Department of Biochemistry and Molecular Biology II, School of Pharmacy, University of Granada, Spain; Institute of Nutrition and Food Technology "José Mataix", Center of Biomedical Research, University of Granada, Avda. del Conocimiento s/n. 18016 Armilla, Granada, Spain; Instituto de Investigación Biosanitaria ibs.GRANADA, 18012 Granada, Spain; CIBEROBN, (Physiopathology of Obesity and Nutrition CB12/03/30038), Institute of Health Carlos III (ISCIII), Madrid 28029, Spain.
CIBEROBN, (Physiopathology of Obesity and Nutrition CB12/03/30038), Institute of Health Carlos III (ISCIII), Madrid 28029, Spain; Growth, Exercise, Nutrition and Development (GENUD) Research Group, University of Zaragoza, Zaragoza, Spain; Instituto Agroalimentario de Aragón (IA2) and Instituto de Investigación Sanitaria de Aragón (IIS Aragón), Zaragoza, Spain.
Metabolism. 2020 Apr;105:154187. doi: 10.1016/j.metabol.2020.154187. Epub 2020 Feb 18.
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.
We aimed to evaluate the association between the protein S100A4 and obesity and IR in children and during pubertal development.
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.
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.
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.
S100A4 是一种与转移相关的蛋白质，也被报道为成人和青少年人群中功能失调的白色脂肪组织（WAT）和胰岛素抵抗（IR）的有前途的标志物。
我们旨在评估蛋白质 S100A4 与儿童肥胖和 IR 之间的关系，并在青春期发育过程中进行评估。
该研究设计包括三个分别有 249、11 和 19 名青春期前儿童的横断面人群（分别命名为研究人群 1、2 和 3），以及一个对 53 名正在经历性成熟的女孩进行的纵向人群（研究人群 4）。所有受试者根据其性别、肥胖和 IR 状况分为实验组。所有研究人群均进行了人体测量、血糖和脂质代谢、炎症和心血管生物标志物以及 S100A4 血浆水平的测量。研究人群 1 旨在作为发现人群，以阐明青春期前儿童肥胖与 IR 与 S100A4 血浆水平之间的关系。横断面人群 2 和 3 进一步计算了 WAT 基因表达数据，以研究这种关联的分子基础。相反，纵向研究人群 4 每个时间记录都有血液全基因组 DNA 甲基化数据，这使得深入了解青春期肥胖与 IR-S1004 之间的关系，并揭示改变 S100A4 血浆水平的潜在表观遗传机制。
S100A4 血浆水平与多种代谢和人体测量结果密切相关，即非糖尿病肥胖儿童的 IR。我们还发现，在青春期过程中，S100A4 水平的升高与 HOMA-IR（P=0.0003，FDR=0.005）和胰岛素水平（P=0.0003，FDR=0.005）的升高之间存在显著的正相关。S100A4 区域两个增强子相关 CpG 位点（cg07245635 和 cg10447638）的甲基化与青春期阶段的 IR 生物标志物以及这些测量的纵向变化相关。我们进一步报告了内脏 WAT（vWAT）S100A4 表达与 HOMA-IR、胰岛素水平和 BMI Z 评分之间的关联，但与循环 S100A4 无关。
我们首次报告了 S100A4 与青春期前人群中 IR 和 WAT 功能障碍的关联，以及在青春期发育过程中，S100A4 血浆水平的变化如何伴随儿童 IR 的纵向轨迹。此外，我们提出了两个甲基化位点的表观遗传变化和改变的 S100A4 vWAT 表达作为肥胖相关这种干扰的潜在分子机制。
