Dysregulated myelopoiesis and enhanced glutaminase-dependent neutrophil survival in preclinical obesity.

Obesity is increasingly recognized as a state of chronic low-grade inflammation associated with altered immune cell function, yet the mechanisms driving these changes remain incompletely understood. This study investigated myeloid cell subpopulations and neutrophil behavior in adult participants exhibiting preclinical obesity (body mass index [BMI] 32-51 kg/m2, n = 12) compared to normal-weight controls (BMI 21-24 kg/m2, n = 9), correlating findings with metabolic and inflammatory markers. Peripheral blood samples were analyzed by flow cytometry to quantify myeloid cell populations and TLR4/IL-1R surface expression. Neutrophils were cultured under normoxic (18% O2) or hypoxic (1% O2) conditions, with or without glutaminase inhibition, to assess spontaneous neutrophil death. Participants with preclinical obesity exhibited increased monocyte numbers and eosinophils, whereas total neutrophil numbers were not significantly different between groups, together with a higher percentage of HLA-DR-/low monocytes and activated immature (CD16-CD11b+CD10-) neutrophils. In participants under 60 yr of age, IL‑1R expression on monocytes was significantly increased in the obesity group. Significant metabolic differences were also noted, including higher 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 (102.33 ± 9.67 vs 65.75 ± 5.54 U/L) in the preclinical obesity cohort, alongside decreased mean cell hemoglobin. Ex vivo neutrophil culture revealed that hypoxia reduced spontaneous neutrophil death in both groups; however, this effect was significantly reduced by glutaminase inhibition specifically in neutrophils from participants with preclinical obesity, suggesting a heightened reliance on glutamine metabolism for survival under hypoxia. These findings demonstrate dysregulated myelopoiesis and altered neutrophil behavior in preclinical obesity, providing mechanistic insight into the early immune consequences of metabolic dysfunction.