TY - JOUR TI - Sexual dimorphism in obesity is governed by RELMα regulation of adipose macrophages and eosinophils AU - Li, Jiang AU - Ruggiero-Ruff, Rebecca E AU - He, Yuxin AU - Qiu, Xinru AU - Lainez, Nancy AU - Villa, Pedro AU - Godzik, Adam AU - Coss, Djurdjica AU - Nair, Meera G A2 - Benayoun, Bérénice A A2 - Melmed, Shlomo A2 - Ocanas, Sarah R VL - 12 PY - 2023 DA - 2023/05/10 SP - e86001 C1 - eLife 2023;12:e86001 DO - 10.7554/eLife.86001 UR - https://doi.org/10.7554/eLife.86001 AB - 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. KW - macrophage KW - eosinophil KW - obesity KW - sexual dimorphism KW - adipose KW - RELMα JF - eLife SN - 2050-084X PB - eLife Sciences Publications, Ltd ER -