GASTROINTESTINAL NUTRIENT SIGNALS CONTROLLING INGESTION

A.具体目标 肥胖症的流行突显了这样一个事实，即许多人难以将食物摄入量限制在 在“现代”或“典型的西方”饮食中保持健康的体重。作为科学和社会的其他部分 在解释和控制现代饮食过度消费的问题上，令人惊讶的是 人们对影响摄取的胃肠道的营养感应能力知之甚少。 没有这样的信息，就不太可能设计出可能最大化或 加强负面反馈循环，最终减少一餐一餐的过度消费。 本建议的总体长期目标是更好地了解营养物质是如何摄入的。 作为评价食物和限制消费的信号。特别是，由于吸收前和吸收后早期 营养素产生的信号构成关键的负反馈，产生饱腹感和停顿 进食，这项建议提出了一系列程序性的实验，旨在评估 营养产生的信号可以通过胃肠道和/或消化器官检测到。 为了解决这些问题，我们最近开发并使用了一种测试范例，使其能够 确定动物在肠道中或在吸收后早期阶段能够检测到的营养信号 (93)。我们暂时将这一新方案称为肠道味觉厌恶范式。这个“ITA”协议 是一种混合程序，它结合了慢性留置胃肠道导管准备的要素 以及条件性的味觉厌恶模式(这样动物就可以避免在生病时检测到的信号) 裁判31)。基本上，在ITA范式的训练阶段，动物接受胃内或肠道内的 注入一种新的营养素，然后通过服用呕吐剂或引起恶心的药物而生病 毒品。在随后的测试中，动物第一次有机会品尝和口服这种营养物质 一直伴随着身体不适。正如我们已经报道的(93)，动物，即使在它的第一次摄取测试中，也能够 通过口腔识别并拒绝先前在肠道或胃中采样的营养物质。实际上，这一新的 该方案提供了对胃肠道的营养敏感性进行感官“心理物理学”的可能性。

a. Specific Aims The obesity epidemic has highlighted the fact that many individuals have difficulty limiting their food intake to maintain a healthy body weight on "modern" or "typical Western" diets. As science and the rest of society wrestle with the problems of explaining and controlling overconsumption of modern diets, it is surprising how little is known about the nutrient-sensing capacities of the gastrointestinal tract that can influence ingestion. Without such information, it is unlikely that it will be practical to design strategies that might maximize or enhance negative feedback loops and, ultimately, curtail meal-by-meal overconsumption. The overall long-term objective of the present proposal is a better understanding of how ingested nutrients are used as signals to evaluate food and to limit consumption. In particular, since pre-absorptive and early postabsorptive signals produced by nutrients constitute critical negative feedback that produces satiety and stops intake of a meal, this proposal suggests a programmatic series of experiments designed to evaluate what nutrient-generated signals can be detected by the gastrointestinal tract and/or organs of digestion. To address these issues, we have recently developed and used a test paradigm that makes it possible to determine what nutrient signals an animal is able to detect in the gut, or in the early post-absorptive phase (93). We have provisionally called this new protocol the intestinal taste aversion paradigm. This "ITA" protocol is a hybrid procedure that combines elements of the chronic indwelling gastrointestinal catheter preparation and the conditioned taste aversion paradigm (so that an animal will avoid a signal that it had detected while ill¿¿ ref. 31). Basically, in the training phase of the ITA paradigm, an animal receives an intragastric or intraintestinal infusion of a novel nutrient and then is made ill by administration of an emetic or nausea-inducing drug. In a subsequent test, the animal is given its first opportunity to taste and consume orally the nutrient that had been paired with malaise. As we have reported (93), an animal, even in its first intake test, is able to recognize by mouth and reject the nutrient previously sampled in the intestines or stomach. In effect, this new protocol offers the possibility of doing sensory "psychophysics" on the nutrient sensitivities of the Gl tract.