Obesity incidence is increasing worldwide with the urgent need to identify new therapeutics. Increased adiposity is associated with chronic inflammation, which can exacerbate a number of obesity-associated diseases, including COVID-19 infection and allergic disease. There are profound sex differences in immune cell activation driving obesity-mediated pathologies. However, there remain critical gaps in knowledge on the immune mechanisms underlying obesity, and whether they are sexually dimorphic. Preliminary data generated from transgenic mice, adoptive immune cell transfer, and adipose single cell sequencing uncovered a new RELMα-eosinophil-macrophage axis that is female-specific and protective in obesity and associated inflammation. Transcriptomic profiling of the adipose macrophages identified novel sex-specific and RELMα-dependent genes such as chemokines, hemoglobins and a long non- coding RNA (lncRNA) as new molecular candidates to treat obesity. Based on these findings, the overarching goal of this study is to investigate sexual dimorphism in innate immune cell crosstalk in obesity, from how gonadal hormones direct macrophage-eosinophil interaction (Aim 1) to determining downstream effectors in macrophages, such as hemoglobins and lncRNA, and their mechanisms of action associated with oxidative stress in the obese adipose tissues (Aim 2). Strengths of the proposed study include the multidisciplinary nature of the experimental design, which combines the co-PIs expertise in reproductive endocrinology and innate immunity, and the public health impact of investigating the understudied area of sex differences and how they may guide more specific treatments for obesity and associated risks for infection and allergic disease.