Excessive iron accumulation in metabolic organs such as the adipose tissue, liver, and skeletal muscle is associated with increased diabetes risk. Tissue-resident macrophages serve multiple roles including managing inflammatory tone and regulating parachymal iron homeostasis; thus protecting against metabolic dysfunction upon iron overload. The scavenger receptor CD163 is uniquely present on tissue-resident macrophages, and plays a significant role in iron homeostasis by clearing extracellular hemoglobin-haptoglobin complexes, thereby limiting oxidative damage caused by free hemoglobin in metabolic tissues. We show that the absence of CD163 exacerbates glucose intolerance and insulin resistance in male mice with obesity. Additionally, loss of CD163 reduced the expression of iron regulatory genes (Tfr1, Cisd1, Slc40a1) in adipose tissue macrophages and anti-inflammatory (M2-like) bone marrow-derived macrophages (BMDMs). Further, CD163 deficiency mediated a pro-inflammatory shift and limited hemoglobin scavenging specifically in M2-like BMDMs. To this end, iron buffering was diminished in inguinal white adipose tissue (iWAT) macrophages in vivo, which culminated in iron spillover into adipocytes and CD45+CD11B− non-myeloid immune cells in iWAT. These findings show that CD163 on tissue-resident macrophages is critical for their anti-inflammatory and hemoglobin scavenging roles, and its absence results in impaired systemic insulin action in an obese setting.

中文翻译：

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血红蛋白-结合珠蛋白受体 CD163 的缺乏会恶化肥胖雄性小鼠的胰岛素敏感性


脂肪组织、肝脏和骨骼肌等代谢器官中铁的过度积累与糖尿病风险增加有关。组织驻留的巨噬细胞具有多种作用，包括管理炎症张力和调节副充质铁稳态;从而防止铁过载时的代谢功能障碍。清道夫受体 CD163 独特存在于组织驻留的巨噬细胞上，通过清除细胞外血红蛋白-结合珠蛋白复合物在铁稳态中发挥重要作用，从而限制代谢组织中游离血红蛋白引起的氧化损伤。我们表明，CD163 的缺失加剧了肥胖雄性小鼠的葡萄糖耐量异常和胰岛素抵抗。此外，CD163 的缺失降低了脂肪组织巨噬细胞和抗炎 （M2 样） 骨髓衍生巨噬细胞 （BMDM） 中铁调节基因 （Tfr1 、 Cisd1 、 Slc40a1） 的表达。此外，CD163 缺陷介导了促炎性转变和限制血红蛋白清除，特别是在 M2 样 BMDM 中。为此，体内腹股沟白色脂肪组织 （iWAT） 巨噬细胞中的铁缓冲减少，最终导致铁溢出到 iWAT 中的脂肪细胞和 CD45+CD11B− 非髓系免疫细胞中。这些发现表明，组织驻留巨噬细胞上的 CD163 对其抗炎和血红蛋白清除作用至关重要，而它的缺失会导致肥胖情况下全身胰岛素作用受损。