Novel thermoregulatory mechanisms in brown adipose tissue

这个DG研究项目的总体目标是确定和了解控制棕色脂肪组织（BAT）产热的综合生物过程，这是小型哺乳动物和冬眠动物体温调节所必需的。我们在全身水平上应用广泛的生理和生化方法，但也在原代细胞和细胞系中进行机制分子研究。我们最近的一些比较生物学研究集中在裸鼹鼠身上，它们具有惊人的BAT特征。我们短期和长期的目标是继续阐明BAT产热过程中新的和生理上重要的控制机制。虽然广泛的研究已经检查了BAT激活的机制，但对于动物如何关闭BAT，当浪费活性BAT所需的高水平能量底物和氧气是不利的，甚至是危及生命的时候，知之甚少。我们的研究将增进对后者的理解。本研究的目的是：1)“关闭热量”，阐明关闭BAT产热的新机制，为动物的适应和生存节省能量和氧气；2)“代谢物对BAT产热的控制”探讨规范代谢物和非规范代谢物驱动或支持BAT产热的影响；3)“BAT的跨代环境控制”研究全球变暖对哺乳动物体温调节的可能影响。在Aim 1中，我们假设存在UCP1和其他关键线粒体蛋白的选择性降解；mitophagy /自噬;当动物从寒冷到温暖，从常氧到缺氧的环境条件下，压力颗粒的形成。研究将在三种小鼠品系和裸鼹鼠身上进行。在Aim 2中，我们将探讨规范和非规范代谢物驱动或支持BAT产热的影响。利用代谢组学方法、高分辨率呼吸测量法和标准生化分析，我们将测试BAT组织外植体制备和分离的线粒体，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Aim 3中，我们将阐明慢性高温和低温对小鼠后代BAT产热的影响。本研究将探讨F1和F2后代的父系和母系机制以及性别二态性。总之，本研究将揭示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年轻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性、多样性和包容性（EDI）。

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).