Metabolic Link Between Peroxisomes and Mitochondria in the Regulation of Thermogenesis

过氧化物酶体和线粒体在产热调节中的代谢联系

• 批准号: 9903325
• 负责人: Irfan J Lodhi
• 金额: $ 39.34万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9903325
• 关键词: Adipocytes; Adipose tissue; Affect; Biogenesis; Brown Fat; Data; Diabetes Mellitus; Diet; Dietary Supplementation; Dynamin; Energy Metabolism; Ethers; Guanosine Triphosphate Phosphohydrolases; Homeostasis; Impairment; Insulin Resistance; Knock-out; Lead; Link; Lipids; Lipolysis; Mediating; Metabolic; Metabolic Diseases; Mitochondria; Mitochondrial DNA; Molecular; Morphology; Mus; Obesity; Organelles; Outer Mitochondrial Membrane; Oxidation-Reduction; Oxides; Phenotype; Phospholipids; Physiological; Plasmalogens; Ploidies; Proteins; Public Health; Regulation; Role; Stable Isotope Labeling; Stimulus; Testing; Thermogenesis; Very Long Chain Fatty Acid; Work; base; insight; lipid metabolism; mitochondrial membrane; mouse model; novel strategies; novel therapeutic intervention; obesity treatment; oxidation; peroxisome; recruit; response; transcription factor; two photon microscopy

Project summary Peroxisomes carry out many key functions related to ROS and lipid metabolism, including oxidation of very long chain fatty acids and synthesis of ether lipids. As highly plastic organelles, peroxisomes can modify their size, morphology, abundance, and function, depending on external stimuli. Our preliminary studies suggest that peroxisomal biogenesis increases in adipose tissue in response to cold exposure, in a manner dependent on the thermogenic transcription factor PRDM16, consistent with the possibility that peroxisomes are involved in thermogenesis. Using a new mouse model of adipose-specific peroxisome deficiency, we discovered that peroxisomes are critical for brown fat-mediated thermogenesis and that the loss of peroxisomes in adipose tissue is associated with decreased energy expenditure and increased adiposity. By pursuing the molecular mechanism through which peroxisomes regulate adipose tissue thermogenesis, our preliminary studies implicate peroxisomes in mitochondrial division. As dynamic organelles, mitochondria undergo repeated cycles of fission and fusion. Combined with the cold-induced stimulation of lipolysis, activation of mitochondrial fission is thought to serve as a critical physiological regulator of energy expenditure and thermogenic function of brown fat. Our studies suggest that the loss of peroxisomes impairs cold-induced mitochondrial fission and decreases mitochondrial DNA content in BAT. These phenotypes do not appear to be related to impaired ability of peroxisomes to oxidize very long chain fatty acids or through an altered redox state in brown adipocytes in the absence of peroxisomes. Instead, our results implicate the ability of peroxisomes to synthesize a type of ether lipids called plasmalogens in the mechanism. Plasmalogens are present in the mitochondrial membrane and inhibition of their synthesis in brown adipocytes mimics the effect of blocking peroxisomal biogenesis on mitochondrial morphology. These data lead us to hypothesize that peroxisomes regulate adipose tissue thermogenesis by channeling plasmalogens to mitochondria to mediate mitochondrial fission. We propose two specific aims to test this hypothesis. In Aim 1, we will elucidate the molecular mechanism through which peroxisomes regulate mitochondrial dynamics and adipose tissue thermogenesis. The second Aim will study the role of peroxisomal lipid synthesis in mitochondrial function, thermogenesis, and metabolic homeostasis using mice with adipose- specific inactivation of plasmalogen synthesis. Together, this work will provide a significant mechanistic insight into the role of peroxisomes in adipose tissue thermogenesis. Understanding how peroxisomes regulate mitochondrial fission could lead to novel strategies to exploit the thermogenic function of brown fat for treatment of obesity and diabetes.

项目摘要 过氧化物酶体执行与ROS和脂质代谢有关的许多关键功能，包括非常氧化 长链脂肪酸和醚脂质的合成。作为高度塑料细胞器，过氧化物酶体可以修改其 大小，形态，丰度和功能，具体取决于外部刺激。我们的初步研究表明 过氧化物酶体生物发生因冷暴露而增加脂肪组织的增加，以某种方式取决于 在热转录因子PRDM16上，与过氧化物酶体涉及的可能性一致 在热发生中。使用新的脂肪特异性过氧化物酶体缺乏的鼠标模型，我们发现 过氧化物酶体对于棕色脂肪介导的热发生至关重要，并且脂肪中过氧化物酶体的丧失 组织与能量消耗降低和肥胖增加有关。通过追求分子 过氧化物酶体调节脂肪组织热发生的机制，我们的初步研究 暗示线粒体分裂中的过氧化物酶体。作为动态细胞器，线粒体发生重复的周期 裂变和融合。结合冷诱导的脂解的刺激，线粒体裂变的激活 被认为是能量消耗和热功能的关键生理调节剂 棕色脂肪。我们的研究表明，过氧化物酶体的丧失会损害冷诱导的线粒体裂变和 降低BAT中的线粒体DNA含量。 这些表型似乎与过氧化物酶体氧化非常长链的能力受损无关。 在没有过氧化物酶体的情况下，脂肪酸或通过棕色脂肪细胞中的氧化还原状态改变。相反，我们的 结果暗示了过氧化物酶体合成一种称为浆元的醚脂质的能力 机制。线粒体膜中存在浆元，并抑制其合成 棕色脂肪细胞模仿阻断过氧化物酶体生物发生对线粒体形态的影响。这些 数据导致我们假设过氧化物酶体通过引导调节脂肪组织热发生 血浆元至线粒体介导线粒体裂变。我们提出了两个特定的目标来测试这一点 假设。在AIM 1中，我们将阐明过氧化物酶体调节的分子机制 线粒体动力学和脂肪组织热发生。第二个目标将研究过氧化物酶体的作用 使用脂肪的小鼠，线粒体功能，热生成和代谢稳态中的脂质合成 浆合成的特异性失活。这项工作将共同提供重要的机械洞察力 进入过氧化物酶体在脂肪组织热发生中的作用。了解过氧化物酶体如何调节 线粒体裂变可能会导致利用棕色脂肪的热功能的新策略 治疗肥胖和糖尿病。