Cytokine Profiling in Pediatric Obesity

靶向PBMC生物能量学是一种强烈支持的调节炎症和预防炎症的策略。 从肥胖发展为2型糖尿病。我们的初步数据显示， 与儿童相比，不健康肥胖成人的静息PBMC，这并不奇怪，因为有证据表明， 与儿童相比，成人肥胖合并症的生理学存在根本差异。 肥胖胰岛素敏感和胰岛素抵抗患者PBMC生物能量学和细胞因子谱的比较 (IR)儿童，从肥胖儿童到肥胖成人的概况对于确定未来的终点至关重要。 对肥胖儿童病理性炎症的机制研究，并提出新的治疗靶点， 阻止儿童肥胖症中的炎性共病。我们假设，与胰岛素敏感性相比， 在儿童中，来自超重/肥胖IR儿童的刺激的PBMC将表现出改变的生物能量学（例如， 升高的糖酵解和/或减少的OXPHOS和FAO），并且它们将产生炎性特征， 与IS儿童和肥胖的IR/T2 D成人不同。在目标1中，我们将测试刺激诱导的假设， 基于肥胖和胰岛素敏感性的儿童PBMC生物能量学改变。我们 将利用从一项正在进行的研究中收集的血液样本， 呼吸，糖酵解和脂肪酸氧化PBMC之间的休息和刺激状态从30 儿童跨越BMI范围和胰岛素敏感性。我们还将进行RNA 对来自组群子集的配对的刺激和未刺激的PBMC样品进行测序。在目标2中， 我们将检验这一假设，即PBMC炎症谱根据肥胖区分儿童， 胰岛素敏感性BMI和胰岛素敏感性测量的偏最小二乘回归 来自30名儿童的PBMC的组合细胞因子谱将鉴定出那些最好地 根据肥胖和胰岛素敏感性来区分儿童。定义PBMC生物能量改变和 基于肥胖和胰岛素敏感性的儿童细胞因子谱将提供关键的初步数据， 完善机制研究，并确定特定的代谢途径作为新的治疗策略。

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.