BACKGROUND S100A4 is a metastasis-associated protein also reported as a promising marker for dysfunctional white adipose tissue (WAT) and insulin resistance (IR) in adult and adolescent populations. OBJECTIVE We aimed to evaluate the association between the protein S100A4 and obesity and IR in children and during pubertal development. DESIGN AND METHODS The study design consisted of three cross-sectional populations of 249, 11 and 19 prepubertal children respectively (named study population 1, 2 and 3), and a longitudinal population of 53 girls undergoing sexual maturation (study population 4). All subjects were classified into experimental groups according to their sex, obesity and IR status. All study populations counted on anthropometry, glucose, and lipid metabolism, inflammation and cardiovascular biomarkers as well as S100A4 plasma levels measured. The study population 1 was intended as the discovery population in which to elucidate the relationship between Obesity-IR and S100A4 plasma levels in prepubertal children. The cross-sectional populations 2 and 3 further counted on WAT gene expression data for investigating the molecular basis of this association. Instead, the longitudinal study population 4 presented blood whole-genome DNA methylation data at each temporal record, allowing deepening into the Obesity-IR-S1004 relationship during puberty as well as deciphering plausible epigenetic mechanisms altering S100A4 plasma levels. RESULTS S100A4 plasma levels were strongly associated with several metabolic and anthropometric outcomes, namely IR, in prepubertal non-diabetic obese children. We also found highly significant positive associations during the course of puberty between the increase in S100A4 levels and the increase in HOMA-IR (P = 0.0003, FDR = 0.005) and insulin levels (P = 0.0003, FDR = 0.005). Methylation in two-enhancer related CpG sites of the S100A4 region (cg07245635 and cg10447638) was associated with IR biomarkers at the prepubertal stage and with longitudinal changes in these measurements. We further reported an association between visceral WAT (vWAT) S100A4 expression and HOMA-IR, insulin levels and BMI Z-Score, but not with circulating S100A4. CONCLUSIONS We report for the first time the association of S100A4 with IR and WAT dysfunction in prepubertal populations as well as how the change in plasma S100A4 levels accompanies longitudinal trajectories of IR in children during pubertal development. Moreover, we propose epigenetic changes in two methylation sites and an altered S100A4 vWAT expression as plausible molecular mechanisms underlying this disturbance in obesity.

中文翻译：

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蛋白质S100A4作为青春期前和青春期肥胖儿童胰岛素抵抗的新标记。

背景技术S100A4是一种转移相关蛋白，也被报道为成人和青少年人群中功能异常的白色脂肪组织（WAT）和胰岛素抵抗（IR）的有前途的标志物。目的我们旨在评估蛋白质S100A4与儿童和青春期发育过程中肥胖和IR的关系。设计与方法研究设计包括三个横断面人群，分别为249个，11个和19个青春期前儿童（分别称为研究人群1、2和3），以及一个纵向性交的53名经历性成熟的女孩（研究人群4）。根据性别，肥胖和IR状态将所有受试者分为实验组。所有研究人群均以人体测量学，葡萄糖和脂质代谢为基础，测量炎症和心血管生物标志物以及S100A4血浆水平。研究人群1旨在作为发现人群，用于阐明青春期前肥胖症IR与S100A4血浆水平之间的关系。横断面种群2和3进一步依靠WAT基因表达数据来研究这种关联的分子基础。相反，纵向研究人群4在每个时间记录处均显示了血液全基因组DNA甲基化数据，从而使青春期肥胖症与IR-S1004的关系更加深了，并揭示了可能的改变S100A4血浆水平的表观遗传机制。结果在青春期前非糖尿病肥胖儿童中，S100A4血浆水平与几种代谢和人体测量结果（即IR）密切相关。我们还发现，在青春期过程中，S100A4水平的升高与HOMA-IR的升高（P = 0.0003，FDR = 0.005）和胰岛素水平（P = 0.0003，FDR = 0.005）之间存在高度显着的正相关。S100A4区域的两个增强子相关CpG位点（cg07245635和cg10447638）中的甲基化与青春期前的IR生物标记物相关，并且与这些测量值的纵向变化有关。我们进一步报道了内脏WAT（vWAT）S100A4表达与HOMA-IR，胰岛素水平和BMI Z评分之间存在关联，但与循环S100A4无关。结论我们首次报道了青春期前S100A4与IR和WAT功能障碍的相关性，以及血浆S100A4水平的变化如何与儿童青春期IR的纵向轨迹相关。此外，