Department of Computational Medicine and Bioinformatics.
The Michigan Institute for Computational Discovery and Engineering.
JCI Insight. 2023 Oct 9;8(19):e171701. doi: 10.1172/jci.insight.171701.
Adipose tissue macrophage (ATM) infiltration is associated with adipose tissue dysfunction and insulin resistance in mice and humans. Recent single-cell data highlight increased ATM heterogeneity in obesity but do not provide a spatial context for ATM phenotype dynamics. We integrated single-cell RNA-Seq, spatial transcriptomics, and imaging of murine adipose tissue in a time course study of diet-induced obesity. Overall, proinflammatory immune cells were predominant in early obesity, whereas nonresident antiinflammatory ATMs predominated in chronic obesity. A subset of these antiinflammatory ATMs were transcriptomically intermediate between monocytes and mature lipid-associated macrophages (LAMs) and were consistent with a LAM precursor (pre-LAM). Pre-LAMs were spatially associated with early obesity crown-like structures (CLSs), which indicate adipose tissue dysfunction. Spatial data showed colocalization of ligand-receptor transcripts related to lipid signaling among monocytes, pre-LAMs, and LAMs, including Apoe, Lrp1, Lpl, and App. Pre-LAM expression of these ligands in early obesity suggested signaling to LAMs in the CLS microenvironment. Our results refine understanding of ATM diversity and provide insight into the dynamics of the LAM lineage during development of metabolic disease.
脂肪组织巨噬细胞（ATM）浸润与小鼠和人类的脂肪组织功能障碍和胰岛素抵抗有关。最近的单细胞数据强调了肥胖症中 ATM 异质性增加，但没有为 ATM 表型动力学提供空间背景。我们在饮食诱导肥胖的时间过程研究中整合了单细胞 RNA-Seq、空间转录组学和小鼠脂肪组织成像。总体而言，促炎免疫细胞在早期肥胖中占优势，而非驻留的抗炎 ATMs 在慢性肥胖中占优势。这些抗炎 ATMs 的一部分在转录组上介于单核细胞和成熟的脂质相关巨噬细胞（LAMs）之间，与 LAM 前体（pre-LAM）一致。pre-LAMs 与早期肥胖的冠状结构（CLS）在空间上相关，这表明脂肪组织功能障碍。空间数据显示，单核细胞、pre-LAMs 和 LAMs 之间与脂质信号相关的配体-受体转录物存在共定位，包括 Apoe、Lrp1、Lpl 和 App。pre-LAMs 在早期肥胖时表达这些配体，表明在 CLS 微环境中向 LAMs 发出信号。我们的研究结果细化了对 ATM 多样性的理解，并为代谢性疾病发展过程中 LAM 谱系的动态提供了深入了解。
