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
RELMa-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 RELMa-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.