Dysregulated Myelopoiesis and Altered Neutrophil Metabolism in Obese Adults: A Role for Glutaminase in Hypoxia-Induced Cell Survival 2260130

Introduction Obesity is associated with myelopoietic dysfunction, metabolic abnormalities, and low-grade inflammation. This study investigated myeloid cell subpopulations and neutrophil behavior in obese versus non-obese adults, correlating findings with metabolic and inflammatory markers. Methods Blood was collected from obese (BMI 32-51 kg/m², n = 12) and normal weight (BMI 21-24 kg/m², n = 9) participants aged 45-65 years (76% female), excluding those with diabetes, acute infection, or overt kidney/liver disease. Complete blood counts, hemoglobin A1c (A1c), c-reactive protein (hs-CRP), and metabolic panels were performed. Myeloid cell populations were analyzed by flow cytometry, quantifying absolute numbers and surface expression of toll-like receptor 4 (TLR4) and interleukin-1 receptor (IL1R). Neutrophils were cultured under normoxia (18% O2) or hypoxia (1% O2), with/without metabolic inhibitors, to assess the impact of obesity on spontaneous neutrophil death. Results Obese participants exhibited increased monocytes associated with a higher percentage of HLA-DRlow monocytes. After excluding adults over 60 years, eosinophil counts and TLR4 expression on immature CD10- neutrophils were elevated in obese individuals, as was IL-1R expression on total and classical monocytes. Increased A1c (5.9±0.1% vs. 5.3±0.1%), hs-CRP (9.01±3.33 vs. 0.69±0.17 mg/L), and alkaline phosphatase were observed in obese participants. In vitro, hypoxia reduced neutrophil death in both groups; however, this effect was more pronouncedly blunted by glutaminase inhibition in neutrophils from obese participants. Conclusion This study demonstrates dysregulated myelopoiesis in obesity — characterized by altered IL-1R expression on monocytes, increased HLA-DRlow monocytes, and elevated TLR4 expression on immature neutrophils — alongside metabolic differences. Ex vivo neutrophil culture suggests an enhanced role for glutaminase in regulating neutrophil death under hypoxic conditions in obese individuals.