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Objectives: To estimate the cost and cost-effectiveness of Bright Bodies, a high-intensity, family-based intervention that has been demonstrated to improve body mass index (BMI) among children with obesity in a randomized controlled trial., Methods: We developed a microsimulation model to project 10-year BMI trajectories of 8 to 16-year-old children with obesity, using data from the National Longitudinal Surveys and Centers for Disease Control and Prevention growth charts, and we validated the model using data from the Bright Bodies trial and a follow-up study. We used the trial data to estimate the average reduction in BMI per person-year over 10 years and the incremental costs of Bright Bodies, compared with the traditional clinical weight management (control), from a health system's perspective in 2020 US dollars. Using results from studies of Medical Expenditure Panel Survey data, we projected the long-term obesity-related medical expenditure., Results: In the primary analysis, assuming depreciating effects postintervention, Bright Bodies is expected to reduce a participant's BMI by 1.67 kg/m 2 (95% uncertainty interval 1.43-1.94) per year over 10 years as compared with control. The incremental intervention cost of Bright Bodies was $360 ($292-$421) per person compared with the clinical control. Nevertheless, savings in obesity-related healthcare expenditure offset these costs and the expected cost-savings of Bright Bodies is $1126 ($689-$1693) per person over 10-years. The projected time to achieve cost-savings compared with clinical control was 3.58 (2.63-5.17) years., Conclusions: Although resource-intensive, our findings suggest that Bright Bodies is cost-saving compared to the clinical control by averting future obesity-related healthcare costs among children with obesity., (Copyright © 2023. Published by Elsevier Inc.)

Objective: This study aimed to examine the extent to which Bright Bodies, a high-intensity, family-based pediatric weight management intervention, improved BMI for participants since publication of the randomized controlled trial establishing efficacy in 2007 and to describe adaptations to the program., Methods: For participants enrolled from 2008 to 2018, linear mixed-effects models were used to estimate monthly change in BMI expressed as percentage of the 95th percentile (%BMIp95) during participants' first beginner-level program., Results: The sample included 396 youth individuals (mean age: 11.7  [SD 2.8] years, 61.6% female, 37.1% non-Hispanic Black, 26.3% Hispanic or Latino, 53.8% with public insurance, 80.1% with severe obesity). Across the 11 years, participants' %BMIp95 reduced on average by 1.63% (95% CI: 1.44%-1.82%) per month during their first program (mean duration: 10 weeks) after adjusting for age, sex, season and year, starting %BMIp95, race and ethnicity, and insurance category. Greater reduction in %BMIp95 was associated with male versus female sex, spring/fall versus winter seasons, enrollment in 2008 to 2018 versus 2015 to 2018, and higher starting %BMIp95 (p value for all <0.001). Adaptations since 2007 included pragmatic changes to increase engagement and address funding shortages., Conclusions: These results suggest sustained clinical effectiveness of Bright Bodies in the context of real-world adaptations., (© 2022 The Obesity Society.)

Aims/hypothesis: We have previously shown that individuals with uncontrolled type 2 diabetes have a blunted rise in brain glucose levels measured by 1 H magnetic resonance spectroscopy. Here, we investigate whether reductions in HbA 1c normalise intracerebral glucose levels., Methods: Eight individuals (two men, six women) with poorly controlled type 2 diabetes and mean ± SD age 44.8 ± 8.3 years, BMI 31.4 ± 6.1 kg/m 2 and HbA 1c 84.1 ± 16.2 mmol/mol (9.8 ± 1.4%) underwent 1 H MRS scanning at 4 Tesla during a hyperglycaemic clamp (~12.21 mmol/l) to measure changes in cerebral glucose at baseline and after a 12 week intervention that improved glycaemic control through the use of continuous glucose monitoring, diabetes regimen intensification and frequent visits to an endocrinologist and nutritionist., Results: Following the intervention, mean ± SD HbA 1c decreased by 24.3 ± 15.3 mmol/mol (2.1 ± 1.5%) (p=0.006), with minimal weight changes (p=0.242). Using a linear mixed-effects regression model to compare glucose time courses during the clamp pre and post intervention, the pre-intervention brain glucose level during the hyperglycaemic clamp was significantly lower than the post-intervention brain glucose (p<0.001) despite plasma glucose levels during the hyperglycaemic clamp being similar (p=0.266). Furthermore, the increases in brain glucose were correlated with the magnitude of improvement in HbA 1c (r = 0.71, p=0.048)., Conclusion/interpretation: These findings highlight the potential reversibility of cerebral glucose transport capacity and metabolism that can occur in individuals with type 2 diabetes following improvement of glycaemic control. Trial registration ClinicalTrials.gov NCT03469492., (© 2022. This is a U.S. government work and not under copyright protection in the U.S.; foreign copyright protection may apply.)

Background: Recent literature suggests that the Western diet's imbalance between high ω-6 (n-6) and low ω-3 (n-3) PUFA intake contributes to fatty liver disease in obese youth., Objectives: We tested whether 12 wk of a low n-6:n-3 PUFA ratio (4:1) normocaloric diet mitigates fatty liver and whether the patatin-like containing domain phospholipase 3 (PNPLA3) rs738409 variant affects the response., Methods: In a single-arm unblinded study, obese youth 9-19 y of age with nonalcoholic fatty liver disease were treated with a normocaloric low n-6:n-3 PUFA ratio diet for 12 wk. The primary outcome was change in hepatic fat fraction (HFF%), measured by abdominal MRI. Metabolic parameters included alanine aminotransferase (ALT), lipids, measures of insulin sensitivity, and plasma oxidized linoleic acid metabolites (OXLAMs). Outcomes were also analyzed by PNPLA3 rs738409 genotype. Wilcoxon's signed rank test, the Mann-Whitney U test, and covariance pattern modeling were used., Results: Twenty obese adolescents (median age: 13.3 y; IQR: 10.5-16.4 y) were enrolled and 17 completed the study. After 12 wk of dietary intervention, HFF% decreased by 25.8% (P = 0.009) despite stable weight. We observed a 34.4% reduction in ALT (P = 0.001), 21.9% reduction in triglycerides (P = 0.046), 3.28% reduction in LDL cholesterol (P = 0.071), and a 26.3% improvement in whole body insulin sensitivity (P = 0.032). The OXLAMs 9-hydroxy-octadecandienoic acid (9-HODE) (P = 0.011), 13-HODE (P = 0.007), and 9-oxo-octadecadienoic acid (9-oxoODE) (P = 0.024) decreased after 12 wk. HFF% declined in both the not-at-risk (CC/CG) and at-risk (GG) PNPLA3 rs738409 genotype groups, with significant (P = 0.016) HFF% reduction in the GG group. Changes in 9-HODE (P = 0.023), 9-oxoODE (P = 0.009), and 13-oxoODE (P = 0.003) differed between the 2 genotype groups over time., Conclusions: These data suggest that, independently of weight loss, a low n-6:n-3 PUFA diet ameliorates the metabolic phenotype of adolescents with fatty liver disease and that response to this diet is modulated by the PNPLA3 rs738409 genotype.This trial was registered at clinicaltrials.gov as NCT01556113., (Copyright © The Author(s) on behalf of the American Society for Nutrition 2020.)

Increased sugar-sweetened beverage consumption has been linked to higher rates of obesity. Using functional MRI, we assessed brain perfusion responses to drinking two commonly consumed monosaccharides, glucose and fructose, in obese and lean adolescents. Marked differences were observed. In response to drinking glucose, obese adolescents exhibited decreased brain perfusion in brain regions involved in executive function (prefrontal cortex [PFC]) and increased perfusion in homeostatic appetite regions of the brain (hypothalamus). Conversely, in response to drinking glucose, lean adolescents demonstrated increased PFC brain perfusion and no change in perfusion in the hypothalamus. In addition, obese adolescents demonstrated attenuated suppression of serum acyl-ghrelin and increased circulating insulin level after glucose ingestion; furthermore, the change in acyl-ghrelin and insulin levels after both glucose and fructose ingestion was associated with increased hypothalamic, thalamic, and hippocampal blood flow in obese relative to lean adolescents. Additionally, in all subjects there was greater perfusion in the ventral striatum with fructose relative to glucose ingestion. Finally, reduced connectivity between executive, homeostatic, and hedonic brain regions was observed in obese adolescents. These data demonstrate that obese adolescents have impaired prefrontal executive control responses to drinking glucose and fructose, while their homeostatic and hedonic responses appear to be heightened. Thus, obesity-related brain adaptations to glucose and fructose consumption in obese adolescents may contribute to excessive consumption of glucose and fructose, thereby promoting further weight gain., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objective: Fructose consumption has risen alongside obesity and diabetes. Gut hormones involved in hunger and satiety (ghrelin and PYY) may respond differently to fructose compared with glucose ingestion. This study evaluated the effects of glucose and fructose ingestion on ghrelin and PYY in lean and obese adolescents with differing insulin sensitivity., Methods: Adolescents were divided into lean (n = 14), obese insulin sensitive (n = 12) (OIS), and obese insulin resistant (n = 15) (OIR). In a double-blind, cross-over design, subjects drank 75 g of glucose or fructose in random order, serum was obtained every 10 minutes for 60 minutes., Results: Baseline acyl-ghrelin was highest in lean and lowest in OIR (P = 0.02). After glucose ingestion, acyl-ghrelin decreased similarly in lean and OIS but was lower in OIR (vs. lean, P = 0.03). Suppression differences were more pronounced after fructose (lean vs. OIS, P = 0.008, lean vs. OIR, P < 0.001). OIS became significantly hungrier after fructose (P = 0.015). PYY was not significantly different at baseline, varied minimally after glucose, and rose after fructose., Conclusions: Compared with lean, OIS adolescents have impaired acyl-ghrelin responses to fructose but not glucose, whereas OIR adolescents have blunted responses to both. Diminished suppression of acyl-ghrelin in childhood obesity, particularly if accompanied by insulin resistance, may promote hunger and overeating., (© 2015 The Obesity Society.)

Objective: In the U.S., an astonishing 12.5 million children and adolescents are now obese, predisposing 17% of our nation's youth to metabolic complications of obesity, such as type 2 diabetes (T2D). Adolescent obesity has tripled over the last three decades in the setting of food advertising directed at children. Obese adults exhibit increased brain responses to food images in motivation-reward pathways. These neural alterations may be attributed to obesity-related metabolic changes, which promote food craving and high-calorie food (HCF) consumption. It is not known whether these metabolic changes affect neural responses in the adolescent brain during a crucial period for establishing healthy eating behaviors., Research Design and Methods: Twenty-five obese (BMI 34.4 kg/m2, age 15.7 years) and fifteen lean (BMI 20.96 kg/m2, age 15.5 years) adolescents underwent functional MRI during exposure to HCF, low-calorie food (LCF), and nonfood (NF) visual stimuli 2 h after isocaloric meal consumption., Results: Brain responses to HCF relative to NF cues increased in obese versus lean adolescents in striatal-limbic regions (i.e., putamen/caudate, insula, amygdala) (P < 0.05, family-wise error [FWE]), involved in motivation-reward and emotion processing. Higher endogenous leptin levels correlated with increased neural activation to HCF images in all subjects (P < 0.05, FWE)., Conclusions: This significant association between higher circulating leptin and hyperresponsiveness of brain motivation-reward regions to HCF images suggests that dysfunctional leptin signaling may contribute to the risk of overconsumption of these foods, thus further predisposing adolescents to the development of obesity and T2D., (© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Objective: The childhood obesity epidemic has been accompanied by an increasing prevalence of type 2 diabetes (T2D), particularly in minority children. Twenty to thirty percent of obese youth have "prediabetes," a precursor to diabetes marked by insulin resistance, β-cell dysfunction, and impaired glucose tolerance. The Diabetes Prevention Program demonstrated that T2D could be prevented/delayed by intensive lifestyle modification in adults with prediabetes, but efficacy of similar interventions in youth has not been established. Therefore, we evaluated the effects of the Bright Bodies (BB) Healthy Lifestyle Program on 2-h oral glucose tolerance test (OGTT) glucose in comparison with adolescents receiving standard of care., Research Design and Methods: A parallel-group randomized controlled trial comparing BB with standard clinical care (CC) in obese adolescents (10-16 years old, Tanner stage >2) with elevated OGTT 2-h blood glucose (130-199 mg/dL) from a racially/ethnically diverse population. OGTTs, including cardiovascular and anthropometric assessments, were conducted at baseline and 6 months. Children attended BB twice per week for exercise and nutrition/behavior modification, and the CC group received CC from their pediatrician. Primary outcome was change in 2-h OGTT glucose and percentage conversion from elevated 2-h blood glucose to nonelevated (<130 mg/dL) 2-h blood glucose. Changes in outcomes were compared between groups using an ANCOVA, with adjustment for baseline outcome and multiple imputation for missing data., Results: Reductions in 2-h glucose were more favorable in BB compared with CC (-27.2 vs. -10.1 mg/dL; difference = -17.1, 95% CI; P = 0.005). Moreover, greater conversion to <130 mg/dL 2-h glucose occurred in BB than CC (P = 0.003), and other insulin sensitivity indices were significantly improved., Conclusions: Compared with standard of care, the Yale BB Program is a more effective means of reducing the risk of T2D in obese adolescents with elevated 2-h glucose levels.

Background: Reports of clinical rickets are particularly evident in minority infants and children, but only limited analyses of vitamin D are available in this demographic group., Objective: We sought to characterize circulating 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)(2)D], and their determinants, including circulating parathyroid hormone (PTH), total alkaline phosphatase activity (ALP), calcium, and phosphorus, in minority infants and children., Design: We obtained demographic information and blood samples for measurement of PTH, ALP, 25(OH)D, and 1,25(OH)(2)D in >750 6-mo- to 3-y-old children. Dietary intake data were obtained and analyzed., Results: The mean (±SD) 25(OH)D concentration was 66 ± 22 nmol/L (26.3 ± 8.7 ng/dL). A total of 15% of children had 25(OH)D concentrations less than the recommended target threshold of 50 nmol/L. Combined elevations of PTH and ALP occurred in only 2.5% of children. Determinants of 25(OH)D included vitamin D intake, age (decreasing with age), skin type (greater concentrations in lighter-skinned children than in darker-skinned children), formula use (higher intakes), season (greater concentrations in the summer and fall than in the winter and spring), and, inversely, PTH. The mean 1,25(OH)(2)D concentration was 158 ± 58 pmol/L (60.6 ± 22.5 pg/mL), which was consistent with a reference range of 41-274 pmol/L or 15.7-105.5 pg/mL. Determinants for 1,25(OH)(2)D were age (decreasing with age), sex (greater concentrations in girls than in boys), skin type (greater concentrations in lighter-skinned children than in darker-skinned children), and, inversely, serum calcium and phosphorus., Conclusions: Although 15% of subjects were vitamin D insufficient, only 2.5% of subjects had elevations of both PTH and ALP. The greater 25(OH)D concentrations observed with formula use confirm that dietary vitamin D fortification is effective in this demographic group. Circulating 1,25(OH)(2)D is higher in infants than in older children and adults and, in contrast to 25(OH)D, is not directly correlated with nutrient intakes.

Background: A single nucleotide polymorphism (SNP), the rs738409, in the patatin like phospholipase 3 gene (PNPLA3) has been recently associated with increased hepatic steatosis and ALT levels in adults and children. Given the potential role of PNPLA3 in fatty liver development, we aimed to explore whether the influence of PNPLA3 genotype on hepatic fat in obese youth might be modulated by dietary factors such as essential omega polyunsaturated fatty acids (PUFA) intake., Materials and Methods: We studied 127 children and adolescents (56 boys, 71 girls; 58 Caucasians; 30 African Americans and 39 Hispanics; mean age 14.7±3.3; mean BMI 30.7±7.2). The dietary composition was assessed by the Nutrition Data System for Research (NDS-R version 2011). The patients underwent a MRI study to assess the liver fat content (HFF%), ALT measurement and the genotyping of the rs738409 SNP by automatic sequencing., Results: As previously observed, HFF% and ALT levels varied according to the genotype in each ethnicity. ALT levels and HFF% were significantly influenced by the interaction between genotype and omega-6/omega-3 PUFA ratio (n-6/n-3), p = 0.003 and p = 0.002, respectively. HFF% and ALT levels were, in fact, related to the n-6/n-3 consumption only in subjects homozygote for the G allele of the rs738409 (r2 = 0.45, p =  0.001 and r2 = 0.40, p = 0.006, respectively)., Conclusions: These findings suggest that the association of a high dietary n-6/n-3 PUFA with fatty liver and liver damage in obese youths may be driven by a predisposing genotype.

Objective: Hemoglobin A(1c) (A1C) has emerged as a recommended diagnostic tool for identifying diabetes and subjects at risk for the disease. This recommendation is based on data in adults showing the relationship between A1C with future development of diabetes and microvascular complications. However, studies in the pediatric population are lacking., Research Design and Methods: We studied a multiethnic cohort of 1,156 obese children and adolescents without a diagnosis of diabetes (male, 40%/female, 60%). All subjects underwent an oral glucose tolerance test (OGTT) and A1C measurement. These tests were repeated after a follow-up time of ∼2 years in 218 subjects., Results: At baseline, subjects were stratified according to A1C categories: 77% with normal glucose tolerance (A1C <5.7%), 21% at risk for diabetes (A1C 5.7-6.4%), and 1% with diabetes (A1C >6.5%). In the at risk for diabetes category, 47% were classified with prediabetes or diabetes, and in the diabetes category, 62% were classified with type 2 diabetes by the OGTT. The area under the curve receiver operating characteristic for A1C was 0.81 (95% CI 0.70-0.92). The threshold for identifying type 2 diabetes was 5.8%, with 78% specificity and 68% sensitivity. In the subgroup with repeated measures, a multivariate analysis showed that the strongest predictors of 2-h glucose at follow-up were baseline A1C and 2-h glucose, independently of age, ethnicity, sex, fasting glucose, and follow-up time., Conclusions: The American Diabetes Association suggested that an A1C of 6.5% underestimates the prevalence of prediabetes and diabetes in obese children and adolescents. Given the low sensitivity and specificity, the use of A1C by itself represents a poor diagnostic tool for prediabetes and type 2 diabetes in obese children and adolescents.

Impaired glucose tolerance (IGT) is a prediabetic state fueling the rising prevalence of type 2 diabetes mellitus (T2DM) in adolescents with marked obesity. Given the importance of insulin resistance, the poor β-cell compensation and the altered fat partitioning as underlying defects associated with this condition, it is crucial to determine the extent to which these underlying abnormalities can be reversed in obese adolescents. We tested, in a pilot study, whether rosiglitazone (ROSI) restores normal glucose tolerance (NGT) in obese adolescents with IGT by improving insulin sensitivity and β-cell function. In a small randomized, double-blind, placebo (PLA)-controlled study, lasting 4 months, 21 obese adolescents with IGT received either ROSI (8 mg daily) (n = 12, 5M/7F, BMI z-score 2.44 ± 0.11) or PLA (n = 9, 4M/5F, BMI z-score 2.41 ± 0.09). Before and after treatment, all subjects underwent oral glucose tolerance test (OGTT), hyperinsulinemic-euglycemic clamp, magnetic resonance imaging, and (1)H NMR assessment. After ROSI treatment, 58% of the subjects converted to NGT compared to 44% in the PLA group (P = 0.528). Restoration of NGT was associated with a significant increase in insulin sensitivity (P < 0.04) and a doubling in the disposition index (DI) (P < 0.04), whereas in the PLA group, these changes were not significant. The short-term use of ROSI appears to be safe in obese adolescents with IGT. ROSI restores NGT by increasing peripheral insulin sensitivity and β-cell function, two principal pathophysiological abnormalities of IGT.

Background: Recently, the deleterious metabolic effects of visceral fat [visceral adipose tissue (VAT)] deposition were challenged, and liver fat emerged as having a key independent role in the modulation of cardiometabolic risk factors., Objective: We explored the relation between liver fat content and VAT in 3 ethnic groups and evaluated whether the ethnic differences in the distributions of lipoprotein concentrations and sizes were associated with the hepatic fat fraction (HFF), VAT, or both., Design: In a multiethnic group of 33 white, 33 African American, and 33 Hispanic obese adolescents with normal glucose tolerance, we measured VAT and HFF by using magnetic resonance imaging. Fasting lipoprotein particle number and size were measured by using nuclear magnetic resonance spectroscopy. To assess the association between VAT and HFF, we categorized VAT into tertiles., Results: In each ethnic group, HFF values increased between successive tertiles of VAT. After multivariate adjustment and in comparison with the 2 other groups, African Americans showed lower triglyceride (P = 0.001) and higher HDL (P = 0.03) concentrations, lower concentrations of total (P = 0.007), large (P = 0.005), and medium (P lt 0.0001) VLDL, but higher concentrations of large HDL particles (P = 0.01) and larger HDL (P = 0.005). In multivariate linear models, independent of ethnicity, VAT was a significant predictor for large HDL (P = 0.003) and total small LDL (P = 0.001) concentrations, whereas HFF significantly predicted large VLDL (P = 0.03) concentrations., Conclusion: Liver fat accretion, independent of VAT, may play a role in the ethnic differences seen in large VLDL particles. This trial was registered at clinicaltrials.gov as NCT00536250.

Objective: To evaluate the impact on glucose metabolism of a lifestyle program (the Yale Bright Bodies Program) for obese children., Research Design and Methods: Thirteen Bright Bodies and ten clinic-care control subjects who were part of a large randomized clinical trial had 75-g oral glucose tolerance tests at the beginning and end of the 12-month study., Results: Bright Bodies subjects had significantly greater decreases in weight, BMI, and body fat than clinic-care subjects, and the Bright Body subjects' changes in body composition were accompanied by marked improvements in insulin sensitivity (P = 0.009) and glucose tolerance (P = 0.04)., Conclusions: An intensive lifestyle program that successfully reduces body weight and body fat can markedly improve insulin sensitivity and glucose metabolism in obese youth.

Objective: To explore whether an imbalance between the visceral and subcutaneous fat depots and a corresponding dysregulation of the adipokine milieu is associated with excessive accumulation of fat in the liver and muscle and ultimately with insulin resistance and the metabolic syndrome., Research Design and Methods: We stratified our multi-ethnic cohort of 118 obese adolescents into tertiles based on the proportion of abdominal fat in the visceral depot. Abdominal and liver fat were measured by magnetic resonance imaging and muscle lipid (intramyocellular lipid) by proton magnetic resonance spectroscopy., Results: There were no differences in age, BMI Z score, or fat-free mass across tertiles. However, as the proportion of visceral fat increased across tertiles, BMI and percentage of fat and subcutaneous fat decreased, while hepatic fat increased. In addition, there was an increase in 2-h glucose, insulin, c-peptide, triglyceride levels, and insulin resistance. Notably, both leptin and total adiponectin were significantly lower in tertile 3 than 1, while C-reactive protein and interleukin-6 were not different across tertiles. There was a significant increase in the odds ratio for the metabolic syndrome, with subjects in tertile 3 5.2 times more likely to have the metabolic syndrome than those in tertile 1., Conclusions: Obese adolescents with a high proportion of visceral fat and relatively low abdominal subcutaneous fat have a phenotype reminiscent of partial lipodystrophy. These adolescents are not necessarily the most severely obese, yet they suffer from severe metabolic complications and are at a high risk of having the metabolic syndrome.

Objective: Type 2 diabetes in obese youth is an emerging problem. The metabolic and anthropometric predictors of change in glucose tolerance status in obese youth are unknown., Research Design and Methods: A total of 117 obese children and adolescents were studied by performing an oral glucose tolerance test (OGTT) at baseline and after approximately 2 years. Data from both OGTTs and changes in weight were examined to identify youth at highest risk for developing diabetes and the factors that have the strongest impact on glucose tolerance., Results: Eighty-four subjects had normal glucose tolerance (NGT) and 33 impaired glucose tolerance (IGT) at baseline. Eight subjects (all of whom had IGT at baseline) developed type 2 diabetes, whereas 15 subjects with IGT reverted to NGT. In this cohort, severe obesity, impaired glucose tolerance, and African-American background emerged as the best predictors of developing type 2 diabetes, whereas fasting glucose, insulin, and C-peptide were nonpredictive. Changes in insulin sensitivity, strongly related to weight change, had a significant impact on the 2-h glucose level on the follow-up study., Conclusions: Severely obese children and adolescents with IGT, particularly of African-American descent, are at very high risk for developing type 2 diabetes over a short period of time. Parameters derived from an OGTT and not fasting samples can serve as predictors of changes in glucose tolerance.

The metabolism and composition of skeletal muscle tissue is of special interest because it is a primary site of insulin action and plays a key role in the pathogenesis of insulin resistance. Intramyocellular (IMCL) triglyceride stores are an accessible form of energy that may decrease skeletal muscle glucose utilization, thereby contributing to impaired glucose metabolism. Because of the invasive nature of muscle biopsies, there is limited, if any, information about intramuscular lipid stores in children. The development of (1)H nuclear magnetic resonance (NMR) spectroscopy provides a unique noninvasive alternative method that differentiates intracellular fat from intercellular fat in muscle tissue. The present study was performed to determine whether IMCL and extramyocellular (EMCL) lipid contents are increased early in the development of juvenile obesity and to explore the relationships between IMCL and EMCL to in vivo insulin sensitivity, independently of total body fat and central adiposity in obese and nonobese adolescents. Eight nonobese (BMI 21 kg/m(2), age 11-16 years) and 14 obese (BMI 35 +/- 1.5 kg/m(2), age 11-15 years) adolescents underwent 1) (1)H-NMR spectroscopy to noninvasively quantify IMCL and EMCL triglyceride content of the soleus muscle, 2) a 2-h euglycemic-hyperinsulinemic clamp (40 mU.m(-2).min(-1)) to assess insulin sensitivity, 3) a dual-energy X-ray absorptiometry scan to measure total percent body fat, and 4) magnetic resonance imaging to measure abdominal fat distribution. Both the IMCL and EMCL content of the soleus muscle were significantly greater in the obese adolescents than in the lean control subjects. A strong inverse correlation was found between IMCL and insulin sensitivity, which persisted and became even stronger after controlling for percent total body fat and abdominal subcutaneous fat mass (partial correlation r = -0.73, P < 0.01) but not when adjusting for visceral fat (r = - 0.54, P < 0.08). In obese adolescents, increase in total body fat and central adiposity were accompanied by higher IMCL and EMCL lipid stores. The striking relationships between both IMCL and EMCL with insulin sensitivity in childhood suggest that these findings are not a consequence of aging but occur early in the natural course of obesity.