Sexual dimorphism in obesity is governed by RELMα regulation of adipose macrophages and eosinophils.
Sexual dimorphism in obesity is governed by RELMα regulation of adipose macrophages and eosinophils.
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肥胖中的性别二态性由脂肪巨噬细胞和嗜酸性粒细胞的 RELMα 调节控制。
DOI：
10.1101/2023.01.13.523880
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发表时间：
2023
期刊：
影响因子：
--
通讯作者：
Nair,MeeraG
中科院分区：
文献类型：
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作者：
Li,Jiang;Ruggiero-Ruff,RebeccaE;He,Yuxin;Qiu,Xinru;Lainez,NancyM;Villa,PedroA;Godzik,Adam;Coss,Djurdjica;Nair,MeeraG
肥胖症的发病率在世界范围内不断增加，迫切需要找到新的治疗方法。免疫细胞活化的性别差异驱动肥胖介导的病理，其中男性更容易患肥胖合并症和炎症加重。在这里，我们证明了巨噬细胞分泌的蛋白质RELMα对高脂饮食（HFD）诱导的肥胖症的女性有重要的保护作用。与雄性小鼠相比，对照组和喂食HFD的雌性小鼠的血清RELMα水平均较高，且与脂肪巨噬细胞和嗜酸性粒细胞的频率相关。RELMα缺乏的雌性动物体重增加更多，脂肪基质血管部分（SVF）中有促炎性巨噬细胞蓄积和嗜酸性粒细胞损失，而RELMα治疗或嗜酸性粒细胞转移挽救了这种表型。对脂肪SVF进行单细胞RNA测序，并确定性别和RELMα依赖性变化。参与氧传感和铁稳态的基因，包括血红蛋白和lncRNA Gm 47283/Gm 21887，与肥胖增加相关，而嗜酸性粒细胞趋化性和对β淀粉样蛋白的反应具有保护作用。在RELMα缺陷动物中，单核细胞向巨噬细胞的转化也失调。总的来说，这些研究暗示RELMα-巨噬细胞-嗜酸性粒细胞轴在针对肥胖的性别特异性保护中，并揭示了肥胖的新治疗靶点。
Obesity incidence is increasing worldwide with the urgent need to identify new therapeutics. Sex differences in immune cell activation drive obesity-mediated pathologies where males are more susceptible to obesity comorbidities and exacerbated inflammation. Here, we demonstrate that the macrophage-secreted protein RELMα critically protects females against high-fat diet (HFD)-induced obesity. Compared to male mice, serum RELMα levels were higher in both control and HFD-fed females and correlated with frequency of adipose macrophages and eosinophils. RELMα-deficient females gained more weight and had proinflammatory macrophage accumulation and eosinophil loss in the adipose stromal vascular fraction (SVF), while RELMα treatment or eosinophil transfer rescued this phenotype. Single-cell RNA-sequencing of the adipose SVF was performed and identified sex and RELMα-dependent changes. Genes involved in oxygen sensing and iron homeostasis, including hemoglobin and lncRNA Gm47283/Gm21887, correlated with increased obesity, while eosinophil chemotaxis and response to amyloid-beta were protective. Monocyte-to-macrophage transition was also dysregulated in RELMα-deficient animals. Collectively, these studies implicate a RELMα–macrophage–eosinophil axis in sex-specific protection against obesity and uncover new therapeutic targets for obesity.