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Childhood obesity is considered one of the most serious public health problems of the 21st century. Obesity-associated inflammation could be one of the mechanisms that triggers insulin resistance that could drive systemic alterations such as metabolic disorder. Recently, circulating levels of S100A4 has been associated with insulin resistance and subcutaneuous white adipose tissue inflammation independently of body mass index (BMI) in a cohort of obese adults. Nonetheless, the link between S100A4 and insulin resistance in children is still not known yet. Thus, the aim of the study was to determine if S100A4 plasma levels were associated with insulin resistance status in a cohort of prepuberal children.
Material and methods:
In this case-control multicentre study, 250 prepuberal children took part and were stratified in six groups according to sex, obesity stage and insulin resistance status. Blood samples were withdrawn in resting conditions after an overnight fasting. Anthropometric measurements and a routine biochemical analyses were performed. Homeostasis model assessment for insulin resistance index (HOMA-IR) was calculated using fasting plasma glucose and insulin values. S100A4 plasma levels were determined by ELISA CSBEL02032HU (Cusabio Biotech, Wuhan, China).
A lineal multiple regresión (α = 0.05) identified a significative association between S100A4 plasma levels and HOMA-IR in the cohort; each HOMA-IR increasing unit correlated with an increase of 0.008mg/dL in S100A4 plasma levels. (SE = 0.003 and p = 0.02). Moreover, we also observed a positive significative association between S100A4 plasma levels and glucose blood levels (p = 0.005) and BMI (p = 0.008). Inter-group comparations analyses revealed significative differences between normal-weight and insulino-resistant obese boys (p = 0.024). The same result was obtained between normal-weight and insulino-resistant obese girls (p = 0.04), finding a higher S100A4 concentration in insulino- resistant children. As expected, plasma S100A4 levels were also higher in obese children versus normal-weight children (p = 0.02).
These data could be clinical relevant due to the possible potential of S100A4 protein as a new circulating biomarker of resistance insulin in a cohort of prepuberal children. These results are supported by other studies in obese adults and adolescents. In conclusion, these results suggest that S100A4 is associated with obesity and insulin resistance in prepuberal children. However, more studies are needed to study the implication and mechanism of this protein in the development of insulin resistance.
Childhood obesity is associated with multiple cardio-metabolic abnormalities. A sensitive hypothesis underlying these alterations is oxidative stress, shown to be present in obesity, often accompanied by a diminished antioxidant defense. Specifically, plasma vitamin concentrations have been observed to be associated with obesity in adults and children. However, their association with cardio-metabolic alterations in children is less clear.
Materials and Methods
985 children (49.2% males, 71.7% prepubertal, 71.9% excess weight) were recruited in a case-control study of obesity in three Spanish hospitals. Pubertal status was assessed and anthropometry (weight, height), systolic and diastolic blood pressure (SBP, DBP) and serum glucose, insulin, triacylglycerols (TAG) and high-density lipoprotein cholesterol (HDL-C) were measured. Plasma concentrations of tocopherols and carotenes were determined with HPLC-MS and referred to TAG. Children were classified as MU if showing one or more of these criteria: SBP or DBP ≥ 90th percentile (age, sex, height), serum TAG > 90th percentile (age, sex), HDL-C < 10th percentile (age, sex), glucose ≥ 100 mg/dL or elevated HOMA-IR (≥ 2.5 prepubertal, ≥ 3.38 pubertal males, ≥ 3.905 pubertal females). Non-fulfillment was indicative of MH status. General linear models adjusted for sex, age, recruitment center and BMI were used to evaluate differences in vitamins between MH and MU children.
Prepubertal and pubertal children with excess weight showed lower tocopherols (Pre: 0.133 ± 0.061 vs 0.165 ± 0.065, P < 0.001; Pub: 0.120 ± 0.057 vs 0.163 ± 0.066, P < 0.001) and carotenes (Pre: 15.63 ± 13.72 vs 30.31 ± 26.04, P < 0.001; Pub: 12.34 ± 9.86 vs 22.98 ± 19.25, P < 0.001) plasma concentrations than normal-weight children. MU prepubertal and pubertal children showed lower tocopherols (Pre: 0.120 ± 0.056 vs 0.165 ± 0.064, P < 0.001; Pub: 0.111 ± 0.051 vs 0.154 ± 0.066, P < 0.001) and carotenes (Pre: 14.07 ± 12.61 vs 25.97 ± 21.94, P < 0.001; Pub: 10.90 ± 8.54 vs 19.03 ± 14.58, P < 0.001) plasma concentrations than MH children, independently of BMI. Individual MU components analyses showed similar associations between tocopherols and carotenes and insulin resistance, low HDL-C values and hypertriglyceridemia in prepubertal children; and between tocopherols and carotenes and elevated SBP, hyperglycemia and hypertriglyceridemia in pubertal children.
Our findings agree with previous studies that showed decreased plasma concentrations of tocopherols and carotenes in children with obesity. However, we observe further implications of low circulating concentrations of non-enzymatic antioxidants in terms of their negative association with cardio-metabolic alterations such as insulin resistance and dyslipidemia in prepubertal and pubertal children, independently of BMI. These results must be considered when designing prevention and treatment strategies of obesity and its complications.
Hypertension is a public health problem and its prevalence in children is on the rise, often continuing into adulthood and increasing the risk related cardiovascular complications. Sleep plays an essential role in children's growth and several studies suggest that insufficient sleep duration is associated with hypertension in adults. However, few studies have evaluated this association in children. Thus, the aim of the study is to ascertain whether the sleep duration is a risk factor for elevated blood pressure (BP) in children.
We studied 776 children (5–18 years old), (46.7% male, 78.8% 5–13 years, 73.6% overweight/obesity). Weight and height were measured and body mass index (BMI) was calculated. BP was measured with an electronic manometer to find a 25.3% of children with an elevated systolic BP (SBP, > P90th) and 14% with an elevated diastolic BP (DBP, > P90th) (Task Force 2017). Sleep duration was assessed by asking the parents “¿How many hours does your child sleep in a typical weekday?”. Weekday sleep hours were considered since they are more representative of children's routines than weekend hours. Hours were converted into a dichotomous variable based on the fulfillment or not of the “Canadian 24-Hour Movement Guidelines for Children and Youth recommendations”: 9–11 hours for 5- to 13-year-olds; 8–10 hours for 14- to 17-year-olds.
A spearman correlation analysis was performed between sleep duration, SBP and DBP. Then, a general linear model analysis adjusted for BMI Z-score was done to evaluate differences in SBP and DBP between children following the sleep recommendations. Analyses were stratified by sex and age range (5–13 and 14–17).
In girls 5–13 years, we found a significant negative correlation between sleep duration and body mass index (BMI) (r = -0.226, p = 0.000) and between sleep and systolic BP (r = -0.188, p = 0.001). Girls 5–13 years not following sleep recommendations showed significantly higher SBP values than those who followed the recommendations (112 ± 11 mmHg vs. 106 ± 12 mmHg, p = 0.007), independently of BMI. No significant differences were observed in girls 14–17 years nor in males.
In the present study, we show that girls 5–13 years with shorter sleep duration show increased SBP values independently of BMI, in contrast to previous studies which showed similar associations that disappeared when adjusting for BMI. Our results support the need for wider strategies in population education so that sleep recommendations are followed by children in the general population.
Obesity is known to be associated with a low-grade inflammatory state. Most studies reporting inflammation in obesity have been done in pubertal children or adults or have focused only on the relation between body mass index (BMI) and the classical inflammatory markers. Nerve growth factor (NGF), monocyte chemoattractant protein–1 (MCP-1) and hepatocyte growth factor (HGF) are adipokines previously shown to be involved in the inflammatory context of obesity and metabolic syndrome but few studies have been conducted in children.
To evaluate the association between NGF, MCP-1, HGF with total and abdominal adiposity and in prepubertal and pubertal children.
889 children participated in a prospective obesity case-control study (50.2% males, 72% prepubertals, 27% overweight and 43% obesity), paired by age and sex. The relationship between total fat (assessed using the BMI, the sum of skinfolds thickness (SF) and fat mass index (FMI) from bioelectrical impedance analysis and waist circumference as a surrogate marker of abdominal obesity) and plasma concentrations of MCP-1, HGF, and NGF was studied in prepubertal and pubertal children.
Linear regression analysis for prepubertal and pubertal children, adjusting for age, sex and center was used.
NGF was associated with WC, with a stronger association in prepubertal than in pubertal children. MCP-1 was positively associated with WC, SF, FMI and BMI in pubertal children whereas HGF was positively associated with WC and BMI only in prepubertal children. The strongest associations were between WC and NGF (β 0.123 95%CI 0.133, 0.709; p < 0.001) in prepubertal children and WC and MCP-1 (β 0.123 95%CI 0.438, 2.035; p < 0.001) in pubertal children.
Total and abdominal adiposity are related to plasma concentrations of adipokines in prepubertal and pubertal children with obesity. Adipokines such as NGF, HGF and MCP-1 have not been so well studied so far in obese children. Particularly, NGF was associated with WC and BMI in prepubertal children and with WC in pubertal children. The association between this neurotrophin, secreted by adipose tissue and involved in the development and survival of sympathetic neurons, with adiposity, especially in prepubertal children, could suggest an anti-inflammatory mechanism and thus be a potential therapeutic target.
Insulin resistance (IR) is the major driver for the development of obesity-associated metabolic and cardiovascular complications. It is well known that IR increase physiologically during puberty; hence, pubertal maturation might favour this metabolic risk in obese children. Recently, a study carried out in adult women with obesity has identified a new adipokine, known as S100A4, strongly associated with IR and inflammation in adipose tissue. On the contrary, little is known about the implication of S100A4 in the development of such metabolic disturbances during the onset and course of pubertal development.
Materials and methods:
A longitudinal study was conducted on 53 Spanish girls distributed in six experimental conditions according to their obesity and IR status (before (T0) and after (T1) the onset of puberty). Anthropometric and biochemical parameters were evaluated in all samples and time points. Classification of pubertal stage was made according to the Tanner scale. S100A4 protein levels were quantified by ELISA CSB-EL02032HU in plasma samples (Cusabio Biotech, Wuhan, China). The statistical analysis of the results was carried out with the “nlme” package in R v3.4.4, using a mixed-effects linear model with random intercept and slope.
At a significance level of alpha = 0.05, a linear mixed-effects model reported a significant association (P = 0.03) between the interaction term “time*experimental group” and S100A4 levels. Post-hoc pairwise comparisons between experimental groups revealed a strong association between a worsening/improvement of the IR status and the increase/decrease of S100A4 levels (yielding significant results for 5 of the 15 comparisons (P = 0.008, P = 0.04, P = 0.02, P = 0.04 and P = 0.02)). Furthermore, a multiple linear regression model reported a positive correlation between the increase in S100A4 levels and the increase in HOMA values during the course of puberty (B = 6.03, SE = 2.66 and P = 0.028).
The S100A4 protein is strongly associated with the development of IR in girls with childhood obesity and this association is accentuated during pubertal development. Increase in S100A4 levels could be one of the molecular mechanisms by which pubertal maturation favour an increased metabolic risk in children with obesity.
Intra-uterine growth restriction (IUGR) may induce significant metabolic and inflammatory anomalies, increasing the risk of obesity and CVD later in life. Similarly, alterations in the adipose tissue may lead to metabolic changes in children with a history of extra-uterine growth restriction (EUGR). These mechanisms may induce alterations in immune response during early life. The aim of the present study was to compare pro-inflammatory markers in prepubertal EUGR children with those in a reference population. A total of thirty-eight prepubertal children with a history of EUGR and a reference group including 123 healthy age- and sex-matched children were selected. Perinatal data were examined. In the prepubertal stage, the concentrations of inflammatory biomarkers were measured in both groups. The serum concentrations of C-reactive protein (CRP) and plasma concentrations of hepatocyte growth factor (HGF), IL-6, IL-8, monocyte chemotactic protein type 1 (MCP-1), neural growth factor, TNF-α and plasminogen activator inhibitor type 1 were determined. The plasma concentrations of inflammatory biomarkers CRP, HGF, IL-8, MCP-1 and TNF-α were higher in the EUGR group than in the reference group (P< 0·001). After adjustment for gestational age, birth weight and length, blood pressure values and TNF-α concentrations remained higher in the EUGR group than in the reference group. Therefore, further investigations should be conducted in EUGR children to evaluate the potential negative impact of metabolic, nutritional and pro-inflammatory changes induced by the EUGR condition.
To evaluate the association between waist-to-height ratio (WHtR) and specific biomarkers of inflammation, CVD risk and endothelial dysfunction in prepubertal obese children.
Prospective, multicentre case–control study matched by age and sex.
Children were recruited between May 2007 and May 2010 from primary-care centres and schools in three cities in Spain (Cordoba, Santiago de Compostela and Zaragoza).
Four hundred and forty-six (223 normal weight and 223 obese) Caucasian prepubertal children aged 6–12 years.
WHtR was higher in the obese than in the normal-weight children. Blood pressure, waist circumference, weight, height, insulin, plasma lipids, leptin, resistin, abnormal neutrophil and monocyte counts, C-reactive protein, IL-6, IL-8, TNF-α, myeloperoxidase, soluble intercellular adhesion molecule-1, selectin and plasminogen activator inhibitor-1 levels were higher in the obese than in the normal-weight group. Adiponectin and HDL-cholesterol were lower and glucose and metalloproteinase-9 showed no differences. Resistin, TNF-α and active plasminogen activator inhibitor-1 were associated with WHtR, a sensitive indicator of central obesity.
Our results lead to the hypothesis that changes in biomarker levels of insulin resistance, inflammation and CVD risk before puberty might induce metabolic consequences of obesity in obese children before reaching adulthood.
White adipose tissue functions not only as an energy store but also as an important endocrine organ and is involved in the regulation of many pathological processes. The obese state is characterised by a low-grade systemic inflammation, mainly a result of increased adipocyte as well as fat resident- and recruited-macrophage activity. In the past few years, various products of adipose tissue including adipokines and cytokines have been characterised and a number of pathways linking adipose tissue metabolism with the immune system have been identified. In obesity, the pro- and anti-inflammatory effects of adipokines and cytokines through intracellular signalling pathways mainly involve the nuclear factor kappa B (NF-κB) and the Jun N-terminal kinase (JNK) systems as well as the I kappa B kinase beta (IKK-β). Mitogen-activated protein kinase (MAPK) and extracellular-signal-regulated kinase (ERK) pathways, which lead to signal transducer and activator of transcription 3 (STAT3) activation, are also important in the production of pro-inflammatory cytokines. Obesity increases the expression of leptin and other cytokines, as well as some macrophage and inflammatory markers, and decreases adiponectin expression in adipose tissue. A number of cytokines, e.g. tumour necrosis factor alpha (TNF-α) and monocyte chemotactic protein 1 (MCP-1), and some pro-inflammatory interleukins, leuckocyte antigens, chemochines, surface adhesion molecules and metalloproteases are up-regulated whereas other factors are down-regulated. The present paper will focus on the molecular mechanisms linking obesity and inflammation with emphasis on the alteration of signalling and gene expression in adipose cell components.
Regulation of energy homeostasis requires precise coordination between peripheral nutrient-sensing molecules and central regulatory networks. Ghrelin is a twenty-eight-amino acid orexigenic peptide acylated at the serine 3 position mainly with an n-octanoic acid, which is produced mainly in the stomach. It is the endogenous ligand of the growth hormone secretagogue (GHS) receptors. Since plasma ghrelin levels are strictly dependent on recent food intake, this hormone plays an essential role in appetite and meal initiation. In addition, ghrelin is involved in the regulation of energy homeostasis. The ghrelin gene is composed of four exons and three introns and renders a diversity of orexigenic peptides as well as des-acyl ghrelin and obestatin, which exhibit anorexigenic properties. Ghrelin stimulates the synthesis of neuropeptide Y (NPY) and agouti-related protein (AgRP) in the arcuate nucleus neurons of the hypothalamus and hindbrain, which in turn enhance food intake. Ghrelin-expressing neurons modulate the action of both orexigenic NPY/AgRP and anorexigenic pro-opiomelanocortin neurons. AMP-activated protein kinase is activated by ghrelin in the hypothalamus, which contributes to lower intracellular long-chain fatty acids, and this appears to be the molecular signal for the expression of NPY and AgRP. Recent data suggest that ghrelin has an important role in the regulation of leptin and insulin secretion and vice versa. The present paper updates the effects of ghrelin on the control of energy homeostasis and reviews the molecular mechanisms of ghrelin synthesis, as well as interaction with GHS receptors and signalling. Relationships with leptin and insulin in the regulation of energy homeostasis are addressed.
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