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。

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).