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

骨骼肌燃料的最佳使用和调节是动物表现和能量动态平衡的关键，因此也是生物体的基本生物学和生态学的关键。然而，脊椎动物之间的种间差异被描述得非常少，而且差异也很少被理解。我的研究计划试图识别和描述两组吃花蜜的脊椎动物中进化出的用于补充高强度运动和管理能量动态平衡的不同“解决方案”。 关于人类和其他陆生哺乳动物锻炼肌肉时的燃料使用模式，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促进肌肉活动，肌肉对果糖的直接利用很少。然而，这些节约的燃料使用模式不可能是普遍的。蜂鸟和花蜜蝙蝠在悬停时表现出所有脊椎动物中最高的有氧代谢率。我的研究表明，这些食蜜者可以使用摄入的糖为大部分或全部盘旋飞行提供燃料。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、吸收和氧化是如何发生和被调控的，人们知之甚少。最令人兴奋的是，蜂鸟和蝙蝠可能使用了根本不同的机制。花蜜蝙蝠和所有哺乳动物一样，在肌肉中表达葡萄糖转运蛋白4(GLUT4)，这是糖吸收和血糖管理系统中至关重要的组成部分。然而，蜂鸟缺乏GLUT4。糖分进入肌肉的快速运输必须在每一组中受到不同的调控。我将描述这些群体中允许肌肉快速摄取和氧化糖的功能增强的特征，强调它们之间的差异，与它们的独立进化有关。 肌肉对糖的吸收和氧化有三个步骤被认为是关键的调节点：1)饮食中糖的吸收，通过循环系统输送到工作肌肉周围的细胞外液，2)糖到肌浆中的运输，3)己糖激酶(HK)酶对糖的磷酸化。 我将1)使用非侵入性技术确定蜂鸟和花蜜蝙蝠体内葡萄糖和果糖氧化的相对动力学和分配；2)直接量化肌肉纤维中每种糖的磷酸化和氧化能力(步骤2)；3)量化组织亲和力和摄取葡萄糖和果糖的能力(步骤3)。 这些研究将描述蜂鸟和花蜜蝙蝠用来耐受和利用它们富含糖分的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。

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.