Li Yan, Zhang Houyu, Ibáñez Carlos F, Xie Meng
Chinese Institute for Brain Research, Zhongguancun Life Science Park, Beijing 102206, China; Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
Chinese Institute for Brain Research, Zhongguancun Life Science Park, Beijing 102206, China; School of Life Sciences, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Beijing 100871, China; PKU-IDG/McGovern Institute for Brain Research, Beijing 100871, China; Department of Neuroscience, Karolinska Institute, Stockholm 17165, Sweden.
Mol Metab. 2025 Mar;93:102105. doi: 10.1016/j.molmet.2025.102105. Epub 2025 Jan 28.
The capacity of mature adipocytes to de-differentiate into fibroblast-like cells has been demonstrated in vitro and a few, rather specific in vivo conditions. A detailed comparison between de-differentiated fat (DFAT) cells and adipose stem and progenitor cells (ASPCs) from different adipose depots is yet to be conducted. Moreover, whether de-differentiation of mature adipocytes from classical subcutaneous and visceral depots occurs under physiological conditions remains unknown.
Here, we used in vitro "ceiling culture", single cell/nucleus RNA sequencing, epigenetic anaysis and genetic lineage tracing to address these unknowns.
We show that in vitro-derived DFAT cells have lower adipogenic potential and distinct cellular composition compared to ASPCs. In addition, DFAT cells derived from adipocytes of inguinal origin have dramatically higher adipogenic potential than DFAT cells of the epididymal origin, due in part to enhanced NF-KB signaling in the former. We also show that high-fat diet (HFD) feeding enhances DFAT cell colony formation and re-differentiation into adipocytes, while switching from HFD to chow diet (CD) only reverses their re-differentiation. Moreover, HFD deposits epigenetic changes in DFAT cells and ASPCs that are not reversed after returning to CD. Finally, combining genetic lineage tracing and single cell/nucleus RNA sequencing, we demonstrate the existence of DFAT cells in inguinal and epididymal adipose depots in vivo, with transcriptomes resembling late-stage ASPCs.
These data uncover the cell type- and depot-specific properties of DFAT cells, as well as their plasticity in response to dietary intervention. This knowledge may shed light on their role in life style change-induced weight loss and regain.
成熟脂肪细胞去分化为成纤维细胞样细胞的能力已在体外及少数特定的体内条件下得到证实。然而，对于来自不同脂肪库的去分化脂肪（DFAT）细胞与脂肪干细胞及祖细胞（ASPCs）之间的详细比较尚未进行。此外，在生理条件下，经典皮下和内脏脂肪库中的成熟脂肪细胞是否会发生去分化仍不清楚。
在此，我们使用体外“悬滴培养”、单细胞/细胞核RNA测序、表观遗传学分析和基因谱系追踪来解决这些未知问题。
我们发现，与ASPCs相比，体外获得的DFAT细胞的成脂潜能较低，且细胞组成不同。此外，腹股沟来源的脂肪细胞衍生的DFAT细胞比附睾来源的DFAT细胞具有显著更高的成脂潜能，部分原因是前者的NF-κB信号增强。我们还表明，高脂饮食（HFD）喂养可增强DFAT细胞集落形成及再分化为脂肪细胞的能力，而从HFD转换为普通饮食（CD）只会逆转其再分化。此外，HFD会在DFAT细胞和ASPCs中沉积表观遗传变化，恢复到CD饮食后这些变化不会逆转。最后，结合基因谱系追踪和单细胞/细胞核RNA测序，我们证明了体内腹股沟和附睾脂肪库中存在DFAT细胞，其转录组类似于晚期ASPCs。
这些数据揭示了DFAT细胞的细胞类型和脂肪库特异性特性，以及它们对饮食干预的可塑性。这一知识可能有助于阐明它们在生活方式改变引起的体重减轻和恢复中的作用。
