Taste-Calorie Consistency and Body Weight Regulation

a.具体目标 稳态是指人类和其他动物在一定的时间内维持生理参数的能力。 相对稳定的水平，面对环境的变化。例如，即使是微小的偏离， 体温、水合作用、渗透压、血压或氧合的稳态水平可具有 对生理和行为功能产生严重不良影响。幸运的是，这些严格的监管和 许多其他参数通常是自动执行的，通常没有身体的有意识。 这些调整有助于保持平衡。沃尔特B。卡农（1932）提到了这种类型的自动 监管控制作为"智慧的身体"（13）。" 术语能量稳态是指调节能量使用和体重的能力， 尽管当地环境在食物供应或摄入量方面存在差异，但水平保持不变。比如不 对于人们来说，沉迷于大量、富含能量的膳食是不寻常的，这些膳食提供的热量远远超过了短期的热量 需要，在其他场合吃更小的“卡路里意识”餐，在其他场合完全跳过餐 次事实上，许多人长期保持正常体重，尽管如此广泛的膳食， 能量摄入量的波动，指出了监管控制机制的存在， 以减少（或增加）热量的时期精确地补偿短期的过量（或不足） 消费不幸的是，这种补偿制度似乎越来越无效， 来自几个来源的数据表明，被归类为超重或肥胖的人口比例 自20世纪80年代中期以来稳步攀升。在两性的整个生命周期中都记录了这种增加 和所有族裔群体（32，67，96）。此外，一个经常被忽视的问题是，许多正常的 体重的人保持体重在恒定水平的能力不再是自动的。相反，它往往 取决于严格遵守自我强加的饮食限制和锻炼方案。 鉴于超重和肥胖对公共卫生的明确和严重影响， 重要的是要确定因素，不仅导致这种类型的失调，但也能够产生 我们现在看到的大规模的失调。以前的许多研究都是针对 发现神经，激素，代谢和遗传控制的摄入量和体重调节。 虽然这项工作提供了许多新的信息，肥胖的原因仍然难以捉摸，令人信服 解释身体生理学或遗传学的变化如何导致目前的肥胖流行病 一直没有进展 本申请中提出的研究从不同的角度解决问题。我们 建议"身体的智慧"包括使用食物线索的能力（例如，味道、质地、香气、外部 与食物相关的线索）来预测进食的营养和热量结果。通过 预测营养物质到达胃肠道，这些线索引起生理反应， 优化这些营养素的利用，并最大限度地减少它们扰乱体内平衡的能力（102）。在过去 25年来，美国超重和肥胖发生率的增加似乎直接相关， 摄入了人造甜味剂我们拟议的研究计划的重点将是研究 食用人工调味的低热量或无热量的食物和饮料可能会起到 "智取"身体的智慧。 这种可能性来自于我们认为是一种新颖的理论公式，它将 将对摄入量和体重的调节控制转化为相对简单的巴甫洛夫条件反射。内 在这个框架下，食用含有很少或不含卡路里的甜味或脂肪味物质， 降低了甜味或脂肪的感官线索预测卡路里的正常能力。的结果 削弱了这种预测关系，含有卡路里的甜味或脂肪味食物变得不那么能够 引起作为严格调节基础的补偿性生理反应。 这一模式为若干初步研究提供了动力。这些研究提供了初步的 有证据表明，有短暂病史的大鼠调节热量摄入和体重的能力受到干扰， 食用人造甜味剂或脂肪替代食品。具体目标1 - 4将试图进一步 描述这种类型的调节干扰及其发生的条件。最终的具体目标 直接评估这一假设，即食用甜味但无热量的物质会干扰 甜味引起可能有助于能量的预期生理反应的正常能力 体内平衡

a. Specific Aims Homeostasis refers to the ability of humans and other animals to maintain physiological parameters at relatively constant levels in the face of environmental flux. For example, even small departures from homeostatic levels of body temperature, hydration, osmolality, blood pressure, or oxygenation can have serious adverse effects on physiological and behavioral functioning. Fortunately, tight regulation of these and many other parameters is typically carried out automatically, often without conscious awareness of the bodily adjustments that serve to that preserve equilibrium. Walter B. Cannon (1932) referred to this type of automatic regulatory control as the "wisdom of the body (13)." The term energy homeostasis refers to the ability to regulate energy use and body weight at relatively constant levels despite local environmental variations in food availability or intake. For example, it is not unusual for people to indulge in large, energy-rich meals that provide calories well in excess of their short-term needs, eat smaller more "calorie conscious" meals on other occasions, and skip meals altogether at other times. The fact that many people maintain normal body weight over the long-term, despite such wide meal-tomeal fluctuations in energy intake, points to the existence of regulatory control mechanisms that enable people to compensate precisely for shorter term excesses (or deficits) with periods of decreased (or increased) caloric consumption. Unfortunately, it appears that this compensatory system is becoming increasingly ineffective, as data from several sources indicate that the proportion of the population classified as overweight or obese has climbed steadily since the mid-1980s. This increase has been documented across the lifecycle in both genders and among all ethnic groups (32, 67, 96). Moreover, a problem often overlooked is that for many normal weight people the ability to maintain body weight at constant level is no longer automatic. Rather, it often depends on careful adherence to self-imposed regimens of dietary restriction and exercise. Given the clear and serious implications of overweight and obesity for public health, it is critically important to identify factors that not only cause this type of dysregulation but are also capable of producing dysregulation on the massive scale that we are witnessing now. Much previous research has been directed at discovering the neural, hormonal, metabolic, and genetic controls of intake and body weight regulation. Although this work has provided much new information, the causes of obesity remain elusive, and compelling explanations about how changes in body physiology or genetics might produce the current obesity epidemic have not been forthcoming. The research proposed in this application approaches the problem from a different perspective. We suggest that the "wisdom of the body" involves the ability to use food cues (e.g., taste, texture, aroma, external cues that are associated with food) to anticipate the nutritive and caloric consequences of eating. By predicting the arrival of nutrients in the gastrointestinal tract, these cues evoke physiological responses that optimize utilization of these nutrients and also minimize their ability to perturb homeostasis (102). Over the last 25 years, increased incidence of overweight and obesity in the United States appears to be directly correlated with the intake of artificial sweeteners. The focus of our proposed research program will be to study the possibility that consumption of artificially-flavored, low- or no-calorie foods and beverages might function to "outwit" the wisdom of the body. This possibility is derived from what we think is a novel theoretical formulation that links the efficiency of the regulatory control of intake and body weight to a relatively simple form of Pavlovian conditioning. Within this framework, consuming sweet- or fatty-tasting substances which contain few or no calories has the effect of degrading the normal ability of sweet or fat orosensory cues to predict calories. As a consequence of weakening this predictive relationship, sweet- or fatty-tasting foods that contain calories become less able to evoke the compensatory physiological responses that underlie tight regulation. This model supplied the impetus for several preliminary studies. These studies provided initial evidence that the ability to regulate caloric intake and body weight is disturbed in rats that have a brief history of consuming artificially-sweetened or fat-substituted foods. Specific Aims 1-4 will attempt to further characterize this type of regulatory disturbance and the conditions under which it occurs. The final specific aim is to assess directly the hypothesis that consuming sweet-tasting but noncaloric substances interferes with the normal ability of sweet tastes to evoke anticipatory physiological responses that may contribute to energy homeostasis.