Histone proteoform analysis reveals epigenetic changes in adult mouse brown adipose tissue in response to cold stress.

BACKGROUND: Regulation of the thermogenic response by brown adipose tissue (BAT) is an important component of energy homeostasis with implications for the treatment of obesity and diabetes. Our preliminary analyses of RNA-Seq data uncovered many nodes representing epigenetic modifiers that are altered in BAT in response to chronic thermogenic activation. Thus, we hypothesized that chronic thermogenic activation broadly alters epigenetic modifications of DNA and histones in BAT. RESULTS: Motivated to understand how BAT function is regulated epigenetically, we developed a novel method for the first-ever unbiased top-down proteomic quantitation of histone modifications in BAT and validated our results with a multi-omic approach. To test our hypothesis, wildtype male C57BL/6J mice were housed under chronic conditions of thermoneutral temperature (TN, 28°C), mild cold/room temperature (RT, 22°C), or severe cold (SC, 8°C) and BAT was analyzed for DNA methylation and histone modifications. Methylation of promoters and intragenic regions in genomic DNA decrease in response to chronic cold exposure. Integration of DNA methylation and RNA expression datasets suggest a role for epigenetic modification of DNA in regulation of gene expression in response to cold. In response to cold housing, we observe increased bulk acetylation of histones H3.2 and H4, increased histone H3.2 proteoforms with di- and trimethylation of lysine 9 (K9me2 and K9me3), and increased histone H4 proteoforms with acetylation of lysine 16 (K16ac) in BAT. CONCLUSIONS: Our results reveal global epigenetically-regulated transcriptional "on" and "off" signals in murine BAT in response to varying degrees of chronic cold stimuli and establish a novel methodology to quantitatively study histones in BAT, allowing for direct comparisons to decipher mechanistic changes during the thermogenic response. Additionally, we make histone PTM and proteoform quantitation, RNA splicing, RRBS, and transcriptional footprint datasets available as a resource for future research.

Histone proteoform analysis reveals epigenetic changes in adult mouse brown adipose tissue in response to cold stress.

Regulation of the thermogenic response by brown adipose tissue (BAT) is an important component of energy homeostasis with implications for the treatment of obesity and diabetes. Our preliminary analyses uncovered many nodes representing epigenetic modifiers that are altered in BAT in response to chronic thermogenic activation. Thus, we hypothesized that chronic thermogenic activation broadly alters epigenetic modifications of DNA and histones in BAT. Motivated to understand how BAT function is regulated epigenetically, we developed a novel method for the first-ever unbiased top-down proteomic quantitation of histone modifications in BAT and validated our results with a multi-omic approach. To test our hypothesis, wildtype male C57BL/6J mice were housed under chronic conditions of thermoneutral temperature (TN, 28.8°C), mild cold/room temperature (RT, 22°C), or severe cold (SC, 8°C) and BAT was analyzed for DNA methylation and histone modifications. Methylation of promoters and intragenic regions in genomic DNA decrease in response to chronic cold exposure. Integration of DNA methylation and RNA expression data suggest a role for epigenetic modification of DNA in gene regulation in response to cold. In response to cold housing, we observe increased bulk acetylation of histones H3.2 and H4, increased histone H3.2 proteoforms with di- and trimethylation of lysine 9 (K9me2 and K9me3), and increased histone H4 proteoforms with acetylation of lysine 16 (K16ac) in BAT. Taken together, our results reveal global epigenetically-regulated transcriptional "on" and "off" signals in murine BAT in response to varying degrees of chronic cold stimuli and establish a novel methodology to quantitatively study histones in BAT, allowing for direct comparisons to decipher mechanistic changes during the thermogenic response. Additionally, we make histone PTM and proteoform quantitation, RNA splicing, RRBS, and transcriptional footprint datasets available as a resource for future research.

Genetic variants in ALDH1L1 and GLDC influence the serine-to-glycine ratio in Hispanic children.

BACKGROUND: Glycine is a proteogenic amino acid that is required for numerous metabolic pathways, including purine, creatine, heme, and glutathione biosynthesis. Glycine formation from serine, catalyzed by serine hydroxy methyltransferase, is the major source of this amino acid in humans. Our previous studies in a mouse model have shown a crucial role for the 10-formyltetrahydrofolate dehydrogenase enzyme in serine-to-glycine conversion. OBJECTIVES: We sought to determine the genomic influence on the serine-glycine ratio in 803 Hispanic children from 319 families of the Viva La Familia cohort. METHODS: We performed a genome-wide association analysis for plasma serine, glycine, and the serine-glycine ratio in Sequential Oligogenic Linkage Analysis Routines while accounting for relationships among family members. RESULTS: All 3 parameters were significantly heritable (h2 = 0.22-0.78; P < 0.004). The strongest associations for the serine-glycine ratio were with single nucleotide polymorphisms (SNPs) in aldehyde dehydrogenase 1 family member L1 (ALDH1L1) and glycine decarboxylase (GLDC) and for glycine with GLDC (P < 3.5 × 10-8; effect sizes, 0.03-0.07). No significant associations were found for serine. We also conducted a targeted genetic analysis with ALDH1L1 exonic SNPs and found significant associations between the serine-glycine ratio and rs2886059 (ß = 0.68; SE, 0.25; P = 0.006) and rs3796191 (ß = 0.25; SE, 0.08; P = 0.003) and between glycine and rs3796191 (ß = -0.08; SE, 0.02; P = 0.0004). These exonic SNPs were further associated with metabolic disease risk factors, mainly adiposity measures (P < 0.006). Significant genetic and phenotypic correlations were found for glycine and the serine-glycine ratio with metabolic disease risk factors, including adiposity, insulin sensitivity, and inflammation-related phenotypes [estimate of genetic correlation = -0.37 to 0.35 (P < 0.03); estimate of phenotypic correlation = -0.19 to 0.13 (P < 0.006)]. The significant genetic correlations indicate shared genetic effects among glycine, the serine-glycine ratio, and adiposity and insulin sensitivity phenotypes. CONCLUSIONS: Our study suggests that ALDH1L1 and GLDC SNPs influence the serine-to-glycine ratio and metabolic disease risk.

COPB2 loss of function causes a coatopathy with osteoporosis and developmental delay.

Coatomer complexes function in the sorting and trafficking of proteins between subcellular organelles. Pathogenic variants in coatomer subunits or associated factors have been reported in multi-systemic disorders, i.e., coatopathies, that can affect the skeletal and central nervous systems. We have identified loss-of-function variants in COPB2, a component of the coatomer complex I (COPI), in individuals presenting with osteoporosis, fractures, and developmental delay of variable severity. Electron microscopy of COPB2-deficient subjects' fibroblasts showed dilated endoplasmic reticulum (ER) with granular material, prominent rough ER, and vacuoles, consistent with an intracellular trafficking defect. We studied the effect of COPB2 deficiency on collagen trafficking because of the critical role of collagen secretion in bone biology. COPB2 siRNA-treated fibroblasts showed delayed collagen secretion with retention of type I collagen in the ER and Golgi and altered distribution of Golgi markers. copb2-null zebrafish embryos showed retention of type II collagen, disorganization of the ER and Golgi, and early larval lethality. Copb2+/- mice exhibited low bone mass, and consistent with the findings in human cells and zebrafish, studies in Copb2+/- mouse fibroblasts suggest ER stress and a Golgi defect. Interestingly, ascorbic acid treatment partially rescued the zebrafish developmental phenotype and the cellular phenotype in Copb2+/- mouse fibroblasts. This work identifies a form of coatopathy due to COPB2 haploinsufficiency, explores a potential therapeutic approach for this disorder, and highlights the role of the COPI complex as a regulator of skeletal homeostasis.

Genetic variants and physical activity interact to affect bone density in Hispanic children.

BACKGROUND: Our aim was to investigate if moderate to vigorous physical activity (MVPA), calcium intake interacts with bone mineral density (BMD)-related single nucleotide polymorphisms (SNPs) to influence BMD in 750 Hispanic children (4-19y) of the cross-sectional Viva La Familia Study. METHODS: Physical activity and dietary intake were measured by accelerometers and multiple-pass 24 h dietary recalls, respectively. Total body and lumbar spine BMD were measured by dual energy X-ray absorptiometry. A polygenic risk score (PRS) was computed based on SNPs identified in published literature. Regression analysis was conducted with PRSs, MVPA and calcium intake with total body and lumbar spine BMD. RESULTS: We found evidence of statistically significant interaction effects between the PRS and MVPA on total body BMD and lumbar spine BMD (p < 0.05). Higher PRS was associated with a lower total body BMD (ß = - 0.040 ± 0.009, p = 1.1 × 10- 5) and lumbar spine BMD (ß = - 0.042 ± 0.013, p = 0.0016) in low MVPA group, as compared to high MVPA group (ß = - 0.015 ± 0.006, p = 0.02; ß = 0.008 ± 0.01, p = 0.4, respectively). DISCUSSION: The study indicated that calcium intake does not modify the relationship between genetic variants and BMD, while it implied physical activity interacts with genetic variants to affect BMD in Hispanic children. Due to limited sample size of our study, future research on gene by environment interaction on bone health and functional studies to provide biological insights are needed. CONCLUSIONS: Bone health in Hispanic children with high genetic risk for low BMD is benefitted more by MVPA than children with low genetic risk. Our results may be useful to predict disease risk and tailor dietary and physical activity advice delivery to people, especially children.

Genetic variants affecting bone mineral density and bone mineral content at multiple skeletal sites in Hispanic children.

CONTEXT: Osteoporosis is a major public health burden with significant economic costs. However, the correlates of bone health in Hispanic children are understudied. OBJECTIVE: We aimed to identify genetic variants associated with bone mineral density (BMD) and bone mineral content (BMC) at multiple skeletal sites in Hispanic children. METHODS: We conducted a cross-sectional genome-wide linkage analysis, genome-wide and exome-wide association analysis of BMD and BMC. The Viva La Familia Study is a family-based cohort with a total of 1030 Hispanic children (4-19 years old at baseline) conducted in Houston, TX. BMD and BMC were measured by Dual-energy X-ray absorptiometry. RESULTS: Significant heritability were observed for BMC and BMD at multiple skeletal sites ranging between 44 and 68% (P < 2.8 × 10-9). Significant evidence for linkage was found for BMD of pelvis and left leg on chromosome 7p14, lumbar spine on 20q13 and left rib on 6p21, and BMC of pelvis on chromosome 20q12 and total body on 14q22-23 (logarithm of odds score > 3). We found genome-wide significant association between BMC of right arm and rs762920 at PVALB (P = 4.6 × 10-8), and between pelvis BMD and rs7000615 at PTK2B (P = 7.4 × 10-8). Exome-wide association analysis revealed novel association of variants at MEGF10 and ABRAXAS2 with left arm and lumber spine BMC, respectively (P < 9 × 10-7). CONCLUSIONS: We identified novel loci associated with BMC and BMD in Hispanic children, with strongest evidence for PTK2B. These findings provide better understanding of bone genetics and shed light on biological mechanisms underlying BMD and BMC variation.

Genetic variation underlying renal uric acid excretion in Hispanic children: the Viva La Familia Study.

BACKGROUND: Reduced renal excretion of uric acid plays a significant role in the development of hyperuricemia and gout in adults. Hyperuricemia has been associated with chronic kidney disease and cardiovascular disease in children and adults. There are limited genome-wide association studies associating genetic polymorphisms with renal urate excretion measures. Therefore, we investigated the genetic factors that influence the excretion of uric acid and related indices in 768 Hispanic children of the Viva La Familia Study. METHODS: We performed a genome-wide association analysis for 24-h urinary excretion measures such as urinary uric acid/urinary creatinine ratio, uric acid clearance, fractional excretion of uric acid, and glomerular load of uric acid in SOLAR, while accounting for non-independence among family members. RESULTS: All renal urate excretion measures were significantly heritable (p <2 × 10-6) and ranged from 0.41 to 0.74. Empirical threshold for genome-wide significance was set at p <1 × 10-7. We observed a strong association (p < 8 × 10-8) of uric acid clearance with a single nucleotide polymorphism (SNP) in zinc finger protein 446 (ZNF446) (rs2033711 (A/G), MAF: 0.30). The minor allele (G) was associated with increased uric acid clearance. Also, we found suggestive associations of uric acid clearance with SNPs in ZNF324, ZNF584, and ZNF132 (in a 72 kb region of 19q13; p <1 × 10-6, MAFs: 0.28-0.31). CONCLUSION: For the first time, we showed the importance of 19q13 region in the regulation of renal urate excretion in Hispanic children. Our findings indicate differences in inherent genetic architecture and shared environmental risk factors between our cohort and other pediatric and adult populations.

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.

Energetic adaptations persist after bariatric surgery in severely obese adolescents.

OBJECTIVE: 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. METHODS: At baseline and at 1.5, 6, and 12 months post-baseline, 24-h room calorimetry, body composition, and fasting blood biochemistries were measured in 11 obese adolescents relative to five matched controls. RESULTS: In the RYGB group, mean weight loss was 44 ± 19 kg at 12 months. Total energy expenditure (TEE), activity EE, basal metabolic rate (BMR), sleep EE, and walking EE significantly declined by 1.5 months (P = 0.001) and remained suppressed at 6 and 12 months. Adjusted for age, sex, fat-free mass, and fat mass, EE was still lower than baseline (P = 0.001). Decreases in serum insulin, leptin, and triiodothyronine (T3), gut hormones, and urinary norepinephrine (NE) paralleled the decline in EE. Adjusted changes in TEE, BMR, and/or sleep EE were associated with decreases in insulin, homeostatic model assessment, leptin, thyroid stimulating hormone, total T3, peptide YY3-36, glucagon-like peptide-2, and urinary NE and epinephrine (P = 0.001-0.05). CONCLUSIONS: Energetic adaptations in response to RYGB-induced weight loss are associated with changes in insulin, adipokines, thyroid hormones, gut hormones, and sympathetic nervous system activity and persists 12 months postsurgery.

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.

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.

Body size, body composition, and metabolic profile explain higher energy expenditure in overweight children.

Lower relative rates of energy expenditure (EE), increased energetic efficiency, and altered fuel utilization purportedly associated with obesity have not been demonstrated indisputably in overweight children. We hypothesized that differences in energy metabolism between nonoverweight and overweight children are attributable to differences in body size and composition, circulating thyroid hormones, sympathetic nervous system, and adrenomedullary activity. A total of 836 Hispanic children, 5-19 y old, participated in 24-h calorimetry, anthropometric, and dual-energy X-ray absorptiometry measurements. Biochemistries were determined by standard techniques. Absolute total EE (TEE) and its components (sleep EE, basal EE, sedentary EE, cycling EE, walking EE, activity EE, nonexercising activity thermogenesis) were higher in overweight children (P = 0.001). Net mechanical energetic efficiency of cycling was lower in overweight children (P = 0.001). Adjusting for body size and composition accounted for differences in TEE, its components, and energetic efficiency. Net carbohydrate and fat utilization did not differ between groups. TEE was independently influenced by sex, Tanner stage, fat free mass, fat mass (FM), fasting serum nonesterified fatty acids (NEFA), leptin, free thyroxine, triiodothyronine, and 24-h urinary norepinephrine and epinephrine. Fat utilization was independently associated with age2, sex, FM, fasting serum NEFA, triacylglycerol, adiponectin, leptin, total thyroxine, and free triiodothyronine. Higher EE in overweight children was largely explained by differences in body size and composition, with minor contributions of thyroid and sympathoadrenal systems. Alterations in EE, energetic efficiency, and substrate utilization were not evident in the overweight 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.

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.

Genetic and environmental factors influencing fasting serum adiponectin in Hispanic children.

CONTEXT: Because of its antiinflammatory and insulin-sensitizing properties, adiponectin may play a role in the development of cardiovascular disease and type 2 diabetes. OBJECTIVES: The aims of these analyses were: 1) to estimate the heritability of fasting serum adiponectin; 2) to evaluate the effects of age, sex, and body composition on fasting serum adiponectin; 3) to test for associations between fasting serum adiponectin and diet, fitness, energy expenditure, and fat oxidation; and 4) to determine the relationships between fasting serum adiponectin, insulin and lipids, and blood pressure in Hispanic children. DESIGN: Genetic and environmental factors influencing fasting serum adiponectin were investigated in a cohort of children participating in the VIVA LA FAMILIA Study in 2000-2005. SETTING: This study was performed at the Children's Nutrition Research Center. PARTICIPANTS: The study participants were 805 Hispanic nonoverweight and overweight children, ages 4-19 yr. MAIN MEASURE: The main measure of the study was fasting serum adiponectin. RESULTS: The heritability of serum adiponectin was 0.93 +/- 0.10 (P = 2.4 x 10(-40)). Adiponectin differed by age (P = 0.001), sex (P = 0.04), and weight (P = 0.001) status. Adiponectin levels declined with age, in association with changes in sex hormones and growth factors. Adiponectin was not associated with macronutrient intake, fitness, 24-h energy expenditure, or fat oxidation. Controlling for age, sex, and percent fat mass, adiponectin was inversely associated with homeostasis model of insulin resistance, triglycerides (TG)/high-density lipoprotein cholesterol (HDL-C), and systolic blood pressure (P = 0.001). Significant positive genetic correlations were detected between adiponectin and total cholesterol (rho(G) = 0.19), HDL-C (rho(G) = 0.32), low-density lipoprotein cholesterol (rho(G) = 0.24), and IGF-binding protein-1 (rho(G) = 0.39), and negative genetic correlations were detected between adiponectin and leptin (rho(G) = -0.30), TG (rho(G) = -0.21), TG/HDL-C (rho(G) = -0.33), and IGF-binding protein-3 (rho(G) = -0.32), indicating shared genetic components in their expression. CONCLUSION: The high heritability of adiponectin and pleiotropy seen between adiponectin and leptin, growth factors, and lipids may play a role in the pathogenesis of cardiovascular disease and type 2 diabetes in overweight Hispanic children.

Energy requirements of women of reproductive age.

BACKGROUND: The energy requirements of women have been based on total energy expenditure (TEE) derived from the factorial approach or as multiples of basal metabolic rate (BMR). OBJECTIVE: This study was designed to reevaluate the energy requirements of healthy, moderately active underweight, normal-weight, and overweight women of reproductive age. DESIGN: The energy requirements of 116 women [n = 13 with a low body mass index (BMI), n = 70 with a normal BMI, and n = 33 with a high BMI] were estimated from TEE measured by the doubly labeled water method. Twenty-four-hour EE and BMR were measured by room respiration calorimetry, activity EE was estimated from nonbasal EE as TEE - BMR, and physical activity level was calculated as TEE/BMR. Body composition was derived from a multicomponent model. Fitness, strength, and physical activity level were assessed, and fasting serum indexes were measured. RESULTS: Energy requirements differed among the low-BMI (8.9 +/- 0.9 MJ/d), normal-BMI (10.1 +/- 1.4 MJ/d), and high-BMI (11.5 +/- 1.9 MJ/d) groups (P = 0.02-0.001, all pairwise comparisons). Major predictors of BMR, 24-h EE, and TEE were weight, height, and body composition; minor predictors were fasting metabolic profile and fitness. Fat-free mass and fat mass accounted for the differences in EE seen between the BMI groups. The mean physical activity level of 1.86 suggested that the multiples of BMR used to estimate energy requirements have been underestimated. CONCLUSION: Recommended energy intakes for healthy, moderately active women of reproductive age living in industrialized societies should be revised on the basis of TEE.