发挥作用 对体重的影响，也为人类提供了独特的、对压力和食物敏感、创新和性价比高的线索 测试减少HP食物渴望、暴饮暴食和体重增加的新疗法的实验室方法。

ABSTRACT The United States is at the forefront of the global obesity epidemic. To understand the mechanisms driving increases in obesity, this first cycle of the R01-DK099039 project developed and validated a novel laboratory model for overeating highly palatable (HP) foods in the context of HP food cue and stressful environments, both of which are associated with weight gain and obesity risk. Findings supported that BMI-related adaptations in cortisol, ghrelin, insulin sensitivity, HP food craving and hunger each predicted HP overeating in a Food Snack Test (FST) in a laboratory experiment, and remarkably, these measures also prospectively predicted weight gain over a longitudinal 2-year outcome period. Recent data suggests glucagon-like peptide-1 (GLP-1) modulates stress biology along with its effects on metabolism. Preliminary work by led by Dr. Jastreboff indicate GLP-1 analogue (GLP-1a) treatment decreases craving, hunger and food intake in both the laboratory and real-world setting. Thus, in this competitive renewal, we propose a multi-PI experimental therapeutics approach with the GLP-1a, semaglutide, in the unique and predictive laboratory model developed in the current project to test the hypothesis that GLP-1a treatment will attenuate HP food cue- and stress-induced food motivation and intake in obesity and also improve metabolic and stress responses and such changes will predict weight outcomes. A randomized, double-blind, placebo-controlled 12-week study with GLP-1a in men and women (N=96) with obesity (BMI 30-39.9 kg/m2) is proposed to test the above overall hypothesis both in a laboratory experiment and over a 12 -week treatment period to assess real-world outcomes. Specific aims are: 1) to examine the effects of GLP-1a vs. PBO treatment on food craving, hunger, food-cue- and stress- induced FST intake and eating topography in the FST; 2) to assess the effects of GLP-1a vs. PBO treatment on weekly food craving and food calorie intake in the real-world setting during the 12-week treatment period; and 3) to examine the effects of GLP-1a treatment on metabolic and stress responses (ghrelin, cortisol, and insulin resistance) on HP food craving and intake in the experimental lab model of food craving and FST intake. Exploratory aims will GLP-1a changes in laboratory outcomes predict weight outcomes and whether specific factors such as gender, chronic stress, disordered eating, diet and physical activity affect outcomes. Utilizing a novel experimental therapeutics approach, the next phase of this project will apply the current cycle’s validated laboratory model of identifying processes underlying greater HP food craving, intake and weight gain to test mechanisms by which a GLP-1a analogue exerts significant weight effects in obesity. Positive findings will not only inform how GLP-1a exerts effects on weight, but also provide a unique, stress and food cue sensitive, innovative and cost-effective human laboratory approach for testing novel therapeutics to decrease HP food craving, overeating and weight gain.