Cytokine Profiling in Pediatric Obesity

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Targeting PBMC bioenergetics is a strongly supported strategy for modulating inflammation and preventing progression from obesity to type 2 diabetes. Our preliminary data show metabolic differences between resting PBMCs in unhealthy obese adults compared to children, which is not surprising given evidence of fundamental differences in the physiology of obesity comorbidities in adults compared to children. Comparing PBMC bioenergetics and cytokine profiles of obese insulin sensitive (IS) and insulin resistant (IR) children, and profiles from obese children to obese adults is vital to define endpoints for future mechanistic studies on pathological inflammation in obese kids, and to suggest new therapeutic targets to halt inflammatory comorbidities in childhood obesity. We hypothesize that compared to insulin sensitive children, stimulated PBMCs from overweight/obese IR children will exhibit altered bioenergetics (e.g. elevated glycolysis and/or reduced OXPHOS and FAO), and they will produce inflammatory profiles that differ from both IS children and obese IR/T2D adults. In aim 1, we will test the hypothesis that stimulationinduced alterations in PBMCs bioenergetics change in children based on obesity and insulin sensitivity. We will leverage blood samples collected from an ongoing study and measure the difference mitochondrial respiration, glycolysis, and fatty acid oxidation PBMCs between resting and stimulated states from 30 children spanning the spectrum of BMI percentiles and insulin sensitivity. We will also conduct RNA sequencing on paired stimulated and unstimulated PBMC samples from a subset of the cohort. In aim 2, we will test the hypothesis that PBMC inflammatory profiles differentiate children based on obesity and insulin sensitivity. Partial least squares regressions of BMI and insulin sensitivity measures on combinatorial cytokine profiles of PBMCs from the 30 children will identify those cytokines that best distinguish children based on obesity and insulin sensitivity. Defining PBMC bioenergetic alterations and cytokine profiles in children based on obesity and insulin sensitivity will provide critical preliminary data to refine mechanistic studies and identify specific metabolic pathways to target as novel treatment strategies.