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 过氧化物酶体执行许多与ROS和脂质代谢相关的关键功能，包括氧化非常 长链脂肪酸和醚脂的合成。过氧化物酶体作为高度可塑性的细胞器， 大小，形态，丰度和功能，取决于外部刺激。我们的初步研究表明 脂肪组织中过氧化物酶体的生物合成在对冷暴露的反应中增加， 在产热转录因子PRDM16上，与过氧化物酶体参与的可能性一致 在产热作用中。使用一种新的脂肪特异性过氧化物酶体缺乏症小鼠模型，我们发现， 过氧化物酶体对于棕色脂肪介导的产热是至关重要的， 组织与降低的能量消耗和增加的肥胖有关。通过追踪分子 通过过氧化物酶体调节脂肪组织产热的机制，我们的初步研究 涉及线粒体分裂中过氧化物酶体。作为动态细胞器，线粒体经历重复的循环 核裂变和核聚变。结合冷诱导的脂解刺激、线粒体分裂激活 被认为是能量消耗和产热功能的重要生理调节剂， 棕色脂肪我们的研究表明，过氧化物酶体的损失损害了冷诱导的线粒体分裂， 降低BAT中线粒体DNA的含量。 这些表型似乎与过氧化物酶体氧化极长链的能力受损无关。 脂肪酸或通过改变氧化还原状态的棕色脂肪细胞在过氧化物酶体的情况下。而我们 结果表明，过氧化物酶体能够合成一种称为缩醛磷脂的醚脂质， 机制缩醛磷脂存在于线粒体膜中，抑制它们的合成， 棕色脂肪细胞模拟阻断过氧化物酶体生物发生对线粒体形态的影响。这些 数据使我们假设过氧化物酶体通过引导 质膜素到线粒体以介导线粒体分裂。我们提出两个具体目标来检验这一点 假说.在目标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产热。第二个目的是研究过氧化物酶体的作用 脂质合成在线粒体功能、产热和代谢稳态中的作用， 缩醛磷脂合成的特异性失活。总之，这项工作将提供一个重要的机械洞察力 过氧化物酶体在脂肪组织产热中的作用。了解过氧化物酶体如何调节 线粒体分裂可能导致新的策略，利用棕色脂肪的产热功能， 治疗肥胖和糖尿病。