Comprehensive quantification of fuel use in cold-induced thermogenesis in vivo

总结 冷诱导产热（CIT）允许包括哺乳动物在内的吸热动物将体温维持在 ~ 37 oC，尽管有时环境温度更低。CIT的药物活化正在 被许多团体研究作为一种潜在的治疗肥胖的方法。尽管经过几十年的调查 然而，CIT的不同燃料在CIT期间如何燃烧，哪些组织，以及在何种程度上，仍然生病- 定义了我们建议在这里进行一个全面的量化系统的代谢通量在寒冷 暴露于小鼠。这些研究是由我们和其他人开发的：（1）稳态输注 在活的、清醒的和走动的小鼠中使用非扰动量的重同位素标记燃料， 精确量化全身燃料周转和每种燃料对组织氧化的相对贡献 速率;和（2）急性动力学研究以允许三羧酸循环周转速率的定量估计， 从而在个体组织中产生VO 2。基于大量的初步数据，我们假设CIT在很大程度上是 由脂肪储存提供燃料，但它仍然严重依赖于回补碳水化合物来源， 由肝脏提供，以维持脂肪酸氧化。我们将有三个目标： 目的1：在小鼠CIT期间全面定量全身燃料转换。 目的2：在小鼠CIT期间，全面量化个体组织中的燃料使用。 目的3：测试CIT期间BAT中碳水化合物通量的作用。

SUMMARY Cold-induced thermogenesis (CIT) allows endotherms, including mammals, to maintain body temperature at ~37oC despite sometimes much colder ambient temperature. Pharmaceutical activation of CIT is being investigated by many groups as a potential therapeutic approach to obesity. Despite decades of investigations of CIT, however, how different fuels are burned during CIT, by which tissues, and to what extent, remains ill- defined. We propose here to carry out a comprehensive quantification of systemic metabolic fluxes during cold exposure in mice. These studies are enabled by the development by us and others of: (1) steady-state infusions with non-perturbative amounts of heavy isotope-labeled fuels in live, awake, and ambulatory mice, allowing precise quantification of whole-body fuel turnover and of relative contribution of each fuel to tissue oxidation rates; and (2) acute kinetic studies to allow quantitative estimates of rates of tricarboxylic acid cycle turnover, and thus of VO2, in individual tissues. Based on extensive preliminary data, we hypothesize that CIT is largely fueled from fat stores, but that it is nevertheless critically dependent on anaplerotic carbohydrate sources, provided by the liver, to sustain fatty acid oxidation. We will have 3 aims: Aim 1: Comprehensive quantification of whole-body fuel turnover during CIT in mice. Aim 2: Comprehensive quantification of fuel use in individual tissues during CIT in mice. Aim 3: Test the role of carbohydrate flux in BAT during CIT.