The role of taste in amino acid appetite

描述（由申请人提供）：该提案解决了哪些生理机制调节动物在多种常量营养素中选择特定食物的能力的关键问题。这项建议的总体目标是研究吸收后，代谢因素的相对影响，味觉输入，糖和氨基酸的摄入量。更具体地说，我们将描述一组生理反应，伴随着氨基酸与碳水化合物的摄入在野生型和基因工程味觉受损小鼠。要监测的生理参数包括氨基酸和碳水化合物消耗后的行为、热量和神经化学反应。我们的中心假设指出，即使排除味觉输入，葡萄糖作为代谢燃料的利用也会调节营养偏好。换句话说，我们假设与糖相关的摄食后奖励信号依赖于葡萄糖作为细胞燃料的利用。作为一个推论，我们特别假设葡萄糖利用水平控制细胞外多巴胺浓度在纹状体，营养偏好最终调节多巴胺信号在这个大脑奖励电路。测试这一中心假设将涉及采用行为，代谢和神经化学测量野生型和Trpm 5基因敲除小鼠暴露于不同的碳水化合物和氨基酸的解决方案。重要的是，通过测试葡萄糖利用假说，该项目将提供关于代谢和大脑奖励回路如何导致消费甜味食物的强大动机的新数据。该提案的具体目标是：1描述葡萄糖代谢在摄食后强化中的作用; 2描述葡萄糖代谢在大脑奖励回路调节中的作用。与我们的中心假设葡萄糖利用有利于碳水化合物摄入超过其他营养素相一致，我们的初步研究使我们得出结论：1）KO小鼠显示出对一些糖和L-氨基酸的味觉不敏感性，同时显示出与L-氨基酸溶液相比以独立于味觉输入的方式增加的对葡萄糖的偏好; 2）葡萄糖利用率是糖摄入水平的有效预测因素，与味觉输入无关; 3）当摄入葡萄糖抵消糖酵解抑制的影响时，甜味受损的Trpm 5基因敲除小鼠将增加的奖励值归因于葡萄糖; 4）大脑奖赏回路中的多巴胺水平对有利于更高葡萄糖利用水平的化合物敏感，而与口感觉刺激无关; 5）这些区域中的多巴胺水平受到糖酵解抑制的负面影响; 6）Trpm 5敲除小鼠显示出正常的代谢和摄取的碳水化合物和蛋白质的吸收;此外，对糖和氨基酸的不同行为反应不能仅仅由胃肠感觉和吸收来解释。我们相信，我们的研究将有助于建立糖奖励的综合生理学，这是一个重要但代表性不足的研究领域。

DESCRIPTION (provided by applicant): This proposal addresses the critical question of which physiological mechanisms regulate the ability of an animal to select particular foods among a diverse array of macronutrients. The overall objective of this proposal is to examine the relative influence of post-absorptive, metabolic factors in contrast to gustatory input, on sugar and amino acid intake. More specifically, we will characterize a set of physiological responses that accompany amino acid vs. carbohydrate intake in both wild-type and genetically engineered taste-impaired mice. The physiological parameters to be monitored include the behavioral, calorimetric and neurochemical reactions that follow amino acid and carbohydrate consumption. Our central hypothesis states that the utilization of glucose as a metabolic fuel regulates nutrient preferences even when taste input is factored out. In other words, we hypothesize that the postingestive reward signals associated with sugars depend on the utilization of glucose as a cellular fuel. As a corollary, we specifically hypothesize that glucose utilization levels control extracellular dopamine concentration in striatum, given that nutrient preferences are ultimately regulated by dopamine signaling in this brain reward circuit. Testing this central hypothesis will involve employing behavioral, metabolic and neurochemical measurements in wild-type and Trpm5 knockout mice exposed to different carbohydrate and amino acid solutions. Importantly, by testing the glucose utilization hypothesis, the proposed project will provide novel data on how the metabolic and brain reward circuitry leads to the powerful motivation to consume sweet-tasting foods. The specific aims of this proposal are: 1 To characterize the role of glucose metabolism in postingestive reinforcement and 2 To characterize the role of glucose metabolism in the regulation of brain reward circuits. Consistent with our central hypothesis that glucose utilization favors carbohydrate intake over other nutrients, our preliminary studies allowed us to conclude that 1) KO mice show taste insensitivity to some several sugars and L-amino acids while displaying increased preferences for glucose compared to L-amino acid solutions in a way that is independent of taste input; 2) Glucose utilization rates are efficient predictors of sugar intake levels independently of taste input; 3) Sweet-impaired Trpm5 knockout mice attribute increased reward value to glucose when its ingestion counteracts the effects of glycolysis inhibition; 4) Dopamine levels in brain reward circuitries are sensitive to compounds that favor higher glucose utilization levels independently of orosensory stimulation; 5) Dopamine levels in these regions are negatively affected by glycolysis inhibition; 6) Trpm5 knockout mice display normal metabolization and absorption of ingested carbohydrate and proteins; in addition, differential behavioral responses to sugars and amino acids are not accounted for solely by gastrointestinal sensing and absorption. We believe that our studies will contribute to establishing an integrative physiology of sugar reward, an important and yet underrepresented area of research.