Associations of prenatal metabolomics profiles with early childhood growth trajectories and obesity risk in African Americans: the CANDLE study.

OBJECTIVE: Prenatal metabolomics profiles, providing measures of in utero nutritional and environmental exposures, may improve the prediction of childhood outcomes. We aimed to identify prenatal plasma metabolites associated with early childhood body mass index (BMI) trajectories and overweight/obesity risk in offspring. METHODS: This study included 450 African American mother-child pairs from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood Study. An untargeted metabolomics analysis was performed on the mothers' plasma samples collected during the second trimester. The children's BMI-z-score trajectories from birth to age 4 [rising-high- (9.8%), moderate- (68.2%), and low-BMI (22.0%)] and overweight/obesity status at age 4 were the main outcomes. The least absolute shrinkage and selection operator (LASSO) was used to select the prenatal metabolites associated with childhood outcomes. RESULTS: The mothers were 24.5 years old on average at recruitment, 76.4% having education less than 12 years and 80.0% with Medicaid or Medicare. In LASSO, seven and five prenatal metabolites were associated with the BMI-z-score trajectories and overweight/obese at age 4, respectively. These metabolites are mainly from/relevant to the pathways of steroid biosynthesis, amino acid metabolism, vitamin B complex, and xenobiotics metabolism (e.g., caffeine and nicotine). The odds ratios (95% CI) associated with a one SD increase in the prenatal metabolite risk scores (MRSs) constructed from the LASSO-selected metabolites were 2.97 (1.95-4.54) and 2.03 (1.54-2.67) for children being in the rising-high-BMI trajectory group and overweight/obesity at age 4, respectively. The MRSs significantly improved the risk prediction for childhood outcomes beyond traditional prenatal risk factors. The increase (95% CI) in the area under the receiver operating characteristic curves were 0.10 (0.03-0.18) and 0.07 (0.02-0.12) for the rising-high-BMI trajectory (P = 0.005) and overweight/obesity at age 4 (P = 0.007), respectively. CONCLUSIONS: Prenatal metabolomics profiles advanced prediction of early childhood growth trajectories and obesity risk in offspring.

Waitlist management in a pediatric weight management clinic: implementing an orientation session.

BACKGROUND: This study evaluates implementation of an orientation session to address a waitlist of more than 2000 referrals to a pediatric weight management clinic in the Mid-South United States. METHODS: An hour-long group-based orientation to the pediatric weight management clinic was implemented to provide information about the structure and expectations of the clinic as well as education on healthy lifestyle recommendations. Families were contacted from the waitlist by telephone and invited to attend an orientation session prior to scheduling a clinic appointment. RESULTS: Of 2251 patients contacted from the waitlist, 768 scheduled an orientation session, of which 264 (34 %) attended. Of the 264 orientation participants, 246 (93 %) scheduled a clinic appointment. Of those, 193 (79 %) completed a clinic visit. Waitlist times decreased from 297.8 ± 219.4 days prior to implementation of orientation sessions to 104.1 ± 219.4 days after. CONCLUSIONS: Orientation has been an effective and efficient way to triage patient referrals while maximizing attendance in limited clinic slots for patients and families demonstrating interest and motivation. Elements of this approach are likely generalizable to other pediatric clinical settings that must strategically manage a large volume of patient referrals.

TGR5 signaling mitigates parenteral nutrition-associated liver disease.

Bile acid receptors regulate the metabolic and immune functions of circulating enterohepatic bile acids. This process is disrupted by administration of parenteral nutrition (PN), which may induce progressive hepatic injury for unclear reasons, especially in the newborn, leading to PN-associated liver disease. To explore the role of bile acid signaling on neonatal hepatic function, we initially observed that Takeda G protein receptor 5 (TGR5)-specific bile acids were negatively correlated with worsening clinical disease markers in the plasma of human newborns with prolonged PN exposure. To test our resulting hypothesis that TGR5 regulates critical liver functions to PN exposure, we used TGR5 receptor deficient mice (TGR5-/-). We observed PN significantly increased liver weight, cholestasis, and serum hepatic stress enzymes in TGR5-/- mice compared with controls. Mechanistically, PN reduced bile acid synthesis genes in TGR5-/-. Serum bile acid composition revealed that PN increased unconjugated primary bile acids and secondary bile acids in TGR5-/- mice, while increasing conjugated primary bile acid levels in TGR5-competent mice. Simultaneously, PN elevated hepatic IL-6 expression and infiltrating macrophages in TGR5-/- mice. However, the gut microbiota of TGR5-/- mice compared with WT mice following PN administration displayed highly elevated levels of Bacteroides and Parabacteroides, and possibly responsible for the elevated levels of secondary bile acids in TGR5-/- animals. Intestinal bile acid transporters expression was unchanged. Collectively, this suggests TGR5 signaling specifically regulates fundamental aspects of liver bile acid homeostasis during exposure to PN. Loss of TGR5 is associated with biochemical evidence of cholestasis in both humans and mice on PN.NEW & NOTEWORTHY Parenteral nutrition is associated with deleterious metabolic outcomes in patients with prolonged exposure. Here, we demonstrate that accelerated cholestasis and parental nutrition-associated liver disease (PNALD) may be associated with deficiency of Takeda G protein receptor 5 (TGR5) signaling. The microbiome is responsible for production of secondary bile acids that signal through TGR5. Therefore, collectively, these data support the hypothesis that a lack of established microbiome in early life or under prolonged parenteral nutrition may underpin disease development and PNALD.

Psychosocial Functioning After One Year of Interdisciplinary Pediatric Weight Management.

Youth with obesity are more likely than normal-weight peers to experience psychosocial problems. Empirically-based recommendations for addressing pediatric obesity include intensive interdisciplinary weight management comprising medical, behavioral health, nutrition, and exercise components. The present study examined changes in psychosocial functioning associated with frequency of participation in an interdisciplinary pediatric weight management program. Participants were 86 patients (55.8% females; median age = 11.5 years; 67.4% Non-Hispanic Black; median BMI percentile = 99.5) enrolled in an interdisciplinary pediatric weight management program for at least one year. Psychosocial functioning was measured with the Pediatric Symptom Checklist (PSC-17), a caregiver-completed mental health screen that assesses internalizing, externalizing, and attention difficulties as well as global functioning. The PSC-17 was completed at the initial clinic visit (baseline) and repeated one-year later (annual). The Wilcoxon Signed Rank test indicated that annual PSC-17 scores were significantly lower than baseline scores across all domains. Spearman correlation coefficients revealed no significant association between total number of clinic visits and PSC-17 global or subscale scores. However, the number of visits for exercise-only sessions was significantly correlated with caregiver-reported improvement in internalizing behaviors. Findings suggest that participation in interdisciplinary pediatric weight management may improve psychosocial functioning in youth with obesity and that attending supervised exercise sessions may be especially beneficial for improving internalizing behavior symptoms.

Maternal metabolic factors during pregnancy predict early childhood growth trajectories and obesity risk: the CANDLE Study.

BACKGROUND: We investigated the individual and additive effects of three modifiable maternal metabolic factors, including pre-pregnancy overweight/obesity, gestational weight gain (GWG), and gestational diabetes mellitus (GDM), on early childhood growth trajectories and obesity risk. METHODS: A total of 1425 mother-offspring dyads (953 black and 472 white) from a longitudinal birth cohort were included in this study. Latent class growth modeling was performed to identify the trajectories of body mass index (BMI) from birth to 4 years in children. Poisson regression models were used to examine the associations between the maternal metabolic risk factors and child BMI trajectories and obesity risk at 4 years. RESULTS: We identified three discrete BMI trajectory groups, characterized as rising-high-BMI (12.6%), moderate-BMI (61.0%), or low-BMI (26.4%) growth. Both maternal pre-pregnancy obesity (adjusted relative risk [adjRR] = 1.96; 95% confidence interval [CI]: 1.36-2.83) and excessive GWG (adjRR = 1.71, 95% CI: 1.13-2.58) were significantly associated with the rising-high-BMI trajectory, as manifested by rapid weight gain during infancy and a stable but high BMI until 4 years. All three maternal metabolic indices were significantly associated with childhood obesity at age 4 years (adjRR for pre-pregnancy obesity = 2.24, 95% CI: 1.62-3.10; adjRR for excessive GWG = 1.46, 95% CI: 1.01-2.09; and adjRR for GDM = 2.14, 95% = 1.47-3.12). In addition, risk of rising-high BMI trajectory or obesity at age 4 years was stronger among mothers with more than one metabolic risk factor. We did not observe any difference in these associations by race. CONCLUSION: Maternal pre-pregnancy obesity, excessive GWG, and GDM individually and jointly predict rapid growth and obesity at age 4 years in offspring, regardless of race. Interventions targeting maternal obesity and metabolism may prevent or slow the rate of development of childhood obesity.

Implementing a condensed dialectical behavior therapy skills group for binge-eating behaviors in adolescents.

PURPOSE: Subthreshold binge-eating disorder (BED) symptoms can lead to additive physical and psychological health challenges and may put youth at risk for developing BED during the early adulthood. We examined the implementation of a condensed dialectical behavior therapy (DBT) skills intervention for subthreshold binge-eating behaviors in adolescents. METHODS: Fifteen 14-18 years old participated in a 10-week DBT skills group, which experientially introduced mindfulness, distress tolerance, emotion regulation, and interpersonal effectiveness skills in the context of emotionally driven overeating behaviors. Adolescents and caregivers completed measures of emotional eating and binge-eating behaviors at baseline and post-intervention, including the Eating Disorder Examination Questionnaire and Emotional Eating Scale for Children and Adolescents. Eleven participants were retained at 3-month follow-up. RESULTS: Descriptive statistics were compared at all three time points. Results suggested a reduction in emotional eating and binge-eating behaviors based on youth self-report and caregiver report. Acceptability ratings of the treatment were high among participants completing the intervention. CONCLUSIONS: Using DBT skills to target emotionally driven overeating behaviors in youth may be useful in the treatment of subthreshold BED behaviors and potentially deter future development of full-criteria BED. LEVEL OF EVIDENCE: Level IV, uncontrolled pilot trial.

Disruption of brain-derived neurotrophic factor production from individual promoters generates distinct body composition phenotypes in mice.

Brain-derived neurotrophic factor (BDNF) is a key neuropeptide in the central regulation of energy balance. The Bdnf gene contains nine promoters, each producing specific mRNA transcripts that encode a common protein. We sought to assess the phenotypic outcomes of disrupting BDNF production from individual Bdnf promoters. Mice with an intact coding region but selective disruption of BDNF production from Bdnf promoters I, II, IV, or VI (Bdnf-e1-/-, -e2-/-, -e4-/-, and -e6-/-) were created by inserting an enhanced green fluorescent protein-STOP cassette upstream of the targeted promoter splice donor site. Body composition was measured by MRI weekly from age 4 to 22 wk. Energy expenditure was measured by indirect calorimetry at 18 wk. Food intake was measured in Bdnf-e1-/- and Bdnf-e2-/- mice, and pair feeding was conducted. Weight gain, lean mass, fat mass, and percent fat of Bdnf-e1-/- and Bdnf-e2-/- mice (both sexes) were significantly increased compared with wild-type littermates. For Bdnf-e4-/- and Bdnf-e6-/- mice, obesity was not observed with either chow or high-fat diet. Food intake was increased in Bdnf-e1-/- and Bdnf-e2-/- mice, and pair feeding prevented obesity. Mutant and wild-type littermates for each strain (both sexes) had similar total energy expenditure after adjustment for body composition. These findings suggest that the obesity phenotype observed in Bdnf-e1-/- and Bdnf-e2-/- mice is attributable to hyperphagia and not altered energy expenditure. Our findings show that disruption of BDNF from specific promoters leads to distinct body composition effects, with disruption from promoters I or II, but not IV or VI, inducing obesity.

Alström syndrome: Renal findings in correlation with obesity, insulin resistance, dyslipidemia and cardiomyopathy in 38 patients prospectively evaluated at the NIH clinical center.

Alström Syndrome is a ciliopathy associated with obesity, insulin resistance/type 2 diabetes mellitus, cardiomyopathy, retinal degeneration, hearing loss, progressive liver and kidney disease, and normal cognitive function. ALMS1, the protein defective in this disorder, localizes to the cytoskeleton, microtubule organizing center, as well as the centrosomes and ciliary basal bodies and plays roles in formation and maintenance of cilia, cell cycle regulation, and endosomal trafficking. Kidney disease in this disorder has not been well characterized. We performed comprehensive multisystem evaluations on 38 patients. Kidney function decreased progressively; eGFR varied inversely with age (p = 0.002). Eighteen percent met the definition for chronic kidney disease (eGFR < 60 mL/min/1.73 m2 and proteinuria); all were adults with median age of 32.8 (20.6-37.9) years. After adjusting for age, there were no significant associations of kidney dysfunction with type 2 diabetes mellitus, dyslipidemia, hypertension, cardiomyopathy or portal hypertension suggesting that kidney disease in AS is a primary manifestation of the syndrome due to lack of ALMS1 protein. Approximately one-third of patients had hyperechogenicity of the renal parenchyma on imaging. While strict control of type 2 diabetes mellitus may decrease kidney-related morbidity and mortality in Alström syndrome, identification of novel targeted therapies is needed.

Characteristics of cardiomyopathy in Alström syndrome: Prospective single-center data on 38 patients.

BACKGROUND: Alström syndrome (AS) is a rare monogenetic disorder with multi-organ involvement. Complex metabolic disturbances are common and cardiomyopathy is a well-recognized feature in infants as well as in older children and adults. Although the mechanism of cardiomyopathy is not known, previous reports suggest that individuals with infantile-onset cardiac disease recover completely. METHODS: In this single center prospective series of 38 children and adults (age range 1.7 to 37.9years; 20 females) with AS, we evaluated cardiac manifestations in detail, in the context of specific ALMS1 mutations and multisystem involvement. All patients underwent ALMS1 sequencing, biochemical testing, electrocardiogram, and echocardiographic imaging with speckle tracking to evaluate systolic strain; 21 patients underwent cardiac magnetic resonance imaging with T1 mapping. RESULTS: Approximately half of patients (17/38) had a previous diagnosis of cardiomyopathy. Global longitudinal strain, a measure of systolic contractile function, was abnormal in 94% of patients and correlated with body mass index (r=0.602, p=0.002) and C-reactive protein level (r=0.56, p=0.004), but only in children. Electrocardiographic abnormalities were seen in two-thirds of patients, and left ventricular dilatation and/or dysfunction was present in 4 adults and 4 children. CONCLUSION: AS patients with a history of resolved infantile cardiomyopathy continue to have residual impairment in cardiac function. For patients with a normal ejection fraction and no prior cardiac history, strain can be abnormal, suggesting subclinical cardiac involvement. Close cardiac screening and aggressive modification of other manifestations of AS that are risk factors for cardiac disease, including obesity, inflammation, diabetes and dyslipidemia, are essential in caring for patients with AS.

PROMIS Sleep Disturbance and Sleep-Related Impairment in Adolescents: Examining Psychometrics Using Self-Report and Actigraphy.

BACKGROUND: The National Institutes of Health Patient-Reported Outcomes Measurement Information System (PROMIS) has self-reported health measures available for both pediatric and adult populations, but no pediatric measures are available currently in the sleep domains. OBJECTIVE: The purpose of this observational study was to perform preliminary validation studies on age-appropriate, self-reported sleep measures in healthy adolescents. METHODS: This study examined 25 healthy adolescents' self-reported daytime sleepiness, sleep disturbance, sleep-related impairment, and sleep patterns. Healthy adolescents completed a physical exam at the National Institutes of Health Clinical Center (Bethesda, MD), had no chronic medical conditions, and were not taking any chronic medications. The Cleveland Adolescent Sleepiness Questionnaire (CASQ), PROMIS Sleep Disturbance (v. 1.0; 8a), and PROMIS Sleep-Related Impairment (v. 1.0; 8b) questionnaires were completed, and sleep patterns were assessed using actigraphy. RESULTS: Total scores on the three sleep questionnaires were correlated (all Spearman's r > .70, p < .001). Total sleep time determined by actigraphy was negatively correlated with the CASQ (p = .01), PROMIS Sleep Disturbance (p = .02), and PROMIS Sleep-Related Impairment (p = .02). DISCUSSION: The field of pediatric sleep is rapidly expanding, and researchers and clinicians will benefit from well-designed, psychometrically sound sleep questionnaires. Findings suggest the potential research and clinical utility of adult versions of PROMIS sleep measures in adolescents. Future studies should include larger, more diverse samples and explore additional psychometric properties of PROMIS sleep measures to provide age-appropriate, validated, and reliable measures of sleep in adolescents.

Exposure to environmentally persistent free radicals during gestation lowers energy expenditure and impairs skeletal muscle mitochondrial function in adult mice.

We have investigated the effects of in utero exposure to environmentally persistent free radicals (EPFRs) on growth, metabolism, energy utilization, and skeletal muscle mitochondria in a mouse model of diet-induced obesity. Pregnant mice were treated with laboratory-generated, combustion-derived particular matter (MCP230). The adult offspring were placed on a high-fat diet for 12 wk, after which we observed a 9.8% increase in their body weight. The increase in body size observed in the MCP230-exposed mice was not associated with increases in food intake but was associated with a reduction in physical activity and lower energy expenditure. The reduced energy expenditure in mice indirectly exposed to MCP230 was associated with reductions in skeletal muscle mitochondrial DNA copy number, lower mRNA levels of electron transport genes, and reduced citrate synthase activity. Upregulation of key genes involved in ameliorating oxidative stress was also observed in the muscle of MCP230-exposed mice. These findings suggest that gestational exposure to MCP230 leads to a reduction in energy expenditure at least in part through alterations to mitochondrial metabolism in the skeletal muscle.

Pineal hypoplasia, reduced melatonin and sleep disturbance in patients with PAX6 haploinsufficiency.

In rodent studies, paired box 6 (PAX6) appears to play an important role in the development of the pineal, the primary source of the circadian regulating hormone, melatonin. Pineal hypoplasia has been previously reported in patients with PAX6 haploinsufficiency (+/−); however, pineal measurement, melatonin concentrations and sleep quality have not been reported. This cross-sectional descriptive study examined pineal volume, melatonin secretion and sleep disturbance in 37 patients with PAX6+/− (age 15.3 ± 9.9 years) and 17 healthy controls (16.0 ± 7.2 years), within an inpatient setting at the Clinical Research Center of the National Institutes of Health, Bethesda, Maryland, USA. Pineal volume was evaluated by magnetic resonance imaging. Diurnal serum cortisol, serum melatonin and urine 6-sulphatoxymelatonin concentrations were measured by enzyme-linked immunosorbent assay. The Child Sleep Habits Questionnaire was administered for patients <13 years old. Pineal volume was fivefold lower in PAX6+/− versus controls (mean ± SD: 25 ± 15 versus 129 ± 50 µL, P < 0.001). Midnight serum cortisol was similar in PAX6+/− versus controls (P = 0.14). Midnight serum melatonin was > twofold lower in PAX6+/− versus controls [median (25th-75 th): 28 (22-42) versus 71 (46-88) pg mL-(1), P < 0.001]. First morning void urinary 6-sulphatoxymelatonin was fourfold lower in PAX6+/− versus controls [11 (6-26) versus 45 (34-61) ng mg(-1) Cr, P = 0.001]. Child Sleep Habits Questionnaire score was higher in PAX6+/− versus controls (48 ± 6 versus 41 ± 5, P = 0.03). The current findings suggest that PAX6+/− is associated with smaller pineal size, lower melatonin secretion and greater parental report of sleep disturbances in children. Further studies are needed to explore the potential use of melatonin replacement for improving sleep quality in patients with PAX6+/−.

Prediction of resting energy expenditure for adolescents with severe obesity: A multi-centre analysis.

BACKGROUND AND OBJECTIVES: Resting energy expenditure (REE) assessments can help inform clinical treatment decisions in adolescents with elevated body mass index (BMI), but current equations are suboptimal for severe obesity. We developed a predictive REE equation for youth with severe obesity and obesity-related comorbidities and compared results to previously published predictive equations. METHODS: Data from indirect calorimetry, clinical measures, and body composition per Dual x-ray absorptiometry (DXA) were collected from five sites. Data were randomly divided into development (N = 438) and validation (N = 118) cohorts. A predictive equation was developed using Elastic Net regression, using sex, race, ethnicity, weight, height, BMI percent of the 95th%ile (BMIp95), waist circumference, hip circumference, waist/hip ratio, age, Tanner stage, fat and fat-free mass. This equation was verified in the validation cohort and compared with 11 prior equations. RESULTS: Data from the total cohort (n = 556, age 15 ± 1.7 years, 77% female, BMIp95 3.3 ± 0.94) were utilized. The best fit equation was REE = -2048 + 18.17 × (Height in cm) - 2.57 × (Weight in kg) + 7.88 × (BMIp95) + 189 × (1 = male, 0 = female), R2 = 0.466, and mean bias of 23 kcal/day. CONCLUSION: This new equation provides an updated REE prediction that accounts for severe obesity and metabolic complications frequently observed in contemporary youth.

Energy expenditure deficits drive obesity in a mouse model of Alström syndrome.

OBJECTIVE: Alström syndrome (AS) is a rare multisystem disorder of which early onset childhood obesity is a cardinal feature. Like humans with AS, animal models with Alms1 loss-of-function mutations develop obesity, supporting the notion that ALMS1 is required for the regulatory control of energy balance across species. This study aimed to determine which component(s) of energy balance are reliant on ALMS1. METHODS: Comprehensive energy balance phenotyping was performed on Alms1tvrm102 mice at both 8 and 18 weeks of age. RESULTS: It was found that adiposity gains occurred early and rapidly in Alms1tvrm102 male mice but much later in females. Rapid increases in body fat in males were due to a marked reduction in energy expenditure (EE) during early life and not due to any genotype-specific increases in energy intake under chow conditions. Energy intake did increase in a genotype-specific manner when mice were provided a high-fat diet, exacerbating the effects of reduced EE on obesity progression. The EE deficit observed in male Alms1tvrm102 mice did not persist as mice aged. CONCLUSIONS: Either loss of ALMS1 causes a developmental delay in the mechanisms controlling early life EE or activation of compensatory mechanisms occurs after obesity is established in AS. Future studies will determine how ALMS1 modulates EE and how sex moderates this process.

Management of Monogenic and Syndromic Obesity.

Similar to the general population, lifestyle interventions focused on nutrition and physical activity form the foundation for treating obesity caused by rare genetic disorders. Additional therapies, including metreleptin and setmelanotide, that target defects within the leptin signaling pathway can effectively synergize with lifestyle efforts to treat monogenic disorders of leptin, leptin receptor, proopiomelanocortin (POMC), and proprotein convertase subtilisin/kexin type 1 (PCSK1) and syndromic conditions, such as the ciliopathies Bardet-Biedl and Alström syndromes, whose pathophysiological mechanisms also converge on the leptin pathway. Investigational treatments for Prader-Willi syndrome target specific defects caused by reduced expression of paternally derived genes within the chromosome 15q region.

Amino-terminal propeptide of C-type natriuretic peptide (NTproCNP) predicts height velocity in healthy children.

OBJECTIVE: C-type natriuretic peptide (CNP) is a paracrine regulatory factor of the growth plate and plays a key role in endochondral growth. Its amino-terminal propeptide (NTproCNP) is an equimolar product of CNP biosynthesis and is easily measured in plasma. Preliminary studies suggest that NTproCNP levels correlate with height velocity in sheep and children. The objectives of the study were to correlate NTproCNP levels with height velocity and to define the reference range for plasma CNP and NTproCNP across childhood. DESIGN: This was a prospective, cross-sectional, observational study of healthy children. PATIENTS: Participants were 258 healthy children between 2 months and 20 years of age. MEASUREMENTS: Anthropometrics were obtained and CNP and NTproCNP levels were determined by radioimmunoassay. RESULTS: For both sexes, CNP and NTproCNP levels were high in infancy, lower in early childhood, rising during puberty, then falling to low adult levels. Levels of NTproCNP peaked at 14·1 years in boys and 11·9 years in girls, coincident with the age of peak height velocity. Levels of NTproCNP varied with pubertal status, peaking at genital Tanner stage IV in boys and III in girls. There was a highly significant correlation between NTproCNP and height velocity. CONCLUSIONS: C-type natriuretic peptide plays an integral role in endochondral growth. We show here that CNP synthesis (as measured by NTproCNP levels in plasma) is closely related to linear growth in healthy children at all ages. We propose NTproCNP as a biomarker of linear growth.

Acceptability of Time-Limited Eating in Pediatric Weight Management.

Background: Adherence to dietary interventions is a significant barrier in the treatment of childhood obesity. Time-limited eating (TLE) is a simple dietary approach that limits food intake to a given number of consecutive hours per day, but parental and youth acceptability of TLE in youth with obesity is unknown. This study explored the feasibility of utilizing TLE among parents and youth attending pediatric weight management (PWM). Methods: Members of COMPASS (Childhood Obesity Multi-Program Analysis and Study System) developed a survey to assess the acceptability of TLE in families attending PWM, which included patient characteristics, current diet and sleep schedules, and interests in trying TLE. The survey was administered electronically via REDCap or manually to parents of patients between the ages of 8-17 years old and to patients 11-17 years old attending one of five PWM practices in the COMPASS network. Results: Patients (n=213) were 13.0 ± 2.5 years old, 58% female, 52% White, 22% Black, 17% Hispanic/Latino, and 47% reported a diagnosed psychological disorder. On average, parents reported their child's daily eating spanned 12.5 ± 1.9 hours (7:35am - 8:05pm) and included 5.6 ± 1.6 eating bouts (meals + snacks). Most parents reported being likely to try TLE ≤12 hours/d (TLE12: 66%), which was similar to the likelihood of following a nutrient-balanced diet (59%). Likelihood was lower for TLE ≤10 hours/d (TLE10: 39%) or ≤8 hours/d (TLE8: 26%) (p<0.001 for both). Interest in TLE was not consistently related to patient age, sex, or ethnicity, but was lower in patients with a psychiatric diagnosis vs. no diagnosis (TLE8: 19% vs. 32%; p=0.034). Patients of parents who reported being likely to try TLE, compared to those unlikely to try TLE, had shorter eating windows (p<0.001) and ate fewer snacks (p=0.006). Conclusions: Two-thirds of parents with children attending PWM programs report interest in TLE ≤12 hours/d regardless of demographic characteristics, but interest wanes when limiting eating to ≤10 or ≤8 hours per day. Time-limited eating appears to be a feasible option in PWM settings provided treatment options are individualized based on the interests and barriers of patients and their families.

Pharmacologic Weight Management in the Era of Adolescent Obesity.

CONTEXT: Pediatric obesity is a serious health problem in the United States. While lifestyle modification therapy with dietary changes and increased physical activity are integral for the prevention and treatment of mild to moderate obesity in youth, only a modest effect on sustained weight reduction is observed in children and young adults with severe obesity. This underscores the need for additional evidence-based interventions for children and adolescents with severe obesity, including pharmacotherapy, before considering invasive procedures such as bariatric surgery. EVIDENCE ACQUISITION: This publication focuses on recent advances in pharmacotherapy of obesity with an emphasis on medications approved for common and rarer monogenic forms of pediatric obesity. EVIDENCE SYNTHESIS: We review medications currently available in the United States, both those approved for weight reduction in children and "off-label" medications that have a broad safety margin. CONCLUSION: It is intended that this review will provide guidance for practicing clinicians and will encourage future exploration for successful pharmacotherapy and other interventions for obesity in youth.

Chronic intake of high dietary sucrose induces sexually dimorphic metabolic adaptations in mouse liver and adipose tissue.

Almost all effective treatments for non-alcoholic fatty liver disease (NAFLD) involve reduction of adiposity, which suggests the metabolic axis between liver and adipose tissue is essential to NAFLD development. Since excessive dietary sugar intake may be an initiating factor for NAFLD, we have characterized the metabolic effects of liquid sucrose intake at concentrations relevant to typical human consumption in mice. We report that sucrose intake induces sexually dimorphic effects in liver, adipose tissue, and the microbiome; differences concordant with steatosis severity. We show that when steatosis is decoupled from impairments in insulin responsiveness, sex is a moderating factor that influences sucrose-driven lipid storage and the contribution of de novo fatty acid synthesis to the overall hepatic triglyceride pool. Our findings provide physiologic insight into how sex influences the regulation of adipose-liver crosstalk and highlight the importance of extrahepatic metabolism in the pathogenesis of diet-induced steatosis and NAFLD.

Prenatal metabolomic profiles mediate the effect of maternal obesity on early childhood growth trajectories and obesity risk: the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) Study.

BACKGROUND: Maternal prepregnancy obesity is an important risk factor for offspring obesity, which may partially operate through prenatal programming mechanisms. OBJECTIVES: The study aimed to systematically identify prenatal metabolomic profiles mediating the intergenerational transmission of obesity. METHODS: We included 450 African-American mother-child pairs from the Conditions Affecting Neurocognitive Development and Learning in Early Childhood (CANDLE) Study pregnancy cohort. LC-MS was used to conduct metabolomic profiling on maternal plasma samples of the second trimester. The childhood growth outcomes of interest included BMI trajectories from birth to age 4 y (rising-high-, moderate-, and low-BMI trajectories) as well as overweight/obesity (OWO) risk at age 4 y. Mediation analysis was conducted to identify metabolite mediators linking maternal OWO and childhood growth outcomes. The potential causal effects of maternal OWO on metabolite mediators were examined using the Mendelian randomization (MR) method. RESULTS: Among the 880 metabolites detected in the maternal plasma during pregnancy, 14 and 11 metabolites significantly mediated the effects of maternal prepregnancy OWO on childhood BMI trajectories and the OWO risk at age 4 y, respectively, and 5 mediated both outcomes. The MR analysis suggested 6 of the 20 prenatal metabolite mediators might be causally influenced by maternal prepregnancy OWO, most of which are from the pathways related to the metabolism of amino acids (hydroxyasparagine, glutamate, and homocitrulline), sterols (campesterol), and nucleotides (N2,N2-dimethylguanosine). CONCLUSIONS: Our study provides further evidence that prenatal metabolomic profiles might mediate the effect of maternal OWO on early childhood growth trajectories and OWO risk in offspring. The metabolic pathways, including identified metabolite mediators, might provide novel intervention targets for preventing the intrauterine development of obesity in the offspring of mothers with obesity.