Divergent mechanisms, convergent phenotype: the comparative physiology of glucose and fructose oxidation in vertebrate nectarivores

不同的机制，趋同的表型：脊椎动物食蜜动物葡萄糖和果糖氧化的比较生理学

• 批准号: RGPIN-2015-06129
• 负责人: Welch, Kenneth
• 金额: $ 2.04万
• 依托单位: University of Toronto
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2016
• 资助国家: 加拿大
• 起止时间: 2016-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=613963
• 关键词: Divergent; mechanisms; convergent; phenotype; comparative

The optimal use and regulation of fuels in skeletal muscles is key to animal performance and energy homeostasis, and thus the fundamental biology and ecology of organisms. Remarkably little of interspecific variation has been described among vertebrates, however, and differences are poorly understood. My research program seeks to identify and characterize the distinct “solutions” that have evolved for fueling intense exercise and managing energy homeostasis in two groups of nectar-eating vertebrates. A great deal has been learned about patterns of fuel use in exercising muscles of humans and other terrestrial mammals. All non-flying mammals apparently have similar capacities for the use of circulating sugars. Ingested glucose only partially fuels muscle activity and muscles make little direct use of fructose. However, these conserved fuel use patterns cannot be universal. Hummingbirds and nectar bats exhibit some of the highest aerobic metabolic rates of any vertebrates when hovering. My research has shown that these nectarivores can fuel most or all of hovering flight using ingested sugar. Evidence now suggests that these animals may even directly utilize fructose as readily as glucose in exercising muscles, a feat no other group of vertebrates can achieve. Yet, little is known regarding how this rapid transport, uptake, and oxidation of sugars occurs and is regulated. Most exciting, hummingbirds and bats likely employ fundamentally different mechanisms. Nectar bats, like all mammals, express glucose transporter protein 4 (GLUT4) in muscle, a critically important component of the sugar uptake and blood glucose management system. Hummingbirds, however, lack GLUT4. Rapid sugar transport into muscles must be regulated differently in each group. I will characterize the functional enhancements that permit the rapid uptake and oxidation of sugars in muscles in these groups, highlighting differences between them related to their independent evolution. Three steps are believed to be key regulation points for the uptake and oxidation of sugar by muscle: 1) absorption of dietary sugar, delivery, via the circulatory system, to the extracellular fluid surrounding working muscles, 2) transport of sugars into the sarcoplasm, and 3) phosphorylation of sugars by a hexokinase (HK) enzyme. I will 1) use non-invasive techniques to determine the relative kinetics, and partitioning of, glucose and fructose oxidation in hummingbirds and nectar bats; 2) quantify capacities for phosphorylation and oxidation of each sugar in muscle fibers directly (step 2); 3) quantify tissue affinities and capacities for uptake of glucose and fructose (step 3). These studies will characterize the potentially novel mechanisms hummingbirds and nectar bats employ to both tolerate and exploit their sugar-rich diet and extreme fluctuations in blood sugar. This program will train 3 PhD, 4 MSc, and 10 undergraduate students.

骨骼肌中燃料的最佳使用和调节是动物性能和能量稳态的关键，因此是生物体的基础生物学和生态学。然而，在脊椎动物中，种间变异的描述非常少，而且对差异的了解也很少。我的研究计划旨在确定和表征不同的“解决方案”，这些解决方案已经进化为两组食蜜脊椎动物的高强度运动和能量稳态管理。 关于人类和其他陆地哺乳动物在锻炼肌肉时使用燃料的模式，人们已经了解了很多。所有不会飞的哺乳动物显然都有类似的利用循环糖的能力。摄入的葡萄糖只能部分地为肌肉活动提供燃料，而肌肉很少直接利用果糖。然而，这些节约燃料的使用模式不可能是普遍的。蜂鸟和花蜜蝙蝠在盘旋时表现出任何脊椎动物中最高的有氧代谢率。我的研究表明，这些食蜜动物可以用摄入的糖来为大部分或全部的悬停飞行提供燃料。现在的证据表明，这些动物甚至可以像葡萄糖一样直接利用果糖来锻炼肌肉，这是其他脊椎动物无法实现的壮举。然而，关于糖的这种快速运输、摄取和氧化是如何发生和调节的知之甚少。最令人兴奋的是，蜂鸟和蝙蝠可能采用根本不同的机制。花蜜蝙蝠，像所有的哺乳动物一样，在肌肉中表达葡萄糖转运蛋白4（GLUT 4），这是糖摄取和血糖管理系统的重要组成部分。然而，蜂鸟缺乏GLUT 4。糖快速运输到肌肉中必须在每个组中进行不同的调节。我将描述这些群体中允许快速摄取和氧化糖的肌肉功能增强，突出它们之间与独立进化相关的差异。 三个步骤被认为是肌肉摄取和氧化糖的关键调节点：1）膳食糖的吸收，通过循环系统递送到工作肌肉周围的细胞外液，2）糖转运到肌浆中，和3）己糖激酶（HK）酶对糖的磷酸化。 我将1）使用非侵入性技术来确定蜂鸟和花蜜蝙蝠中葡萄糖和果糖氧化的相对动力学和分配; 2）直接量化肌纤维中每种糖的磷酸化和氧化能力（步骤2）; 3）量化组织亲和力和葡萄糖和果糖摄取能力（步骤3）。 这些研究将描述蜂鸟和花蜜蝙蝠用于容忍和利用其高糖饮食和血糖极端波动的潜在新机制。该项目将培养3名博士，4名硕士和10名本科生。