Ucp1-independent functions in brown and beige adipocytes

棕色和米色脂肪细胞中独立于 Ucp1 的功能

• 批准号: 10532159
• 负责人: Biao Wang
• 金额: $ 57.71万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-12-01 至 2025-11-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10532159
• 关键词: Abbreviations; Ablation; Acids; Acute; Adipocytes; Adipose tissue; Aging; Brown Fat; Cell Nucleus; Cells; Defect; Diet; Dietary Proteins; Diphtheria Toxin; Energy Metabolism; Etiology; Exhibits; Family; Future; Genetic; Health; High Fat Diet; Homeostasis; Human; In Vitro; Investigation; Knock-out; Knockout Mice; Leigh Disease; Leucine; Lipids; Mass Spectrum Analysis; Mediating; Metabolic; Metabolic Diseases; Metabolic dysfunction; Metabolism; Mitochondria; Mitochondrial DNA; Molecular; Mus; Mutation; Physiologic Thermoregulation; Physiological; Process; Protein-Restricted Diet; Proteins; Proteome; RNA; Receptor Signaling; Regulation; Respiration; Role; Side; Stress Tests; Temperature; Therapeutic; Thermogenesis; Variant; Visualization; Work; beta-adrenergic receptor; cold stress; complex IV; conditional knockout; cytochrome c oxidase; energy balance; feeding; improved; in vivo; metabolic fitness; mouse model; novel; novel therapeutic intervention; obesity treatment; overexpression; programs; response; uncoupling protein 1; uptake

ABSTRACT Uncoupling protein 1/Ucp1-mediated adaptive thermogenesis in brown adipose tissue/BAT is essential for thermoregulation and energy balance. Increasing adaptive thermogenesis in human brown fat has been considered as an alternative strategy to increase energy expenditure, and ultimately to improve metabolic health, since brown fat activity gradually declines with aging and metabolic diseases. Our previous work identified a unique phenomenon that brown adipocyte-specific Lrpprc knockout mice can trade off mitochondria-fueled Ucp1-dependent thermogenesis in BAT for systemic metabolic fitness. This proposal will use this new mouse model to investigate Ucp1-independent functions. Aim 1 will investigate the underlying mechanisms of the ATF4-driven thermogenesis in brown adipocytes. Aim 2 will determine the physiological regulation of this process. Aim 3 will address its metabolic contributions to systemic metabolism. Collectively, this proposal will reveal novel functions of brown (and/or beige) adipocytes beyond Ucp1-dependent thermogenesis.

抽象的 棕色脂肪组织/蝙蝠中的解偶联蛋白1/UCP1介导的适应性热发生对于 温度调节和能量平衡。人类棕色脂肪中的适应性生热增加已经是 被认为是增加能源消耗的替代策略，并最终以改善代谢健康， 由于棕色脂肪活性随老化和代谢疾病而逐渐下降。 我们以前的工作确定了一种独特的现象，即棕色脂肪细胞特异性LRPPRC敲除小鼠可以 在BAT中以线粒体驱动的UCP1依赖性生热作用，以进行全身代谢适应性。这 提案将使用这种新的鼠标模型来研究无关紧要的函数。 AIM 1将调查 棕色脂肪细胞中ATF4驱动的热发生的基本机制。 AIM 2将确定 该过程的生理调节。 AIM 3将解决其对系统新陈代谢的代谢贡献。 总的来说，该建议将揭示棕色（和/或米色）脂肪细胞的新功能，而不是UCP1依赖性 热发生。