Sexual 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 co-morbidities and exacerbated inflammation. Here, we demonstrate that the macrophage-secreted protein RELM critically protects females against high fat diet-induced obesity. Compared to male mice, RELM levels were elevated in both control and high fat dietfed females and correlated with adipose macrophages and eosinophils. RELM-deficient females gained more weight and had pro-inflammatory macrophage accumulation and eosinophil loss, while both RELM treatment and eosinophil transfer rescued this phenotype. Single cell RNA-sequencing of the adipose stromal vascular fraction was performed and identified sex and RELM-dependent changes. Genes involved in oxygen sensing and iron homeostasis, including hemoglobin and lncRNA Gm47283, correlated with increased obesity, while eosinophil chemotaxis and response to amyloid-beta were protective. Monocyte-to-macrophage transition was also dysregulated in RELM-deficient animals. Collectively, these studies implicate a RELM-macrophage-eosinophil axis in sex-specific protection against obesity and uncover new therapeutic targets for obesity.