Obesity is an increasingly prevalent disease that affects 36% of adults and 16% of children and costs the United States (U.S.) healthcare system $150-$190 billion annually. Consequently, there is an urgent need to better understand the factors that regulate the development of obesity. Recent studies indicate that white adipose tissue (WAT)-resident immune cell populations critically regulate WAT homeostasis and produce cytokines that regulate systemic metabolic homeostasis and energy expenditure. This suggests that immune cells can contribute to the development of obesity and associated metabolic dysfunction. However, despite our growing understanding of the influence of inflammation on obesity, how the immune system regulates the development of obesity remains poorly defined. In preliminary studies I have identified a population of group 2 innate lymphoid cells (ILC2s) in human and murine WAT. This recently identified cell type lacks markers for a variety of well-described cell types such as T cells, B cells, dendritic cells, macrophages, natura killer cells and granulocytes and is therefore referred to as lineage-negative (Lin-) but does express CD90, CD25 and CD127 as well as the receptors for IL-33, IL-25 and thymic stromal lymphopoeitin (TSLP). Consistent with the properties of ILC2s in other tissue sites, I found that WAT ILC2s were developmentally dependent on the transcription factors Id2 and TCF-1. Further, this cell type responded to recombinant IL-33 in vivo and in vitro and produced the TH2 cell-associated effector cytokines IL-5 and IL-13, both of which are reported to regulate energy expenditure and metabolic homeostasis. My new data demonstrate that ILC2s are dysregulated in WAT of high fat diet (HFD)-fed obese mice compared to mice fed a control diet. Mice lacking IL-33, a cytokine that is essential for ILC2 function, exhibited more severe obesity. In contrast, exogenous IL-33 increased WAT ILC2s and decreased WAT mass. Collectively, my preliminary data provoke the hypothesis that the IL-33-WAT ILC2 axis negatively regulates obesity. This hypothesis forms the basis of my two aims.
In Aim 1, I will determine the phenotype of ILCs in human and murine WAT and investigate the developmental requirements and functional potential of murine WAT ILCs.
In Aim 2, I will test whether WAT ILC2s are sufficient to limit the development of obesity, investigate whether IL-33 negatively regulates obesity in an ILC2-dependent manner in mice, and compare WAT ILC2 frequencies in obese vs non- obese humans.
These aims will be addressed employing the intellectual and scientific resources available to me in the Artis lab, novel murine strains and ILC2-activating reagents, and a suite of metabolism and immunology core facilities at the University of Pennsylvania.
Obesity is one of the most significant public health problems in the US and is linked to the development of many illnesses such as type 2 diabetes, heart disease and cancer. Immune cells have been linked to the development of obesity. The proposed studies will investigate the role of a recently discovered immune cell population called the group 2 innate lymphoid cell (ILC2) in the regulation of obesity to aid in the identification o new pathways that could potentially be targeted therapeutically to prevent or treat obesity.
|Brestoff, Jonathan R; Artis, David (2015) Immune regulation of metabolic homeostasis in health and disease. Cell 161:146-60|
|Brestoff, Jonathan R; Kim, Brian S; Saenz, Steven A et al. (2015) Group 2 innate lymphoid cells promote beiging of white adipose tissue and limit obesity. Nature 519:242-6|
|Kim, Brian S; Wang, Kelvin; Siracusa, Mark C et al. (2014) Basophils promote innate lymphoid cell responses in inflamed skin. J Immunol 193:3717-25|