2025 Theses Doctoral

Bone Marrow Neutrophil Density Controls Myelopoiesis During Obesity and Weight Loss

Waterbury, Quin Thomas

Obesity is a state of chronic, sterile, and systemic inflammation that alters the body’s metabolic and endocrine functions. One hallmark of obesity-associated inflammation is an increase in the frequency of myeloid cells in the circulation. These myeloid cells accumulate in tissues such as the adipose tissue, where they disrupt the tissue’s normal function, leading to metabolic changes such as insulin resistance.

Weight loss is the main treatment for obesity, but there is evidence that metabolic inflammation persists after weight loss. The bone marrow (BM) is the site of immune cell production and is altered in obesity to promote myeloid cell generation, and these changes are refractory to weight loss, though the mechanisms driving these persistent changes remain unclear. Here, we show that obesity promotes myelopoiesis by altering the density of neutrophils in the BM. Endotoxemia is developed during obesity and promotes adipose tissue macrophages to recruit neutrophils from the BM in mice. Recruitment of BM neutrophils activates hematopoietic stem cells, which overproduce myeloid cells that accumulate in the circulation and drive inflammation.

This recruitment is not resolved by weight loss, leading to sustained myelopoiesis in previously obese mice. Inhibiting neutrophil recruitment out of the BM in obese mice or during weight loss reduces BM myelopoiesis, adipose tissue inflammation, and improves glucose tolerance. In humans with obesity, plasma neutrophil chemokines are increased, correlate with increased insulin resistance, but do not decrease with weight loss. These results demonstrate that neutrophil recruitment is a key mediator of myelopoiesis during obesity, and targeting this pathway is a potential strategy to improve inflammation during obesity and weight loss.