Obesity is a significant global health problem. A new category of brown fat-like cells, “beige” cells residing within white fat, have been identified. These cells burn fuels to generate heat and therefore may reduce obesity by burning rather than storing excess energy. Immune cells – including macrophages, innate lymphoid cells and eosinophils – appear to be essential in the “beiging” of white adipocytes.
Mice with a deletion in the gene encoding the transcription factor Kruppel-like Factor 3 (KLF3) are lean and are protected from diet-induced obesity. Interestingly, these mice show evidence of more beige fat and an increased capacity for thermogenesis. To test the involvement of adipose-resident immune cells in this process, we performed a bone marrow transplantation and were able to confer the lean beige phenotype on wild type mice. This suggested that KLF3 deficiency in haematopoietic lineages drives leanness in this mouse model. We interrogated different types of adipose-resident immune cells and discovered that there are three times as many eosinophils in KLF3-deficient adipose tissue.
We then performed genome-wide expression analyses on eosinophils isolated from white adipose tissue and uncovered widespread gene expression differences. This suggests that KLF3 is an important regulator of gene expression within eosinophils. Interestingly, we saw expression of a number of genes that encode secreted proteins known for their role in beiging. Our data suggest that eosinophils may contribute to beige fat activation by secreting these factors. We also detected expression of a number of novel secreted proteins in adipose tissue-derived eosinophils. We are now testing whether these novel secreted proteins are able to induce beiging and energy expenditure in cell culture and in vivo models, which may lead to new therapeutic agents to drive beiging and combat obesity. We are also exploring novel transcription factors that regulate gene expression in adipose-tissue eosinophils.