In humans, brown adipose tissue (BAT) undergoes progressive involution or atrophy with increasing age, as manifested by decreased prevalence and mass, transformation to white adipose tissue (WAT), and reduction in thermogenic activity. This involution process cannot be fully recapitulated in rodent models and thus underlying cellular mechanisms are poorly understood. Here, we show that the interscapular BAT (iBAT) in rabbits involutes rapidly in early life, similarly to that in humans. The transcriptomic remodeling and identity switch of mature adipocytes are accompanied with the loss of brown adipogenic competence of their precursor cells. Through single-cell RNA sequencing, we surveyed the heterogenous populations of mesenchymal cells within the stromal vascular fraction of rabbit and human iBAT. An analogous FSTL1high population of brown adipocyte progenitors exists in both species while gradually disappear during iBAT involution in rabbits. In mice, FSTL1 is highly expressed by adipocyte progenitors in iBAT and genetic deletion of FSTL1 causes defective WNT signaling and iBAT atrophy in neonates. Our results underscore the BAT-intrinsic contribution from FSTL1high progenitors to age-related tissue involution and point to a potential therapeutic approach for obesity and its comorbidities.

中文翻译：

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表达FSTL1的脂肪细胞祖细胞的丢失驱动与年龄相关的棕色脂肪组织的退化

在人类中，棕色脂肪组织（BAT）随着年龄的增长而进行性退化或萎缩，表现为患病率和体重降低，向白色脂肪组织（WAT）的转化以及生热活性的降低。在啮齿动物模型中不能完全概括这种对合过程，因此对潜在的细胞机制了解甚少。在这里，我们显示了兔子的肩inter间BAT（iBAT）在早期生活中迅速进化，与人类相似。成熟脂肪细胞的转录组重塑和身份转换伴随着其前体细胞棕色脂肪形成能力的丧失。通过单细胞RNA测序，我们调查了兔和人iBAT基质血管部分内的间充质细胞的异质群体。在两个物种中都存在类似的FSTL1高密度棕色脂肪细胞祖细胞，但在兔子的iBAT进化过程中逐渐消失。在小鼠中，FSTL1在iBAT中由脂肪细胞祖细胞高度表达，而FSTL1的基因缺失会导致新生儿的WNT信号缺陷和iBAT萎缩。我们的结果强调了FSTL1high祖细胞对年龄相关的组织退化的BAT内在贡献，并指出了肥胖症及其合并症的潜在治疗方法。