The protein S100A4 as a novel marker of insulin resistance in prepubertal and pubertal children with obesity.
- 作者列表："Anguita-Ruiz A","Méndez-Gutiérrez A","Ruperez AI","Leis R","Bueno G","Gil M","Tofe I","Gomez-Llorente C","Moreno LA","Gil Á","Aguilera CM
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.
背景: 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失调的白色脂肪组织 (WAT) 和胰岛素抵抗 (IR) 的有希望的标志物。 目的: 我们旨在评估 S100A4 蛋白与儿童和青春期发育过程中肥胖和 IR 的相关性。 设计和方法: 研究设计由三个横断面人群组成，分别为 249 、 11 和 19 名青春期前儿童 (命名为研究人群 1 、 2 和 3), 和 53 个女孩经历性成熟的纵向人群 (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。所有研究人群均计算人体测量学、葡萄糖和脂质代谢、炎症和心血管生物标志物以及测量的 S100A4 血浆水平。研究人群 1 旨在作为阐明青春期前儿童肥胖-IR 与 S100A4 血浆水平关系的发现人群。横断面种群 2 和 3 进一步统计 WAT 基因表达数据，以调查该关联的分子基础。相反，纵向研究群体 4 在每个时间记录上提供了血液全基因组 DNA 甲基化数据，允许在青春期深入到 Obesity-IR-S1004 关系，以及破译改变 S100A4 血浆水平的合理表观遗传机制。 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。我们还发现青春期 S100A4 水平升高与 HOMA-IR 升高之间存在高度显著的正相关 (P = 0.0003，FDR = 0.005) 和胰岛素水平 (P = 0.0003，FDR = 0.005)。S100A4 区域 (cg07245635 和 cg10447638) 的两个增强子相关 CpG 位点的甲基化与青春期前阶段的 IR 生物标志物相关，并与这些测量值的纵向变化相关。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 评分之间的相关性，但与循环 S100A4 无关。 结论: 我们首次报道了 S100A4 与青春期前人群 IR 和 WAT 功能障碍的相关性，以及血浆 S100A4 水平的变化如何伴随青春期发育过程中儿童 IR 的纵向轨迹。此外，我们提出两个甲基化位点的表观遗传改变和 S100A4 vWAT 表达改变是肥胖这种紊乱的合理分子机制。
METHODS:BACKGROUND:Given the importance of habitual dietary protein intake, distribution patterns and dietary sources in the aetiology of age-related declines of muscle mass and function, the present study examined these factors as a function of sex and age in Irish adults aged 18-90 years comprising The National Adult Nutrition Survey (NANS). METHODS:In total, 1051 (males, n = 523; females, n = 528) undertook a 4-day semi-weighed food diary. Total, body mass relative intake and percentage contribution to total energy intake of dietary protein were determined in addition to protein distribution scores (PDS), as well as the contribution of food groups, animal- and plant-based foods to total protein intake. RESULTS:Total and relative protein intake [mean (SD)] were highest in those aged 18-35 years [96 (3) g day , 1.32 (0.40) g kg day ], with lower protein intakes with increasing age (i.e. in adults aged ≥65 years [82 (22) g, 1.15 (0.34) g kg day , P < 0.001 for both]. Differences in protein intake between age groups were more pronounced in males compared to females. Protein distribution followed a skewed pattern for all age groups [breakfast, 15 (10) g; lunch, 30 (15) g; dinner, 44 (17) g]. Animal-based foods were the dominant protein source within the diet [63% (11%) versus 37% (11%) plant protein, P < 0.001]. CONCLUSIONS:Protein intake and the number of meals reaching the purported threshold for maximising post-prandial anabolism were highest in young adults, and lower with increasing age. For main meals, breakfast provided the lowest quantity of protein across all age categories and may represent an opportunity for improving protein distribution, whereas, in older adults, increasing the number of meals reaching the anabolic threshold regardless of distribution pattern may be more appropriate.
METHODS:BACKGROUND:Low cardiorespiratory fitness (CRF) increases risk of all-cause mortality and cardiovascular events. Periodic CRF assessment can have an important preventive function. OBJECTIVE:To develop a protocol-free method to estimate CRF in daily life based on heart rate (HR) and body acceleration measurements. METHODS:Acceleration and HR data were collected from 37 subjects (M=49%) while performing a standardized laboratory activity protocol (sitting, walking, running, cycling) and during a 5-days free-living monitoring period. CRF was determined by oxygen uptake (VO2max) during maximal exercise testing. A doubly-labeled water validated equation was used to predict total energy expenditure (TEE) from acceleration data. A fitness index was defined as the ratio between TEE and HR (TEE-pulse). Activity recognition techniques were used to process acceleration features and classify sedentary, ambulatory and other activity types. Regression equations based on TEE-pulse data from each activity type were developed to predict VO2max. RESULTS:TEE-pulse measured within each activity type of the laboratory protocol was highly correlated to VO2max (r from 0.74 to 0.91). Averaging the outcome of each activity-type specific equation based on TEE-pulse from the laboratory data led to accurate estimates of VO2max (RMSE: 300.0 mlO2/min or 10%). The difference between laboratory and free-living determined TEE-pulse was 3.7 ± 11% (r =0.85). The prediction method preserved the prediction accuracy when applied to free-living data (RMSE: 367 mlO2/min or 12%). CONCLUSIONS:Measurements of body acceleration and HR can be used to predict VO2max in daily life. Activity-specific prediction equations are needed to achieve highly accurate estimates of CRF.
METHODS:OBJECTIVE:Postprandial dyslipidemia is a common feature of insulin resistant states and contributes to increased cardiovascular disease risk. Recently, bile acids have been recognized beyond their emulsification properties as important signaling molecules that promote energy expenditure, improve insulin sensitivity, and lower fasting lipemia. While bile acid receptors have become novel pharmaceutical targets, their effects on postprandial lipid metabolism remain unclear. Here we investigated the potential role of bile acids in regulation of postprandial chylomicron production and triglyceride excursion. Approach and Results: Healthy C57BL/6 mice were given an intraduodenal infusion of taurocholic acid (TA) under fat-loaded conditions and circulating lipids were measured. Targeting of bile acid receptors was achieved with GW4064, a synthetic agonist to the farnesoid X receptor (FXR), and with deoxycholic acid (DCA), an activator of the Takeda G-protein-coupled receptor 5. TA, GW4064, and DCA treatments all lowered postprandial lipemia. FXR agonism also reduced intestinal triglyceride content and activity of microsomal triglyceride transfer protein, involved in chylomicron assembly. Importantly, TA effects (but not DCA) were largely lost in FXR knockout mice. These bile acid effects are reminiscent of the anti-diabetic hormone glucagon-like peptide-1 (GLP-1). While the GLP-1 receptor agonist exendin-4 retained its ability to acutely lower postprandial lipemia during bile acid sequestration and FXR deficiency, it did raise hepatic expression of the rate limiting enzyme for bile acid synthesis. CONCLUSIONS:Bile acid signaling may be an important mechanism of controlling dietary lipid absorption and bile acid receptors may constitute novel targets for the treatment of postprandial dyslipidemia.