Obesity is a global problem and represents a significant health and economic burden. Recently 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. Cells of the immune system – macrophages, innate lymphoid cells and recently 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. The adipocytes were not responsible for this phenomenon so to test the involvement of adipose-resident immune cells, 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 also 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 vivomodels, which may lead to new therapeutic agents to drive beiging and combat obesity.