The role of taste in amino acid appetite

描述（由申请人提供）：该提案解决了一个关键问题，即哪种生理机制调节动物在多种宏量营养素中选择特定食物的能力。本提案的总体目标是研究吸收后代谢因素对糖和氨基酸摄入的相对影响，而不是味觉输入。更具体地说，我们将在野生型和基因工程的味觉受损小鼠中描述一组伴随氨基酸和碳水化合物摄入的生理反应。要监视的生理参数包括行为、热量和神经化学反应,氨基酸和碳水化合物的消耗。我们的中心假设是，即使味觉输入被排除在外，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进食后奖励信号依赖于葡萄糖作为细胞燃料的利用。作为推论，我们特别假设葡萄糖利用水平控制纹状体细胞外多巴胺浓度，考虑到营养偏好最终由大脑奖赏回路中的多巴胺信号调节。为了验证这一中心假设，将对暴露于不同碳水化合物和氨基酸溶液中的野生型和Trpm5基因敲除小鼠进行行为、代谢和神经化学测量。重要的是，通过测试葡萄糖利用假说，拟议的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。本研究的具体目的是：1 .阐明糖代谢在摄食后强化中的作用；2 .阐明糖代谢在脑奖赏回路调节中的作用。与我们的中心假设一致，葡萄糖的利用倾向于碳水化合物的摄入而不是其他营养物质，我们的初步研究使我们得出以下结论：1)与l -氨基酸溶液相比，KO小鼠对某些糖和l -氨基酸溶液表现出味觉不敏感，而与味觉输入相比，对葡萄糖的偏好增加；2)葡萄糖利用率是独立于味觉输入的糖摄入水平的有效预测因子；3)甜味受损的Trpm5基因敲除小鼠认为，当糖酵解抑制作用被葡萄糖摄入抵消时，奖励价值增加；4)脑奖励回路中的多巴胺水平对独立于感官刺激的有利于提高葡萄糖利用水平的化合物敏感；5)这些区域的多巴胺水平受到糖酵解抑制的负面影响；6) Trpm5基因敲除小鼠对摄入的碳水化合物和蛋白质的代谢和吸收正常；此外,微分的行为反应,糖和氨基酸并不仅仅占胃肠道传感和吸收。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. PUBLIC HEALTH RELEVANCE: Uncovering sweet-independent reward signals favoring carbohydrate intake might significantly further our understanding on the reciprocal roles of gustatory and metabolic signals in stimulating the excessive consumption of sugars observed worldwide. In fact, there are several lines of evidence to suggest that currently undetermined sweetness-independent signals produced during glucose metabolism function to reinforce carbohydrate intake. Our work may provide new insights on the exact roles of taste quality and metabolism in sugar overconsumption.