ORF03-02 - A Comprehensive Approach to Evaluate Adolescent Metabolic Risk using New Obesity Definitions, Glucose Impairment and Meta-Inflammatory Monocyte Markers

Background:
The prevalence of obesity continues to rise in children and adolescents, with a corresponding increase in obesity-related complications. However, the risk of disease is not uniform across the BMI spectrum. Inflammatory monocytes and macrophages appear to be predictive of insulin resistance, especially in male animal models. We hypothesized that monocyte profiles may be able to identify those individuals at risk of cardiometabolic disease and further help with clinical interventions.
Study design:
14-18 years old, were recruited for a two-visit clinical study with an oral glucose tolerance test (OGTT) at visit 1 and a mixed-meal tolerance test (MMTT) at visit 2. Metabolic, dietary and anthropometric measurements were obtained during visits. Clinical obesity in these participants was defined by meeting at least one of several criteria relating to Relative Fat Mass, BMI percentile, waist circumference, or waist circumference-to-height percentile. Glucose impairment was defined by meeting one or several thresholds for hemoglobin A1c, fasting glucose, two-hour OGTT glucose, or HOMA-IR. Four risk categories were then identified based on clinical obesity (+/-) and glucose impairment (+/-) status. We performed monocyte evaluations following isolation and cell culture with lipopolysaccharide (LPS), palmitic acid, or oleic acid treatments compared to vehicle. To investigate inflammatory responses to MMTT, we conducted whole blood flow cytometry assessments and compared fasting with the 3 hour-MMTT timepoint. Group differences were assessed using ANOVA, with post-hoc pairwise comparisons adjusted using Tukey’s method.

Results:
Current analysis includes 48 adolescents. Vehicle and LPS stimulation significantly increased CD14+/CD16+ monocytes in individuals with both clinical obesity and glucose impairment compared to those with neither condition. Sex-stratified analyses showed that males with glucose impairment had higher CD16+ monocyte responses than females across all stimuli, and males with clinical obesity also had elevated CD16+ levels compared to females. Changes in lipid uptake (LipidTOX staining) in CD14+/CD16+ monocytes were significantly higher in participants with glucose impairment and clinical obesity relative to those with neither condition. Notably, in males with glucose impairment, 3h-post MMTT, lipid uptake was significantly higher in total monocytes and all population markers compared to females with glucose impairment. Additionally, lipid uptake in total monocytes were higher in males with clinical obesity versus females with clinical obesity.

Conclusions:
These findings demonstrate sex-specific monocyte responses in adolescents with obesity and glucose impairment, with monocyte activation markers providing potential indicators for metabolic disease risk for guiding targeted interventions.