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

Abstract

Abstract 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. Funding Source NIGMS Topic Categories Immune Mechanisms of Human Disease (HUM)