Nitesh R. Mehta

Risk for nonalcoholic fatty liver disease in hispanic youth with BMI ≥95th percentile

Objectives:To characterize children at risk for nonalcoholic fatty liver disease (NAFLD) and to explore possible mechanisms underlying the development of NAFLD in Hispanic youth with a body mass index ≥95th percentile. Patients and Methods:Hispanic nonoverweight (n = 475) and overweight (n = 517) children, ages 4 to 19 y, were characterized in terms of body composition (dual-energy x-ray absorptiometry), maturation (Tanner stage), diet (24-h recall), physical activity (accelerometry), fitness (maximal oxygen uptake), and biochemical profile (fasting alanine aminotransferase [ALT], glucose, insulin, and lipids; inflammation markers such as adiponectin, leptin, C-reactive protein, and soluble intercellular adhesion molecule-1; and total antioxidants) using standard laboratory techniques. Risk for NAFLD was defined by fasting serum ALT values >97.5th percentile for age- and sex-specific reference values. Results:Fasting serum ALT was elevated in 24% of overweight children and in only 4% of nonoverweight children. Therefore, to identify risk factors associated with elevated ALT, the remaining statistical analysis was restricted to the overweight group. The percentage of overweight children with elevated ALT did not differ by sex, age, or Tanner stage. Weight, body mass index, z score, waist-to-hip ratio, fat-free mass, fat mass, and percent truncal fat mass were higher in the overweight children with elevated ALT. Fasting insulin, glucose, and homeostasis model-insulin resistance were higher in the overweight children with elevated ALT, as were triglycerides, total cholesterol, low-density lipoprotein, thyroid-stimulating hormone, and triiodothyronine. Fasting serum leptin, C-reactive protein, and soluble intercellular adhesion molecule-1 were significantly higher and adiponectin was lower in the overweight children with elevated ALT. Conclusions:The risk for developing NAFLD was high in the overweight Hispanic children. The proportion of “at risk” children was not influenced by gender, age, or maturation. The risk for elevated ALT was predicted by the severity of obesity, central adiposity, hyperinsulinemia, hypertriglyceridemia, elevated thyroid-stimulating hormone, and systemic inflammation.

Quantitative Genetic Analysis of the Metabolic Syndrome in Hispanic Children

Childhood obesity is associated with a constellation of metabolic derangements including glucose intolerance, hypertension, and dyslipidemia, referred to as metabolic syndrome. The purpose of this study was to investigate genetic and environmental factors contributing to the metabolic syndrome in Hispanic children. Metabolic syndrome, defined as having three or more metabolic risk components, was determined in 1030 Hispanic children, ages 4–19 y, from 319 families enrolled in the VIVA LA FAMILIA study. Anthropometry, body composition by dual energy x-ray absorptiometry, clinical signs, and serum biochemistries were measured using standard techniques. Risk factor analysis and quantitative genetic analysis were performed. Of the overweight children, 20%, or 28% if abnormal liver function is included in the definition, presented with the metabolic syndrome. Odds ratios for the metabolic syndrome were significantly increased by body mass index z-score and fasting serum insulin; independent effects of sex, age, puberty, and body composition were not seen. Heritabilities ± SE for waist circumference, triglycerides (TG), HDL, systolic blood pressure (SBP), glucose, and alanine aminotransferase (ALT) were highly significant. Pleiotropy (a common set of genes affecting two traits) detected between SBP and waist circumference, SBP and glucose, HDL and waist circumference, ALT and waist circumference, and TG and ALT may underlie the clustering of the components of the metabolic syndrome. Significant heritabilities and pleiotropy seen for the components of the metabolic syndrome indicate a strong genetic contribution to the metabolic syndrome in overweight Hispanic children.

Global metabolomic profiling targeting childhood obesity in the Hispanic population

BACKGROUND Metabolomics may unravel important biological pathways involved in the pathophysiology of childhood obesity. OBJECTIVES We aimed to 1) identify metabolites that differ significantly between nonobese and obese Hispanic children; 2) collapse metabolites into principal components (PCs) associated with obesity and metabolic risk, specifically hyperinsulinemia, hypertriglyceridemia, hyperleptinemia, and hyperuricemia; and 3) identify metabolites associated with energy expenditure and fat oxidation. DESIGN This trial was a cross-sectional observational study of metabolomics by using gas chromatography-mass spectrometry and ultrahigh-performance liquid chromatography-tandem mass spectrometry analyses performed on fasting plasma samples from 353 nonobese and 450 obese Hispanic children. RESULTS Branched-chained amino acids (BCAAs) (Leu, Ile, and Val) and their catabolites, propionylcarnitine and butyrylcarnitine, were significantly elevated in obese children. Strikingly lower lysolipids and dicarboxylated fatty acids were seen in obese children. Steroid derivatives were markedly higher in obese children as were markers of inflammation and oxidative stress. PC6 (BCAAs and aromatic AAs) and PC10 (asparagine, glycine, and serine) made the largest contributions to body mass index, and PC10 and PC12 (acylcarnitines) made the largest contributions to adiposity. Metabolic risk factors and total energy expenditure were associated with PC6, PC9 (AA and tricarboxylic acid cycle metabolites), and PC10. Fat oxidation was inversely related to PC8 (lysolipids) and positively related to PC16 (acylcarnitines). CONCLUSIONS Global metabolomic profiling in nonobese and obese children replicates the increased BCAA and acylcarnitine catabolism and changes in nucleotides, lysolipids, and inflammation markers seen in obese adults; however, a strong signature of reduced fatty acid catabolism and increased steroid derivatives may be unique to obese children. Metabolic flexibility in fuel use observed in obese children may occur through the activation of alternative intermediary pathways. Insulin resistance, hyperleptinemia, hypertriglyceridemia, hyperuricemia, and oxidative stress and inflammation evident in obese children are associated with distinct metabolomic profiles.

Nutrient Accretion in Preterm Infants Fed Formula With Different Protein: Energy Ratios

BACKGROUND Although standard formulas for preterm infants promote intrauterine rates of weight gain, fat deposition in preterm infants fed these formulas has been reported to be considerably higher than that in the fetus. We hypothesized that a preterm infant formula with a higher protein:energy (P:E) ratio would promote accretion rates of fat, fat-free mass, and minerals closer to those of the fetus. METHODS As part of a larger study to determine whether accretion rates of fat and fat-free mass closer to those of the fetus can be achieved with a higher P:E ratio, we present a descriptive analysis of 72-h nutrient balance studies performed on a subset (n = 15/30) of the infants randomly assigned to be fed formula with a P:E ratio of either 3.2 g/100 kcal or 2.6 g/100 kcal. RESULTS Despite the higher intake and net absorption of nitrogen by infants fed the higher P:E formula, there was no statistically significant difference in net nitrogen retention between groups. There also were no statistically significant differences between groups in digestible energy, metabolizable energy, energy expenditure, or energy storage. Thus, partitioning of stored energy as protein and fat did not differ between groups. The retention of calcium, phosphorus, sodium, potassium, copper, and zinc also did not differ between groups, and nitrogen intake did not affect mineral retention. CONCLUSIONS In this study, formula for preterm infants with a P:E ratio of 3.2 g/100 kcal vs. 2.6 g/100 kcal provided no apparent benefit in terms of the proportion of fat to lean tissue accretion as determined from nutrient balance data.

Energetic adaptations persist after bariatric surgery in severely obese adolescents

Energetic adaptations induced by bariatric surgery have not been studied in adolescents or for extended periods postsurgery. Energetic, metabolic, and neuroendocrine responses to Roux‐en‐Y gastric bypass (RYGB) surgery were investigated in extremely obese adolescents.

A genetic contribution to circulating cytokines and obesity in children.

Cytokines are considered to be involved in obesity-related metabolic diseases. Study objectives are to determine the heritability of circulating cytokine levels, to investigate pleiotropy between cytokines and obesity traits, and to present genome scan results for cytokines in 1030 Hispanic children enrolled in VIVA LA FAMILIA Study. Cytokine phenotypes included monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-alpha), leptin, adiponectin, soluble intercellular adhesion molecule-1 (sICAM-1), transforming growth factor beta 1 (TGF-beta1), C-reactive protein (CRP), regulated upon activation, normal T-cell expressed and secreted (RANTES) and eotaxin. Obesity-related phenotypes included body mass index (BMI), fat mass (FM), truncal FM and fasting serum insulin. Heritabilities ranged from 0.33 to 0.97. Pleiotropy was observed between cytokines and obesity traits. Positive genetic correlations were seen between CRP, leptin, MCP-1 and obesity traits, and negative genetic correlations with adiponectin, ICAM-1 and TGF-beta1. Genome-wide scan of sICAM-1 mapped to chromosome 3 (LOD=3.74) between markers D3S1580 and D3S1601, which flanks the adiponectin gene (ADIPOQ). Suggestive linkage signals were found in other chromosomal regions for other cytokines. In summary, significant heritabilities for circulating cytokines, pleiotropy between cytokines and obesity traits, and linkage for sICAM-1 on chromosome 3q substantiate a genetic contribution to circulating cytokine levels in Hispanic children.

Serum uric acid concentrations and SLC2A9 genetic variation in Hispanic children: the Viva La Familia Study

BACKGROUND Elevated concentrations of serum uric acid are associated with increased risk of gout and renal and cardiovascular diseases. Genetic studies in adults have consistently identified associations of solute carrier family 2, member 9 (SLC2A9), polymorphisms with variation in serum uric acid. However, it is not known whether the association of serum uric acid with SLC2A9 polymorphisms manifests in children. OBJECTIVE The aim was to investigate whether variation in serum uric acid is under genetic influence and whether the association with SLC2A9 polymorphisms generalizes to Hispanic children of the Viva La Familia Study. DESIGN We conducted a genomewide association study with 1.1 million genetic markers in 815 children. RESULTS We found serum uric acid to be significantly heritable [h(2) ± SD = 0.45 ± 0.08, P = 5.8 × 10(-11)] and associated with SLC2A9 variants (P values between 10(-16) and 10(-7)). Several of the significantly associated polymorphisms were previously identified in studies in adults. We also found positive genetic correlations between serum uric acid and BMI z score (ρG = 0.45, P = 0.002), percentage of body fat (ρG = 0.28, P = 0.04), fat mass (ρG = 0.34, P = 0.02), waist circumference (ρG = 0.42, P = 0.003), and waist-to-height ratio (ρG = 0.46, P = 0.001). CONCLUSIONS Our results show that variation in serum uric acid in Hispanic children is under considerable genetic influence and is associated with obesity-related phenotypes. As in adults, genetic variation in SLC2A9 is associated with serum uric acid concentrations, an important biomarker of renal and cardiovascular disease risk, in Hispanic children.

Genome-wide scan for serum ghrelin detects linkage on chromosome 1p36 in Hispanic children: Results from the Viva La Familia study

This study was conducted to investigate genetic influence on serum ghrelin and its relationship with adiposity-related phenotypes in Hispanic children (n = 1030) from the Viva La Familia study (VFS). Anthropometric measurements and levels of serum ghrelin were estimated and genetic analyses conducted according to standard procedures. Mean age, body mass index (BMI), and serum ghrelin were 11 ± 0.13 y, 25 ± 0.24 kg/m2 and 38 ± 0.5 ng/mL, respectively. Significant heritabilities (p < 0.001) were obtained for BMI, weight, fat mass, percent fat, waist circumference, waist-to-height ratio, and ghrelin. Bivariate analyses of ghrelin with adiposity traits showed significant negative genetic correlations (p < 0.0001) with weight, BMI, fat mass, percent fat, waist circumference, and waist-to-height ratio. A genome-wide scan for ghrelin detected significant linkage on chromosome 1p36.2 between STR markers D1S2697 and D1S199 (LOD = 3.2). The same region on chromosome 1 was the site of linkage for insulin (LOD = 3.3), insulinlike growth factor binding protein 1 (IGFBP1) (LOD = 3.4), homeostatic model assessment method (HOMA) (LOD = 2.9), and C-peptide (LOD = 2.0). Several family-based studies have reported linkages for obesity-related phenotypes in the region of 1p36. These results indicate the importance of this region in relation to adiposity in children from the VFS.

Genome-wide association replicates the association of Duffy antigen receptor for chemokines (DARC) polymorphisms with serum monocyte chemoattractant protein-1 (MCP-1) levels in Hispanic children

Obesity is associated with a chronic low inflammatory state characterized by elevated levels of chemokines. Monocyte chemoattractant protein-1 (MCP-1) is a member of the cysteine-cysteine (CC) chemokine family and is increased in obesity. The purpose of this study was to identify loci regulating serum MCP-1 in obese Hispanic children from the Viva La Familia Study. A genome-wide association (GWA) analysis was performed in 815 children, ages 4-19 years, using genotypes assayed with the Illumina HumanOmni1-Quad v1.0 BeadChips. All analyses were performed in SOLAR using a linear regression-based test under an additive model of allelic effect, while accounting for the relatedness of family members via a kinship variance component. The strongest association for MCP-1 levels was found with a non-synonymous single nucleotide polymorphism (SNP), rs12075, resulting in an amino acid substitution (Asp42Gly) in the Duffy antigen receptor for chemokines (DARC) gene product (minor allele frequency=43.6%, p=1.3 × 10(-21)) on chromosome 1. Four other DARC SNPs were also significantly associated with MCP-1 levels (p<10(-16)-10(-6)). The Asp42Gly variant was associated with higher levels of MCP-1 and accounted for approximately 10% of its variability. In addition, MCP-1 levels were significantly associated with SNPs in chemokine receptor 3 (CCR3) and caspase recruitment domain family, member 9 (CARD9). In summary, the association of the DARC Asp42Gly variant with MCP-1 levels replicates previous GWA results substantiating a potential role for DARC in the regulation of pro-inflammatory cytokines.

Energy Requirements during First Two Years of Life Based on Measurements of Energy Expenditure and Growth

Energy Requirements during First Two Years of Life Based on Measurements of Energy Expenditure and Growth