Adhesion-Related Macrophages Regulates Metabolic Homeostasis through CAV-1 Dependency

The significance of adipose tissue macrophages (ATMs) in regulating adipose tissue function is well-established. However, our investigation revealed a previously overlooked subpopulation of macrophages adhered to adipocytes, which we term adhesion-related macrophages (ARMs). We developed an approach to isolate ARMs and compared them with traditional macrophages from the stromal vascular fraction. Our findings demonstrate that ARMs constitute the predominant expanded subpopulation of adipose tissue macrophages during obesity, exhibiting heightened adhesion, proliferation, and lipid-processing capacities. Notably, ARMs can be characterized by a key functional marker, Caveolin-1. Genetic ablation of Caveolin-1 in immune cells significantly diminishes ARM abundance, disrupting their adhesion capacity and lipid content, leading to adipocyte hypertrophy, adipose tissue expansion, and impaired glucose homeostasis. Reintroducing ARMs from lean mice into eWAT mitigate obesity-induced adipose tissue inflammation and insulin resistance. Our studies uncover a previously unexplored macrophage subpopulation, ARMs, revealing potential therapeutic targets for obesity-induced insulin resistance and opening avenues for identifying similar paradigms in other tissues and diseases. To investigate the function of ARM, we collected ARM and SM from ewat in ND mice and HFD mice

脂肪组织巨噬细胞（adipose tissue macrophages, ATMs）在调控脂肪组织功能中的核心作用已得到学界广泛证实。然而，本研究发现了一类此前被忽视的、黏附于脂肪细胞表面的巨噬细胞亚群，我们将其命名为黏附相关巨噬细胞（adhesion-related macrophages, ARMs）。我们开发了一套分离ARMs的实验方法，并将其与基质血管组分（stromal vascular fraction）中获取的传统巨噬细胞进行了对照分析。研究结果表明，在肥胖状态下，ARMs是脂肪组织巨噬细胞中扩增最为显著的亚群，其黏附能力、增殖活性及脂质处理能力均显著增强。值得注意的是，ARMs可通过关键功能标志物窖蛋白-1（Caveolin-1）进行特征鉴定。在免疫细胞中敲除Caveolin-1可显著降低ARMs的丰度，破坏其黏附能力与脂质积累特性，进而引发脂肪细胞肥大、脂肪组织异常扩张及葡萄糖稳态失衡。将瘦小鼠来源的ARMs回输至附睾白色脂肪组织（epididymal white adipose tissue, eWAT）可有效缓解肥胖诱导的脂肪组织炎症与胰岛素抵抗。本研究揭示了一类此前未被报道的巨噬细胞亚群ARMs，为肥胖诱导的胰岛素抵抗找到了潜在治疗靶点，同时也为在其他组织与疾病中发掘类似的细胞调控范式开辟了全新研究路径。为探究ARMs的具体功能，我们从正常饮食（normal diet, ND）与高脂饮食（high-fat diet, HFD）小鼠的eWAT中分别分离得到ARMs与基质巨噬细胞（stromal macrophages, SM）。