Ucp1-independent functions in brown and beige adipocytes

摘要 解偶联蛋白1/Ucp1在棕色脂肪组织/BAT中的适应性产热是必需的 体温调节和能量平衡。人类棕色脂肪中不断增加的适应性产热作用 被认为是增加能量消耗并最终改善新陈代谢健康的替代战略， 因为随着年龄的增长和代谢性疾病，棕色脂肪的活性会逐渐下降。 我们之前的工作发现了一种独特的现象，棕色脂肪细胞特异的Lrpprc基因敲除小鼠可以 在蝙蝠体内权衡线粒体驱动的Ucp1依赖的产热作用，以换取全身代谢的健康。这 Proposal将使用这个新的鼠标模型来研究Ucp1独立的功能。目标1将调查 棕色脂肪细胞中ATF4驱动产热的潜在机制。目标2将决定 这一过程的生理调节。目标3将阐述其代谢对系统新陈代谢的贡献。 总的来说，这项提议将揭示棕色(和/或米色)脂肪细胞的新功能，而不是依赖于Ucp1 生热作用。

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.