Abstract

Obesity is accompanied by low-grade systemic inflammation that etiologically contributes to obesity-induced cardiovascular disease (CVD). Growing evidence supports that neutrophil, the most abundant type of leukocytes in human, is most likely to be the target peripheral leukocyte subtype initiating the inflammatory cascade in obesity. However, few studies have systematically assessed the genome wide changes in neutrophils associated with obesity. In this study, a hypothesis-free OMIC approach (i.e. the discovery phase) and a target approach (i.e. the validation phase) were used to identify obesity related neutrophil activation markers and their roles on CVD risks. In the discovery phase, genome wide DNA methylation, RNA-sequencing and quantitative proteomics were obtained from purified neutrophils (12 obese vs. 12 lean). In the validation phase, gene expression levels of the promising genes from the OMIC platforms were measured in 81 obese cases vs. 83 lean controls, and the association between the expression levels and CVD risks were evaluated. Significant difference was found for one gene, alkaline phosphatase, liver/bone/kidney (ALPL), across 3 OMIC platforms. In the validation phase, the gene expression levels of ALPL in leukocytes were significantly higher in obese compared with lean subjects (p < 0.05). Within the obese population, we observed that ALPL expression level showed significantly positive association with CVD risk factors (p < 0.05) including systolic blood pressure, diastolic blood pressure, mean arterial pressure, carotid intima–media thickness and borderline significance with fasting insulin (p = 0.08). This study identified one novel marker ALPL of neutrophil activation in response to obesity and provided evidence that obesity induced change in ALPL expression was associated with CVD risk factors.

Highlights

  • While neutrophil depletion can reduce cardiometabolic abnormalities in mice fed on a high-fat diet, depleting neutrophils is clearly not a choice in humans

  • We conducted a series of hypothesis-free OMIC studies of the epigenomic, transcriptomic and proteomic changes in neutrophils, from which a potential target gene, ALPL, was found to be more activated in obese subjects

  • We further replicated the expression change of ALPL in obese status, and observed the up-regulated ALPL expression level associated with cardiovascular disease (CVD) risk factors

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Summary

Introduction

While neutrophil depletion can reduce cardiometabolic abnormalities in mice fed on a high-fat diet, depleting neutrophils is clearly not a choice in humans. In this regard, identification of obesity induced neutrophil activation markers serves as a prerequisite to develop targeted treatment. Our previous study pointed to the activation of innate immunity in obesity and especially the activation of neutrophils in obese African American (AA) males[14]. For this reason, the discovery phase was conducted in AA males. The current study provided convincing evidence that neutrophil alkaline phosphatase could serve as a novel marker of neutrophil activation in response to obesity and its related cardiometabolic risks

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