The prevalence of obesity has increased globally over the past decades and has resulted in a significant increase in obesity-related diseases. Roughly 40% of US adults are obese, leading to a strong need to better understand the mechanisms of obesity and obesity-related diseases. Research from the Singer lab has shown that high-fat diet (HFD) in mice and patients induces the production of pro-inflammatory Ly6Chi monocytes and neutrophils that home to expanding adipose tissue to promote tissue and metabolic dysfunction that increase the risk for obesity-associated diseases like cancer, renal disease, atherosclerosis, and liver disease. Our lab also connected this increased myelopoiesis with biasing of the hematopoietic stem cell (HSC) pool in the bone marrow (BM) towards the myeloid lineage. The HSC pool is known to be critically reliant on specialized bone marrow stromal cells, known as the HSC niche, for proper regulation. The bone marrow neutrophil has also been shown to regulate the HSC niche in a manner that indirectly regulates the HSC pool. As obesity is associated with metainflammation, research has also suggested that the blocking of certain cytokines, like TNFa, ameliorate the negative effects of HFD. Therefore, we hypothesize that HFD-induced neutrophil expansion promotes the skewing of HSCs towards myelopoiesis through TNFa signaling via the HSC niche. In Aim 1, we will investigate the role of neutrophil expansion on the promotion of HSC skewing and obesity-induced metabolic disorder. Through the use of mouse models, we will evaluate the necessity and sufficiency of neutrophils exposed to HFD to skew the HSC pool towards myelopoiesis and promote metabolic dysfunction. Additionally, we will also determine the impact of neutrophil heterogeneity on HSC niche regulation and how this heterogeneity shifts under HFD. In Aim 2, we will explore the role of the pro-inflammatory cytokine, TNFa, as a key modulator of obesity-induced myelopoiesis by signaling through the HSC niche. As in Aim 1, we will use mouse models to determine the contribution of neutrophil-derived TNFa during obesity and elucidate the involvement of the HSC niche in promoting HSC biasing via TNFa. We will utilize flow cytometry to quantify changes to BM populations on HFD. We will use CLAMS and glucose and insulin tolerance testing for metabolic profiling. Completion of this proposal will expand our understanding of how obesity-induced inflammation drives changes in myelopoiesis.
|Program type||Postdoctoral Fellowship|
|Effective start/end date||01/01/2020 → 06/30/2022|