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

摘要 美国是全球肥胖流行的最前沿。为了理解 肥胖增加，R 01-DK 099039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，过度食用高适口性（HP）食物的模型， 其中有一部分与体重增加和肥胖风险有关。研究结果支持BMI相关的适应， 皮质醇、生长激素释放肽、胰岛素敏感性、HP对食物的渴望和饥饿感都可以预测HP在食物零食中过量进食 测试（FST）在实验室实验中，值得注意的是，这些措施也前瞻性地预测体重增加 在纵向2年的结果期间。最近的数据表明胰高血糖素样肽-1（GLP-1）调节 压力生物学沿着其对新陈代谢的影响。Jastreboff博士领导的初步工作表明GLP-1 在实验室和现实世界中，类似物（GLP-1a）治疗减少了渴望，饥饿和食物摄入 设置.因此，在这种竞争性更新中，我们提出了一种多PI实验治疗方法， GLP-1a，Semaglutide，在当前项目中开发的独特和预测性实验室模型中，以检测 假设GLP-1a治疗将减弱HP食物提示和应激诱导食物动机和摄入， 肥胖，也改善代谢和压力反应，这些变化将预测体重结果。一 一项在男性和女性（N=96）中进行的GLP-1a随机化、双盲、安慰剂对照12周研究， 提出肥胖（BMI 30-39.9 kg/m2）来在实验室实验和健康检查中检验上述总体假设。 并在12周的治疗期内评估真实世界的结果。具体目标是：1）检查影响 GLP-1a与PBO治疗对食物渴望、饥饿、食物提示和应激诱导的FST摄入和进食的影响 FST中的地形图; 2）评估GLP-1a与PBO治疗对每周食物渴望和食物的影响 12周治疗期间真实环境中的卡路里摄入量;以及3）检查 GLP-1a处理对HP食物代谢和应激反应（生长激素释放肽、皮质醇和胰岛素抵抗）的影响 在实验室食物渴望和FST摄入模型中的渴望和摄入。探索性目的将GLP-1a 实验室结果的变化可以预测体重结果，以及是否有特定因素，如性别、慢性 压力、饮食失调、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的验证实验室模型， 更大的HP食物渴望，摄入和体重增加的潜在过程，以测试GLP-1a 类似物在肥胖症中具有显著的体重效应。积极的发现不仅将告知GLP-1a如何发挥作用， 对体重的影响，而且还提供了一个独特的，压力和食物线索敏感，创新和具有成本效益的人类 实验室方法测试新的疗法，以减少HP食物渴望，暴饮暴食和体重增加。

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.