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

体内冷诱导生热过程中燃料使用的综合量化

• 批准号: 10637680
• 负责人: Zoltan P Arany
• 金额: $ 57.23万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2028-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10637680
• 关键词: Acute; Adipose tissue; Adult; Alanine; Animals; Biology; Blood; Body Temperature; Brown Fat; Burn injury; Calories; Carbohydrates; Carbon; Chronic; Citric Acid Cycle; Data; Development; Exposure to; Fasting; Fatty acid glycerol esters; Foundations; Gluconeogenesis; Glucose; Glutamine; Glycerol; Goals; Human; Individual; Infusion procedures; Investigation; Isotope Labeling; Ketones; Kinetics; Label; Liver; Mammals; Maps; Mass Spectrum Analysis; Measures; Metabolic; Metabolic Pathway; Mus; Nature; Obesity; Organ; Organism; Palmitates; Pathway interactions; Pharmacologic Substance; Play; Positioning Attribute; Process; Pyruvate; Role; Skeletal Muscle; Solid; Source; Techniques; Technology; Temperature; Testing; Therapeutic; Thermogenesis; Tissues; Work; awake; carboxylate; carboxylation; fatty acid oxidation; in vivo; metabolic abnormality assessment; metabolomics; oxidation; pyruvate dehydrogenase; recruit; sugar; therapeutic target; wasting

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.

概括 冷诱导产热 (CIT) 允许吸热动物（包括哺乳动物）将体温维持在 尽管有时环境温度要冷得多，但仍可达 37oC。 CIT 的药物激活正在进行中 许多团体将其作为肥胖症的潜在治疗方法进行研究。尽管经过数十年的调查 然而，CIT 期间如何燃烧不同的燃料、哪些组织仍然患病以及患病程度如何？ 定义的。我们在此建议对寒冷期间的全身代谢通量进行全面量化 小鼠暴露。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，允许 精确量化全身燃料周转率以及每种燃料对组织氧化的相对贡献 费率； (2) 急性动力学研究，以定量估计三羧酸循环周转率， 从而影响个体组织中的摄氧量 (VO2)。基于大量的初步数据，我们假设 CIT 很大程度上是 由脂肪储存提供能量，但它仍然严重依赖回补碳水化合物来源， 由肝脏提供，维持脂肪酸氧化。我们将有 3 个目标： 目标 1：全面量化小鼠 CIT 期间的全身燃料周转率。 目标 2：全面量化小鼠 CIT 期间各个组织的燃料使用情况。 目标 3：测试 CIT 期间碳水化合物通量在 BAT 中的作用。