Loss of FSTL1-expressing adipocyte progenitors drives the age-related involution of brown adipose tissue

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. HIGHLIGHTSO_LIRabbit BAT irreversibly transforms to WAT before puberty. C_LIO_LIiBAT adipocyte progenitors reprogram transcriptome and lose brown adipogenic ability. C_LIO_LIComparable FSTL1high brown adipocyte progenitors exist in rabbit and human iBAT. C_LIO_LILoss of FSTL1 in brown adipocyte progenitors causes iBAT atrophy in mice. C_LI