Stress, 'comfort' food, and obesity

项目摘要 大多数人报告说，作为一种压力手段，吃美味的、高热量的“舒适”食物是一种手段 如释重负。事实上，有吃可口食物历史的人改善了情绪，减少了 对压力的生理和情绪反应。然而，舒适的喂养要付出巨大的代价 新陈代谢健康，因为与压力相关的进食者有更高的BMI，更难减肥。尽管 有明确证据表明，舒适喂养是许多人肥胖的主要原因，但我们对此知之甚少 为什么会是这样。这项建议解决了我们知识中的两个关键差距。首先，它确定 舒适性喂养缓解正常体重个体压力的机制。其次，它标识了 这种压力缓解在饮食诱导肥胖(DIO)期间受损的程度。这对健康很重要 暗示，因为它暗示了一个恶性循环，肥胖的人不断增加他们的 以新陈代谢健康恶化为代价的美味食物，以保持有效的压力缓解。我们建议 用可口的“零食”范例来研究这些关系，在这个范例中，老鼠每天有两次机会接触到 少量可口的蔗糖溶液，或水作为对照。给予有限蔗糖摄入量(LSI)的大鼠 范例减少他们的食物摄入量，以补偿蔗糖中的卡路里，并保持正常的身体 体重，使我们能够分离出LSI在正常体重下降低应激反应的机制 个人。事实上，LSI大鼠的神经内分泌(HPA轴)、行为和代谢(能量)都有所减弱 动员)对压力挑战的反应。此外，LSI不能在DIO大鼠中提供应激钝化作用， 这表明肥胖可能会增加缓解压力所需的可口食物的数量。大规模集成电路 因此，范式为确定有效应激背后的机制提供了独特的机会 正常体重啮齿动物的缓解，DIO如何扰乱这些机制，以及DIO是否升级 摄入蔗糖，从而恢复有效的压力缓解，但代价是代谢健康恶化。此外， 我们之前的工作表明，前脑区域(BLA，mPFC)是缓解LSI压力的关键部位，尽管 调节这种压力钝化的神经回路机制尚不清楚。我们新的初步数据表明 内源性大麻素(ECB；内源性大麻类分子)作为这一机制在这个回路中起作用。 例如，束缚应激会迅速增加LSI大鼠的BLA ECB含量，但不会增加水分 众所周知，BLA中的ECB信号会钝化应激反应。全身型大麻素受体 1对抗也阻碍了LSI压力的缓解。因此，这个建议解决了这样一个假设，即可口性 食物通过在应激过程中通过欧洲央行信号改变前脑回路功能来抑制应激反应。建议数 实验确定了PL-BLA投射和前脑ECB信号对LSI应激缓解的贡献。 实验还测试了DIO对LSI后前脑ECB信号的干扰程度，以及 在DIO过程中，蔗糖消耗增加对恢复前脑ECB信号和应激钝化的能力。

Project Summary The majority of people report eating highly palatable, calorically-dense ‘comfort’ foods as a means of stress relief. Indeed, individuals with a history of eating palatable foods have improved mood and reduced physiological and emotional responses to stress. However, comfort feeding comes at a significant cost to metabolic health, as stress-related eaters have higher BMIs and have more difficulty losing weight. Despite clear evidence that comfort feeding is a primary cause of obesity for many people, we know very little about why this is the case. This proposal addresses two critical gaps in our knowledge. First, it determines the mechanisms by which comfort feeding gives stress relief in normal weight individuals. Second, it identifies the extent that this stress relief is impaired during diet-induced obesity (DIO). This has important health implications, as it suggests a vicious cycle whereby obese individuals continually increase their consumption of palatable foods to maintain effective stress relief at the cost of worsening metabolic health. We propose to study these relationships using a palatable ‘snacking’ paradigm in which rats are given twice-daily access to a small amount of palatable sucrose solution, or water as a control. Rats given this limited sucrose intake (LSI) paradigm reduce their chow intake to compensate for the calories in the sucrose and maintain normal body weight, allowing us to isolate the mechanisms by which LSI reduces stress responses in normal weight individuals. Indeed, LSI rats have attenuated neuroendocrine (HPA axis), behavioral, and metabolic (energy mobilization) responses to a stress challenge. Moreover, LSI is unable to provide stress-blunting in DIO rats, suggesting that obesity may increase the amount of palatable food needed to obtain stress relief. The LSI paradigm therefore provides the unique opportunity to determine the mechanism underlying effective stress relief in normal weight rodents, how these mechanisms are disrupted by DIO, and whether DIO escalates sucrose intake thereby restoring effective stress relief at the cost of worsening metabolic health. Furthermore, our prior work implicates forebrain regions (BLA, mPFC) as key sites for LSI stress relief, though the neurocircuit mechanism that mediates this stress-blunting is not known. Our new preliminary data point to endocannabinoids (eCB; endogenous marijuana-like molecules) acting within this circuit as this mechanism. For instance, restraint stress rapidly increases BLA eCB (anandamide) content in LSI rats, but not water controls, and eCB signaling in the BLA is known to blunt stress responses. Systemic cannabinoid receptor type 1 antagonism also prevents LSI stress relief. This proposal therefore addresses the hypothesis that palatable foods curb stress responses by altering forebrain circuit function via eCB signaling during stress. The proposed experiments determine the contribution of PL-BLA projections and forebrain eCB-signaling to LSI stress relief. Experiments also test the extent to which DIO interferes with forebrain eCB signaling after LSI, as well as the ability of escalated sucrose consumption to recover forebrain eCB signaling and stress-blunting during DIO.