Sexual dimorphism in obesity is governed by RELM 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 RELM alpha critically protects females against high-fat diet (HFD)-induced obesity. Compared to male mice, serum RELM alpha levels were higher in both control and HFD-fed females and correlated with frequency of adipose macrophages and eosinophils. RELM alpha-deficient females gained more weight and had proinflammatory macrophage accumulation and eosinophil loss in the adipose stromal vascular fraction (SVF), while RELM alpha treatment or eosinophil transfer rescued this phenotype. Single-cell RNA-sequencing of the adipose SVF was performed and identified sex and RELM alpha-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 RELM alpha-deficient animals. Collectively, these studies implicate a RELM alpha-macrophage-eosinophil axis in sex-specific protection against obesity and uncover new therapeutic targets for obesity.