Novel thermoregulatory mechanisms in brown adipose tissue

棕色脂肪组织中的新型温度调节机制

• 批准号: RGPIN-2020-04468
• 负责人: Harper, MaryEllen
• 金额: $ 4.74万
• 依托单位: University of Ottawa
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=744321
• 关键词: Novel; thermoregulatory; mechanisms; brown; adipose

The overall goal of this DG research program has been to identify and understand the integrative biological processes controlling brown adipose tissue (BAT) thermogenesis, which is necessary for thermoregulation in small mammals and hibernators. We apply a wide range of physiological and biochemical approaches at the whole-body level, but also conduct mechanistic molecular studies in primary cells and cell lines. Some of our recent comparative biological studies have focused on naked mole rats, which have astonishing BAT characteristics. Our goal in the short and long terms is to continue to elucidate novel and physiologically important control mechanisms in BAT thermogenesis. While extensive research has examined mechanisms of BAT activation, little is known about how an animal turns off BAT, when it is disadvantageous or even life-threatening to waste the high levels of energy substrates and oxygen required by active BAT. Our research will improve understanding of the latter. The aims of the proposed research are: 1) "Switching off the heat" To elucidate novel mechanisms that shut-off BAT thermogenesis conserving energy and oxygen for adaptation and survival of animals; 2) "Metabolite control of BAT thermogenesis" To explore the impact of canonical and non-canonical metabolites driving or supporting BAT thermogenesis; and, 3) "Transgenerational environmental control of BAT" To examine possible implications of the effects of global warming on mammalian thermoregulation. In Aim 1, we hypothesize that there is selective degradation of UCP1 and other key mitochondrial proteins; mitophagy/autophagy; and stress granule formation when animals move from cold to warm, and normoxic to hypoxic environmental conditions. Studies will be conducted in three mouse strains, and in the naked mole rat. In Aim 2, we will explore the impact of canonical and non-canonical metabolites driving or supporting BAT thermogenesis. Using metabolomic approaches in parallel with high resolution respirometry, and standard biochemical analyses, we will test in BAT tissue explant preparations and isolated mitochondria, the importance of leucine and canonical substrates in controlling oxidative and ancillary processes in BAT. In Aim 3, we will elucidate effects of chronic high vs low environmental temperatures on BAT thermogenesis in mouse offspring. Paternal and maternal mechanisms as well as sex dimorphism in F1 and F2 offspring will be explored. Altogether, the proposed research will uncover novel aspects of BAT thermogenesis and its control, and thus improve our understanding of animal thermoregulatory physiology. The planned work will provide a comprehensive practical and theoretical training and mentorship for many bright junior scientists with an ongoing priority on equity, diversity and inclusion (EDI).

该 DG 研究计划的总体目标是识别和了解控制棕色脂肪组织 (BAT) 产热的综合生物过程，这对于小型哺乳动物和冬眠动物的体温调节是必需的。我们在全身水平上应用广泛的生理和生化方法，同时也在原代细胞和细胞系中进行机械分子研究。我们最近的一些比较生物学研究集中在裸鼹鼠，它们具有惊人的 BAT 特征。我们的短期和长期目标是继续阐明 BAT 产热过程中新颖且具有生理意义的重要控制机制。虽然大量研究已经检验了 BAT 激活的机制，但当浪费活性 BAT 所需的高水平能量底物和氧气是不利的甚至危及生命时，动物如何关闭 BAT 却知之甚少。我们的研究将增进对后者的理解。 拟议研究的目的是： 1) “关闭热量” 阐明关闭 BAT 生热作用的新机制，为动物的适应和生存保存能量和氧气； 2）“BAT生热作用的代谢控制”探索典型和非典型代谢物驱动或支持BAT生热作用的影响； 3)“BAT 的跨代环境控制”研究全球变暖对哺乳动物体温调节影响的可能影响。在目标 1 中，我们假设 UCP1 和其他关键线粒体蛋白存在选择性降解；线粒体自噬/自噬；当动物从寒冷到温暖、从正常含氧量到低氧环境条件时，应激颗粒的形成。研究将在三种小鼠品系和裸鼹鼠中进行。在目标 2 中，我们将探讨规范和非规范代谢物驱动或支持 BAT 生热作用的影响。使用代谢组学方法与高分辨率呼​​吸测定法和标准生化分析并行，我们将在 BAT 组织外植体制剂和分离的线粒体中测试亮氨酸和典型底物在控制 BAT 氧化和辅助过程中的重要性。在目标 3 中，我们将阐明长期高环境温度与低环境温度对小鼠后代 BAT 生热作用的影响。将探讨 F1 和 F2 后代的父本和母本机制以及性别二态性。 总而言之，拟议的研究将揭示 BAT 产热及其控制的新方面，从而提高我们对动物体温调节生理学的理解。计划中的工作将为许多聪明的初级科学家提供全面的实践和理论培训和指导，并持续优先考虑公平、多样性和包容性（EDI）。