biostudies-literatureLi JNICHD NIH HHSNIAID NIH HHSNational Institutes of HealthNIH HHSe86001https://www.ebi.ac.uk/biostudies/studies/S-EPMC10171862biostudies-literatureUnknown12Obesity 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-seLifeSexual dimorphism in obesity is governed by RELMα regulation of adipose macrophages and eosinophils.PMC10171862S10 OD026929R01 HD091167R01HD091167R01AI153195R01 AI153195Li JQiu XHe YGodzik ACoss DNair MGVilla PRuggiero-Ruff RELainez NfalseSexual dimorphism in obesity is governed by RELMα regulation of adipose macrophages and eosinophils.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-s2023-01-01T00:00:00Z2023 May2026-05-28T18:40:00.356Z2025-02-19T04:44:05.073ZS-EPMC101718623716219010.7554/eLife.86001