Taste-Calorie Consistency and Body Weight Regulation

A.具体目标 动态平衡是指人类和其他动物将生理参数维持在 在面对环境变化时相对恒定的水平。例如，即使是很小的偏离 体温、水合作用、渗透压、血压或氧合作用的动态平衡水平 对生理和行为功能产生严重不良影响。幸运的是，对这些和 许多其他参数通常是自动执行的，通常是在没有意识到身体的情况下 为保持平衡而进行的调整。沃尔特·B·坎农(Walter B.Cannon)(1932)提到了这种类型的自动 监管被誉为“智慧之身(十三)”。 能量动态平衡这个术语指的是调节能量使用和体重的能力。 尽管当地环境在食物可获得性或摄入量方面存在差异，但仍保持不变的水平。例如，它不是 不寻常的是，人们沉溺于富含能量的大餐，提供的卡路里远远超过短期摄入的热量 需要的时候，在其他场合吃更少的“卡路里”餐，在其他场合完全不进餐 泰晤士报。事实是，许多人长期保持正常体重，尽管饮食时间如此宽广 能量摄入的波动，表明存在监管控制机制，使人们 通过减少(或增加)卡路里的周期来精确地弥补短期的过度(或赤字) 消费。不幸的是，这种补偿制度似乎正变得越来越无效，因为 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。这种增长在两性的整个生命周期中都有记录 各民族(32、67、96)。此外，一个经常被忽视的问题是，对于许多正常的人来说 体重人将体重保持在恒定水平的能力不再是自动的。相反，它经常 依赖于认真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众健康的明显和严重影响，它是至关重要的 重要的是要确定不仅导致这种类型的调节失调，而且能够产生 我们现在所目睹的大规模的监管失调。以前的许多研究都是针对 发现摄入量和体重调节的神经、激素、代谢和遗传控制。 尽管这项工作提供了许多新的信息，但肥胖的原因仍然难以捉摸，而且令人信服 关于身体生理或遗传变化如何可能导致当前肥胖流行的解释 还没有准备好。 本申请中提出的研究从不同的角度来处理这个问题。我们 建议“身体的智慧”包括使用食物暗示的能力(例如，味道、质地、香味、外部 与食物相关的暗示)，以预测进食的营养和卡路里后果。通过 预测营养物质到达胃肠道时，这些信号会引起生理反应， 优化这些营养素的利用，并尽量减少它们扰乱体内平衡的能力(102)。在过去的几年里 25年来，美国超重和肥胖发病率的增加似乎直接相关 随着人工甜味剂的摄入。我们建议的研究计划的重点将是研究 食用人工调味、低卡路里或无卡路里的食品和饮料可能会起到 “智胜”身体的智慧。 这种可能性源于我们认为的一种新的理论公式，该公式将 对摄入量和体重的调节控制变成了一种相对简单的巴甫洛夫条件反射。在 这种结构，食用甜味或脂肪味的物质，只含很少或不含卡路里，其效果是 降低甜食或脂肪或感官信号预测卡路里的正常能力。作为一个结果 削弱这种预测关系，甜味或富含卡路里的食物变得更不能 唤起作为严格调控基础的代偿性生理反应。 这一模型为几项初步研究提供了动力。这些研究初步提供了 有短暂病史的大鼠调节卡路里摄入量和体重的能力受到干扰的证据 食用人工加糖或脂肪替代品的食物。具体目标1-4将尝试进一步 描述这种类型的监管干扰及其发生的条件。最终的具体目标 是直接评估这样一种假设，即食用甜味但不含热量的物质会干扰 甜味的正常能力能唤起预期的生理反应，这可能有助于能量 动态平衡。

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.