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Objective Extreme obesity is a core phenotypic feature of Prader–Willi syndrome (PWS). Among numerous metabolic regulators, the endocannabinoid (eCB) system is critically involved in controlling feeding, body weight, and energy metabolism, and a globally acting cannabinoid-1 receptor (CB1R) blockade reverses obesity both in animals and humans. The first-in-class CB1R antagonist rimonabant proved effective in inducing weight loss in adults with PWS. However, it is no longer available for clinical use because of its centrally mediated, neuropsychiatric, adverse effects. Methods We studied eCB ‘tone’ in individuals with PWS and in the Magel2-null mouse model that recapitulates the major metabolic phenotypes of PWS and determined the efficacy of a peripherally restricted CB1R antagonist, JD5037 in treating obesity in these mice. Results Individuals with PWS had elevated circulating levels of 2-arachidonoylglycerol and its endogenous precursor and breakdown ligand, arachidonic acid. Increased hypothalamic eCB ‘tone’, manifested by increased eCBs and upregulated CB1R, was associated with increased fat mass, reduced energy expenditure, and decreased voluntary activity in Magel2-null mice. Daily chronic treatment of obese Magel2-null mice and their littermate wild-type controls with JD5037 (3 mg/kg/d for 28 days) reduced body weight, reversed hyperphagia, and improved metabolic parameters related to their obese phenotype. Conclusions Dysregulation of the eCB/CB1R system may contribute to hyperphagia and obesity in Magel2-null mice and in individuals with PWS. Our results demonstrate that treatment with peripherally restricted CB1R antagonists may be an effective strategy for the management of severe obesity in PWS., Highlights • Circulating levels of endocannabinoids are increased in individuals with PWS. • Magel2 is a negative regulator of hypothalamic endocannabinoid ‘tone’. • Peripherally-restricted CB1 receptor blockade reverses obesity in Magel2-null 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.

Background Telomere length

Many neuropsychiatric risk genes contribute to epigenetic regulation of gene expression but very little is known about specific chromatin-associated mechanisms governing the formation and maintenance of neuronal connectivity. Here we show that transcallosal connectivity is critically dependent on C11orf46 (also known as ARL14EP), a small nuclear protein encoded in the chromosome 11p13 Wilms Tumor, Aniridia, Genitourinary Abnormalities, intellectual disability (formerly referred to as Mental Retardation) (WAGR) risk locus. C11orf46 haploinsufficiency in WAGR microdeletion cases was associated with severe hypoplasia of the corpus callosum. In utero short hairpin RNA-mediated C11orf46 knockdown disrupted transcallosal projections of cortical pyramidal neurons, a phenotype that was rescued by wild type C11orf46 but not the C11orf46R236H mutant associated with autosomal recessive intellectual disability. Multiple genes encoding key regulators of axonal growth and differentiation, including Sema6A, were hyperexpressed in C11orf46-knockdown neurons. Importantly, RNA-guided epigenetic editing of neuronal Sema6a gene promoters via a dCas9 protein-conjugated SunTag scaffold with multimeric (10x) C11orf46 binding during early developmental periods, resulted in normalization of expression and rescue of transcallosal dysconnectivity via repressive chromatin remodeling, including up-regulated histone H3K9 methylation by the KAP1-SETDB1 repressor complex. Our study demonstrates that interhemispheric communication is highly sensitive to locus-specific remodeling of neuronal chromatin, revealing the therapeutic potential for shaping the brain’s connectome via gene-targeted designer activators and repressor proteins.

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.

Cranial radiation therapy (CRT) contributes to cognitive late effects that require rehabilitative interventions. Physical activity (PA) targets CRT-damaged brain mechanisms and cognitive functions. We conducted a pilot RCT to evaluate the feasibility of an innovative home PA intervention program for children treated with CRT for brain tumors. Eligible children 8-17 years, >two years post-CRT, with cognitive late effects were randomized to the Intervention Group (IG), which followed a 12-week home program to increase PA then maintained PA for 12 weeks, or the Control Group (CG), which monitored usual PA for 12 weeks followed by the 12-week program. Psychologists taught Acceptance and Commitment Therapy (ACT) techniques to facilitate PA engagement. Participants used Zamzee accelerometers/website to track moderate-to-vigorous PA (MVPA). Evaluations included plasma/serum circulating growth factors, cardiovascular fitness, cognitive function pre/post the first 12 weeks, and child/parent feasibility questionnaires (1-5 ratings, categories, open-ended questions). Six children (mean age=13.8 years, 10-17; IG=3; CG=3) enrolled and completed the study. Participants enjoyed the activity tracker (mean=3.8) and wore it 3-4 times/week to daily, but it broke easily; most liked the website’s activity graphs, rewards, and challenges (mean=3.3; uploaded data/viewed

Time-restricted feeding (TRF) limits the duration of food availability without altering diet composition and can combat obesity in humans and mice. For this study we evaluated the effect of timing of food access during a TRF protocol on weight gain, adiposity, and inflammation. Young male C57BL/6 mice were placed on a high-fat (HF) diet (45% fat) for 8 weeks. Food access was unrestricted (HF) or restricted to 6 h per day, either for the first half (HF-early) or the second half (HF-late) of the active phase to resemble a window of time for food consumption early or late in the day in a human population. Weight, obesity-associated parameters, and inflammation were measured. TRF reduced weight gain over the 8-week period in mice consuming the same high-fat diet. Consistent with decreased weight gain in the TRF groups, body fat percentage, liver triglycerides, and plasma leptin and cholesterol levels were reduced. Adipose tissue inflammation, measured by CD11b+F4/80+ macrophage infiltration, was reduced in both TRF groups, but systemic tumor necrosis factor-α was increased in all groups consuming the high-fat diet. The HF-late group gained more weight than the HF-early group and had increased insulin resistance, while the HF-early group was protected. Therefore, a TRF protocol is beneficial for weight management when a high-fat diet is consumed, with food consumption earlier in the day showing greater health benefits. However, increased inflammatory markers in the TRF groups suggest that diet components can still increase inflammation even in the absence of overt obesity.

BACKGROUND: Alström syndrome (AS), a monogenic form of obesity, is caused by recessive mutations in the centrosome- and basal body–associated gene ALMS1. AS is characterized by retinal dystrophy, sensory hearing loss, cardiomyopathy, childhood obesity, and metabolic derangements. OBJECTIVE: We sought to characterize the endocrine and metabolic features of AS while accounting for obesity as a confounder by comparing patients with AS to body mass index (BMI)–matched controls. METHODS: We evaluated 38 patients with AS (age 2 to 38 years) who were matched with 76 controls (age 2 to 48 years) by age, sex, race, and BMI. Fasting biochemistries, mixed meal test (MMT), indirect calorimetry, dual-energy X-ray absorptiometry, and MRI/magnetic resonance spectroscopy were performed. RESULTS: Frequent abnormalities in AS included 76% obesity, 37% type 2 diabetes mellitus (T2DM), 29% hypothyroidism (one-third central, two-thirds primary), 3% central adrenal insufficiency, 57% adult hypogonadism (one-third central, two-thirds primary), and 25% female hyperandrogenism. Patients with AS and controls had similar BMI z scores, body fat, waist circumference, abdominal visceral fat, muscle fat, resting energy expenditure (adjusted for lean mass), free fatty acids, glucagon, prolactin, ACTH, and cortisol. Compared with controls, patients with AS were shorter and had lower IGF-1 concentrations (Ps ≤ 0.001). Patients with AS had significantly greater fasting and MMT insulin resistance indices, higher MMT glucose, insulin, and C-peptide values, higher HbA1c, and higher prevalence of T2DM (Ps < 0.001). Patients with AS had significantly higher triglycerides, lower high-density lipoprotein cholesterol, and a 10-fold greater prevalence of metabolic syndrome (Ps < 0.001). Patients with AS demonstrated significantly greater liver triglyceride accumulation and higher transaminases (P < 0.001). CONCLUSION: Severe insulin resistance and T2DM are the hallmarks of AS. However, patients with AS may present with multiple other endocrinopathies affecting growth and development.

Objective:PAX6 haploinsufficiency ( +/−) can occur due to mutations involving only PAX6 in patients with isolated aniridia or as contiguous gene deletions in patients with Wilms tumor, aniridia, genitourinary anomalies, and range of developmental and intellectual disabilities syndrome. Given the role of PAX6 in pineal development and circadian regulation, adolescents with PAX6+/− may experience sleep–wake disturbances. The purpose of this observational study was to explore sleep-related phenotypes in adolescents with PAX6+/−.Methods:This study compared sleep phenotypes of nine subjects with PAX6+/− (aged 10–19 years) with previously published data on healthy adolescents ( n = 25, aged 10–18 years). Subjects completed the Cleveland Adolescent Sleepiness Questionnaire (CASQ), Patient Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance (v. 1.0; 8a), and PROMIS Sleep-Related Impairment (v. 1.0; 8b) Questionnaires and wore actigraphs for seven nights to record sleep patterns.Results:Total CASQ, PROMIS sleep-related impairment, and PROMIS sleep disturbance scores were not statistically different between the groups ( ps > .15). Actigraph data for lights off to sleep-onset time were found to be significantly higher in subjects with PAX6+/− versus the healthy comparison group (adjusted mean [95% confidence interval]: 20.1 min [8.1, 49.8] vs. 6.2 min [3.7, 10.4], respectively, p = .04).Conclusion:Both adolescents with PAX6+/− and the healthy comparison group on average slept less than 8 hr/night, and overall sleep deprivation in adolescents may have masked differences between groups. This study used rare genetic disorders with biological vulnerability to sleep problems as a genotype–phenotype model. Knowledge of sleep-related phenotypes will assist in designing studies to manage sleep-related symptoms in adolescents.

We investigated executive functioning in 25 children and adolescents with Prader-Willi syndrome (PWS) on the Behavior Rating Inventory of Executive Function (BRIEF). Significant deficits emerged, with mean scores on all but two scales reaching levels of clinical significance (T score ≥ 65). Older children tended to have higher scores than younger children. Children with uniparental disomy demonstrated higher scores than children with deletion and were more likely than children with deletion to have ratings in the clinically significant range on two scales. The PWS BRIEF profile resembles that of children with autism and intellectual disability from previous studies. Results are discussed in the context of intervention development.

Our clinical experience with low dose loxapine (5-15 mg/day) suggests promising efficacy and safety for irritability in autism spectrum disorders (ASD). We studied low dose loxapine prospectively in adolescents and adults with ASD and irritability. Additionally, we measured loxapine and metabolite concentrations, and brain-derived neurotrophic factor (BDNF) as a biomarker of neuromodulation.We performed a 12 week open trial of add-on loxapine in subjects, ages 13-65 years, diagnosed with ASD, and Aberrant Behavior Checklist-Irritability (ABC-I) subscale scores14. Loxapine was dosed flexibly up to 15 mg daily, starting with 5 mg on alternate days. From weeks 1 to 6, other psychoactive medications were tapered if possible; from weeks 6 to 12, all medication doses were held stable. The primary outcome was the Clinical Global Impressions-Improvement subscale (CGI-I), ratings of Much Improved or Very Much Improved. Secondary outcomes were the ABC-I, Repetitive Behavior Scale-Revised, and Schalock Quality of Life scale. Serum BDNF and loxapine and metabolite concentrations were assayed. BDNF rs6265 was genotyped.Sixteen subjects were enrolled; 12 completed all visits. Median age was 18 years (range 13-39). Median final loxapine dose was 7.5 mg/day (2.5-15). All 14 subjects (100%) with data at week 12 were rated as Much Improved on CGI-I at 12 weeks. Mean change on ABC-I at 12 weeks was -31%, p=0.01. Mean body mass index (BMI)-Z decreased between weeks 6 and 12, p=0.03. Side effects were minimal, and prolactin elevation occurred in only one subject. BDNF concentrations measured in 11 subjects increased significantly (p=0.04). Subjects with AG genotype for BDNF rs6265 required a lower dose of loxapine at study end, but had similar behavioral and BDNF concentration changes as the GG genotype.Low dose loxapine shows promise as a repurposed drug for irritability in ASD. Loxapine effects on BDNF warrant further study.

Background Alstrom 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 37.9 years; 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.

Objective Hyperphagia is a central feature of inherited disorders (e.g., Prader–Willi Syndrome) in which obesity is a primary phenotypic component. Hyperphagia may also contribute to obesity as observed in the general population, thus raising the potential importance of common underlying mechanisms and treatments. Substantial gaps in understanding the molecular basis of inherited hyperphagia syndromes are present as are a lack of mechanistic of mechanistic targets that can serve as a basis for pharmacologic and behavioral treatments. Design and Methods International conference with 28 experts, including scientists and caregivers, providing presentations, panel discussions, and debates. Results The reviewed collective research and clinical experience provides a critical body of new and novel information on hyperphagia at levels ranging from molecular to population. Gaps in understanding and tools needed for additional research were identified. Conclusions This report documents the full scope of important topics reviewed at a comprehensive international meeting devoted to the topic of hyperphagia and identifies key areas for future funding and research.

Shared decision-making (SDM) is a best practice for delivering high-quality, patient-centered care when there are multiple options from which to choose. A patient decision aid (PDA) to promote SDM for the treatment of adolescent severe obesity was piloted among 12−17-year-olds (n = 31) from six pediatric weight management programs within the Childhood Obesity Multi Program Analysis and Study System (COMPASS). Medical providers used a brochure that described indications, risks, and benefits of intensive lifestyle management alone versus bariatric surgery plus lifestyle. Immediately after, patients/families completed a survey. Patient/family perceptions of provider effort to promote understanding of health issues, to listen to what mattered most to them, and to include what mattered most to them in choosing next steps averaged 8.6, 8.8, and 8.7, respectively (0 = no effort, 9 = every effort). Nearly all (96%) reported knowing the risks/benefits of each treatment option and feeling clear about which risks/benefits mattered most to them. Most (93%) reported having enough support/advice to make a choice, and 89% felt sure about what the best choice was. Providers largely found the PDA to be feasible and acceptable. This pilot will guide a more rigorous study to determine the PDA’s effectiveness to support decision-making for adolescent severe obesity treatment.

Objective Obesity is a major public health problem that increases risk for a broad spectrum of co-morbid conditions. Despite evidence for a strong genetic contribution to susceptibility to obesity, previous efforts to discover the relevant genes using positional cloning have failed to account for most of the apparent genetic risk variance.

Detection of human microdeletion and microduplication syndromes poses significant burden on public healthcare systems in developing countries. With genome-wide diagnostic assays frequently inaccessible, targeted low-cost PCR-based approaches are preferred. However, their reproducibility depends on equally efficient amplification using a number of target and control primers. To address this, the recently described technique called Microdeletion/Microduplication Quantitative Fluorescent PCR (MQF-PCR) was shown to reliably detect four human syndromes by quantifying DNA amplification in an internally controlled PCR reaction. Here, we confirm its utility in the detection of eight human microdeletion syndromes, including the more common WAGR, Smith-Magenis, and Potocki-Lupski syndromes with 100% sensitivity and 100% specificity. We present selection, design, and performance evaluation of detection primers using variety of approaches. We conclude that MQF-PCR is an easily adaptable method for detection of human pathological chromosomal aberrations.

Bardet-Biedl syndrome (BBS) is a rare, genetically heterogeneous disorder (1, 2) with retinal dystrophy, post-axial polydactyly, developmental delay, renal abnormalities, and obesity in 70–90% (1, 3, 4). Genes involved in formation, stability, and function of cilia are implicated as causes of BBS (5–7). The high penetrance of the obesity phenotype in patients suggests that ciliary proteins play an important role in body energy balance and weight regulation. Several mouse models of BBS recapitulate features of the human phenotype and have altered protein/vesicle trafficking in leptin-sensing hypothalamic neurons, possibly inducing leptin resistance and hyperphagia, consistent with the observation that BBS knockout mice consume 20–30% more energy than controls (8, 9). Human studies characterizing the obesity phenotype of patients with BBS are few (10–12) and do not provide definitive data for the contributions of increased energy intake, decreased physical activity or altered metabolism to their obesity. A study of energy homeostasis in 20 BBS overweight or obese subjects and 20 controls reported no differences in energy intake or resting energy expenditure, but found physical activity (by actigraphy) was slightly, but significantly, lower among patients with BBS (10). This study, however, used a self-report 7-day food diary for energy intake assessment that, given the cognitive impairment of patients with BBS, may need to be interpreted cautiously. There are several syndromes where obesity occurs together with cognitive dysfunction and the obesity is associated with hyperphagic symptoms (13–16). One example is the Prader-Willi syndrome (PWS) (13). Patients with PWS show defects in post-meal satiation and satiety in the laboratory setting (17, 18). They have many hyperphagic characteristics, in addition to overeating, that include preoccupation with food (hyperphagic drive), excessive food seeking such as waking up at night to seek food, foraging through trash, stealing and hiding food (hyperphagic behavior), and significant functional impairment and distress when denied food. To address the challenges of requiring intellectually-impaired participants to report their own behaviors, Dykens et al. (13) developed and validated in patients with PWS, a questionnaire that assesses hyperphagic symptoms by asking caregivers to report their observations. Given the convincing data for hyperphagia found in BBS mouse models (8, 9), we hypothesized that, if increased food intake was a cause of obesity in humans with BBS, the caregivers of patients with BBS would report greater hyperphagic symptoms than would caregivers of equally obese non-syndromic controls. We recruited a convenient sample of 13 patients diagnosed with BBS using clinical criteria (19) from among participants in an observational study of the genetic and clinical characteristics of patients with BBS (http://clinicaltrials.gov/ct2/show/NCT00078091). Healthy control subjects (with no known syndrome associated with obesity or major illness affecting appetite) were selected from among participants in studies of eating behavior and metabolism (http://clinicaltrials.gov/ct2/show/NCT00758108, http://clinicaltrials.gov/ct2/show/NCT00631644, and http://clinicaltrials.gov/ct2/show/NCT01237041). The studies were approved by the NICHD or NHGRI IRBs. Participants provided consent/assent for participation. The Hyperphagia Questionnaire (13) is a 13-item questionnaire with 11 items rated on a 5-point Likert scale (from 1= not a problem at all, to 5= extremely problematic) that produce a total hyperphagic score (range 11–55) and three sub-scales: hyperphagic behavior (range 5–25), hyperphagic drive (range 4–20), and hyperphagic severity (range 2–10) (13). Questions 12 and 13 seek information on the age when a child’s interest in food increased and on how much the child’s interest in food changes from day to day. The Hyperphagia Questionnaire was completed by the parent/guardian who spent the most time with the participant. Using analyses of covariance (ANCOVA), we compared Hyperphagia Questionnaire scale scores for BBS vs. the control group, adjusting for age, sex, race, and BMI-Z score. Chi-square test was used to compare the two groups for the additional questions; day-to-day variability in behavior is not reported because of many missing responses in the control group. Characteristics of study subjects are summarized in Table 1. The subjects in the two groups did not differ significantly in sex, age, race, or BMI-Z score, although height was significantly lower among BBS, which might be attributable to slower growth in adolescence (20). Among patients with BBS, genomic sequencing confirmed 1 case had mutations in BBS6, 1 in BBS7, and 6 in BBS10 (data not shown). In unadjusted comparisons, the total hyperphagia score (p=0.005), behavioral subscale (p=0.001), and drive subscale scores (p=0.040) were significantly greater in patients with BBS than controls (Figure 1). After adjustment for age, sex, race, and BMI-Z score, group differences remained significant for total hyperphagia score (p=0.032) and the behavioral subscale (p=0.003). Among those whose caregivers reported an age when they first observed increased interest in food, 91% (10/11) of patients with BBS, versus 42% (5/12) of controls reported increased interest in food before age 5 y (p=0.013). Each of the subscales and total hyperphagia score were highly correlated across the sample (r’s >0.85 for correlations between scores, all p

Culturally tailored and comprehensive prevention strategies are vital for addressing the epidemic of obesity and rising rates of type 2 diabetes, particularly among ethnic and racial minority youth (1). The Diabetes Prevention Program (DPP) has demonstrated the efficacy of lifestyle modification in adults (2). However, studies on lifestyle programs for diabetes prevention in youth are limited, and none have reported comprehensive physical fitness outcomes (3–5). We conducted a pilot prospective uncontrolled study (ClinicalTrials.gov identifier NCT03042936) evaluating feasibility and changes in metabolic and physical fitness parameters for the Insulin Superheroes Club (ISC) curriculum, a DPP designed for youth from culturally diverse, minority backgrounds. Youth aged 7–15 years and a parent with impaired glucose tolerance enrolled in the ISC as a supplement to the Centers for Disease Control and Prevention’s adult DPP. The ISC is a 12-month, multilevel program that includes 16 weekly (phase 1), 3 biweekly (phase 2), and 6 monthly (phase 3) sessions. Participants attended sessions that included 60 min of physical fitness and 30 min of education. The education portion included interactive …

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 patients13 years old. Pineal volume was fivefold lower in PAX6+/− versus controls (mean ± SD: 25 ± 15 versus 129 ± 50 μL, P0.001). Midnight serum cortisol was similar in PAX6+/− versus controls (P = 0.14). Midnight serum melatonin wastwofold lower in PAX6+/− versus controls [median (25th-75 th): 28 (22-42) versus 71 (46-88) pg mL-(1), P0.001]. 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+/−.

Rare genetic disorders that cause BDNF haploinsufficiency, such as WAGR syndrome, 11p deletion, and 11p inversion, serve as models for understanding the role of BDNF in human energy balance and neurocognition. Patients with BDNF haploinsufficiency or inactivating mutations of the BDNF receptor exhibit hyperphagia, childhood-onset obesity, intellectual disability, and impaired nociception. Prader–Willi, Smith–Magenis, and ROHHAD syndromes are separate genetic disorders that do not directly affect the BDNF locus but share many similar clinical features with BDNF haploinsufficiency, and BDNF insufficiency is believed to possibly contribute to the pathophysiology of each of these conditions. In the general population, common variants of BDNF that affect BDNF gene expression or BDNF protein processing have also been associated with modest alterations in energy balance and cognitive functioning. Thus, variable degrees of BDNF insufficiency appear to contribute to a spectrum of excess weight gain and cognitive impairment that ranges in phenotypic severity. In this modern era of precision medicine, genotype-specific therapies aimed at increasing BDNF signaling in patients with rare and common disorders associated with BDNF insufficiency could serve as useful approaches for treating obesity and neurodevelopmental disorders.

SummaryObjective 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.

Bardet-Biedl syndrome (BBS) is a genetically heterogeneous disorder of the primary cilium associated with obesity. In BBS mouse models, ciliary dysfunction leads to impaired leptin signaling and hyperleptinemia before obesity onset. To study the pathophysiology of obesity in BBS, we compared patients with BBS and body mass index Z-score (BMI-Z)-matched controls.Fifty patients with BBS were matched 2:1 by age, sex, race, and BMI-Z with 100 controls. Patients with BBS and controls were compared for differences in body composition (dual-energy x-ray absorptiometry, abdominal magnetic resonance imaging), blood pressure Z-score (BP-Z; standardized for age, sex, and height), and fasting concentrations of leptin, lipids, insulin, and glucose. Patients with BBS were also compared by genotype.Leptin, triglycerides, intraabdominal fat mass, and diastolic BP-Z were significantly greater in patients with BBS than in the controls. BBS1 (27%) and BBS10 (30%) mutations were the most prevalent. Patients with BBS10 mutations had significantly higher BMI-Z, greater visceral adiposity, and greater insulin resistance than those with BBS1 mutations.Patients with BBS had higher leptin than expected for their degree of adiposity, consistent with the notion that ciliopathy-induced leptin signaling dysfunction is associated with leptin resistance. The preferential deposition of fat intraabdominally in patients with BBS may indicate a predisposition for metabolic complications, including hypertension and hypertriglyceridemia. The observation of disparate results in the BBS10 vs. BBS1 mutation groups is the first demonstration of physiological differences among patients with BBS caused by mutations in distinct genes. These results suggest that the obesity of BBS is distinct from nonsyndromic obesity.

The worldwide prevalence of childhood obesity has increased greatly over the past 3 decades. The increasing occurrence in children of disorders, such as type 2 diabetes, is believed to be a consequence of this obesity epidemic. Much progress has been made in understanding the genetics and physiology of appetite control and from this, the elucidation of the causes of some rare obesity syndromes. However, these rare disorders have so far taught us only limited lessons on how to prevent or reverse obesity in most children. Calorie intake and activity recommendations need to be re-assessed and better quantified, on a population level, given the more sedentary life of children today. For individual treatment, the currently recommended calorie prescriptions may be too conservative given the evolving insight on the “energy gap.” Whilst quality of research in both prevention and treatment has improved, there is still a need for high-quality multi-centre trials with long-term follow-up. Meanwhile, prevention and treatment approaches that aim to increase energy expenditure and decrease intake need to continue. Most recently, the spiralling increase in obesity prevalence may be abating for children. Thus, even greater efforts need to be made on all fronts to continue this potentially exciting trend.

A female patient with a partial trisomy 16q was described previously. Her clinical characteristics included obesity, severe anisomastia, moderate to severe mental retardation, attention deficit hyperactivity disorder, dysmorphic facies, and contractions of the small joints. In this article, we describe a more detailed analysis of the genetic anomaly in this patient. We were particularly interested in the involvement of the fat mass and obesity associated gene (PTO) in her duplication. Single nucleotide polymorphisms in FTO have been associated with obesity. The breakpoints of the duplication were precisely mapped using high-resolution oligonucleotide array comparative genomic hybridization (CGH). We found that the duplication spans 11.45 Mb on 16q11.2 to 16q13 and it includes FTO. The increased copy number of FTO was confirmed with a qPCR on genomic DNA of the patient. We investigated the influence of the increased FTO copy number on FTO gene expression in immortalized lymphocytes from the patient using qPCR. No evidence of increased FTO expression was detected in the patient's lymphocytes. We discuss these findings and we review clinical findings in patients with overlapping 16q duplications to determine the relationship between increased FTO copy number and obesity. Our review suggests that duplication of the FTO gene does not necessarily result in obesity. (C) 2010 Wiley-Liss, Inc.

Background: Children with rs9939609 FTO variant alleles (homozygous = AA and heterozygous = AT) are predisposed to greater adiposity than are those with 2 wild-type alleles (TT). Objective: Because FTO is highly expressed in hypothalamic regions that are important for appetite, FTO genotype may affect energy balance by influencing eating behavior. Loss of control (LOC) eating, a behavior commonly reported by overweight youth, predicts excessive weight gain in children. However, the relation between FTO genotype and LOC eating has not been previously examined. Design: Two-hundred eighty-nine youth aged 6–19 y were genotyped for rs9939609, underwent body-composition measurements, and were interviewed to determine the presence or absence of LOC eating. A subset (n = 190) participated in a lunch buffet test meal designed to model an LOC eating episode. Subjects with AA and AT genotypes were grouped together for comparison with wild-type TT subjects. Results: Subjects with at least one A allele (67.7%) had significantly greater body mass indexes, body mass index z scores (P < 0.01), and fat mass (P < 0.05). Of the AA/AT subjects, 34.7% reported LOC compared with 18.2% of the TT subjects (P = 0.002). Although total energy intake at the test meal did not differ significantly by genotype (P = 0.61), AA/AT subjects consumed a greater percentage of energy from fat than did the TT subjects (P < 0.01). Conclusions: Children and adolescents with 1 or 2 FTO rs9939609 obesity-risk alleles report more frequent LOC eating episodes and select foods higher in fat at a buffet meal. Both LOC eating and more frequent selection of energy-dense, palatable foods may be mechanisms through which variant FTO alleles lead to excess body weight.

Context: Some studies suggest the presence of metabolic syndrome before adulthood may identify those at high risk for later cardiovascular morbidity, but there are few data examining the reliability of pediatric metabolic syndrome. Objective: To examine the short- and long-term stability of pediatric metabolic syndrome. Design: Metabolic syndrome was defined as having at least three of the following: waist circumference, blood pressure, and fasting serum triglycerides in the 90th or higher percentile for age/sex; high-density lipoprotein-cholesterol 10th or lower percentile for age/sex; and fasting serum glucose of at least 100 mg/dl. Short-term metabolic syndrome stability (repeated measurements within 60 d) was assessed in obese youth ages 6–17 yr. Long-term metabolic syndrome stability (repeated measurements more than 1.5 yr apart) was studied in 146 obese and nonobese children age 6–12 yr at baseline. Patients and Setting: Convenience samples of obese and nonobese youth ages 6–17 yr participating in research studies were collected at a clinical research hospital. Results: Short-term metabolic syndrome stability (repeat measurements performed 19.7 ± 13.1 d apart) was assessed in 220 children. The diagnosis of metabolic syndrome was unstable in 31.6% of cases. At their short-term follow-up visit, incidence of metabolic syndrome among participants who did not have metabolic syndrome at baseline was 24%. In the long term (repeat measurements performed 5.6 ± 1.9 yr apart), the diagnosis of metabolic syndrome was unstable in 45.5% of cases. Conclusions: Cutoff-point-based definitions for pediatric metabolic syndrome have substantial instability in the short and long term. The value of making a cutoff-point-based diagnosis of metabolic syndrome during childhood or adolescence remains in question.

Background: Homozygosity for 2 protein-altering polymorphisms in the melanocortin-3 receptor gene (MC3R) coding sequence, C17A and G241A, has been reported to be associated with an obesity phenotype in children, yet how these polymorphisms affect energy homeostasis is unknown. Association between adult body weight and +2138InsCAGACC, another variant in the 3# untranslated region of MC3R, has also been described. Objective: The objective of this study was to examine associations of C17A + G241A and +2138InsCAGACC MC3R variants with children’s energy balance. Design: Children aged 6–19 y were genotyped for MC3R C17A, G241A, and +2138InsCAGACC. Subjects underwent studies of energy intake from a 9835-kcal food array (n = 185), resting energy expenditure (REE) by using indirect calorimetry (n = 302), or total daily energy expenditure (TEE) by using doubly labeled water (n = 120). Linear regression was used to examine the associations between MC3R polymorphisms and the measures of energy balance. Results: Body mass index and fat mass were greater in those with double homozygosity for C17A + G241A (P = 0.001). After accounting for covariates (including body composition), the number of minor C17A + G241A alleles was associated with significantly greater energy intake (b = +0.15, P = 0.02) but not altered REE or TEE. No significant associations were observed between +2138InsCAGACC and measures of either fat mass or energy balance. Conclusions: C17A + G241A polymorphisms may be associated with pediatric obesity because of greater energy intake rather than because of diminished energy expenditure. +2138InsCAGACC does not appear to be associated with obesity or measures of energy balance in children. Am J Clin Nutr 2009;90:912–20.

WAGR (Wilms tumor, Aniridia, Genitourinary malformations and mental Retardation) syndrome is a rare genomic disorder caused by deletion of the 11p14-p12 chromosome region. The majority of WAGR patients have mental retardation and behavioral problems, and more than 20% of the patients also have features of autism. While the Wilms tumor/genitourinary anomalies and aniridia are caused by deletion of WT1 and PAX6 respectively, the genomic cause of mental retardation and autism in WAGR syndrome remains unknown. Using oligonucleotide arrays, we have characterized the 11p14-p12 deletions in 31 patients and identified all the genes involved in each deletion. The deletions had sizes ranging from 4.9 to 23 Mb that encompass 18–62 genes (40 on average). In addition to WT1 and PAX6, all the patients had deletion of PRRG4 (transmembrane gamma-carboxyglutamic acid protein 4). The majority of them had deletion of BDNF (brain-derived neurotrophic factor) and SLC1A2 [solute carrier family 1 (glial high affinity glutamate transporter) member 2]. Deletion of BDNF and SLC1A2 occurred in patients with autism more frequently than in those without autism. Literature review on the functions of the genes suggests that haploinsufficiency of SLC1A2, PRRG4, and BDNF may contribute to mental retardation and behavioral problems. In particular, BDNF may modulate the risk of autism in WAGR patients as suggested by its link with Rett syndrome as a target of MECP2. We observed that all the de novo deletions occurred in the chromosome 11 inherited from the father in the families genotyped, implying a predisposition for de novo mutations occurring in spermatogenesis and possible involvement of imprinting in cognitive impairment in WAGR patients.

The neurotrophin brain-derived neurotrophic factor (BDNF) inhibits food intake, and rodent models of BDNF disruption all exhibit increased food intake and obesity, as well as hyperactivity. We report an 8-year-old girl with hyperphagia and severe obesity, impaired cognitive function, and hyperactivity who harbored a de novo chromosomal inversion, 46,XX,inv(11)(p13p15.3), a region encompassing the BDNF gene. We have identified the proximal inversion breakpoint that lies 850 kb telomeric of the 5′ end of the BDNF gene. The patient’s genomic DNA was heterozygous for a common coding polymorphism in BDNF, but monoallelic expression was seen in peripheral lymphocytes. Serum concentration of BDNF protein was reduced compared with age- and BMI-matched subjects. Haploinsufficiency for BDNF was associated with increased ad libitum food intake, severe early-onset obesity, hyperactivity, and cognitive impairment. These findings provide direct evidence for the role of the neurotrophin BDNF in human energy homeostasis, as well as in cognitive function, memory, and behavior.

A simple method is described for preparation of 2-nitro-5-thiobenzoic acid (NTB), a compound with versatile applications but is commercially unavailable. In this method, NTB is produced by the reduction of 5,5′-dithiobis(2-nitrobenzoic acid) (DTNB) with thiopropyl sepharose, which is then separated from NTB by filtration. Two molecules of NTB can be generated from each molecule of DTNB when a large excess of thiopropyl sepharose is used. Thiopropyl sepharose is commercially available and can be readily regenerated for repeated use in the preparation of NTB. This method is simple and more effective than any other reported methods of NTB preparation.

A simple spectrophotometric method for quantitative determination of hypochlorite (OCl−) or hypochlorous acid (HOCl) is described. The OCl−or HOCl sample is first incubated with an excess amount of tris(2-carboxyethyl)phosphine (TCEP). The concentration of the residual TCEP is then measured as the amount of 2-nitro-5-thiobenzoate produced after reaction with 5,5′-dithiobis(2-nitrobenzoic acid). The concentration of OCl−or HOCl is equivalent to the amount of decrease in the concentration of TCEP because one molecule of TCEP is rapidly and irreversibly oxidized to TCEP oxide by one molecule of OCl−or HOCl. This method is more sensitive and convenient than the standard procedure of NaOCl assay which involves reaction with potassium iodide followed by titration of the liberated triiodide with thiosulfate.

In rodents, hypothalamic brain-derived neurotrophic factor (BDNF) expression appears to be regulated by melanocortin-4 receptor (MC4R) activity. The impact of MC4R genetic variation on circulating BDNF in humans is unknown. The objective of this study is to compare BDNF concentrations of subjects with loss-of-function (LOF) and gain-of-function (GOF) MC4R variants with those of controls with common sequence MC4R. Circulating BDNF was measured in two cohorts with known MC4R sequence: 148 subjects of Pima Indian heritage ((mean±s.d.): age, 15.7±6.5 years; body mass index z-scores (BMI-Z), 1.63±1.03) and 69 subjects of Hispanic heritage (10.8±3.6 years; BMI-Z, 1.57±1.07). MC4R variants were characterized in vitro by cell surface expression, receptor binding and cyclic AMP response after agonist administration. BDNF single-nucleotide polymorphisms (SNPs) rs12291186, rs6265 and rs7124442 were also genotyped. In the Pima cohort, no significant differences in serum BDNF was observed for 43 LOF subjects versus 65 LOF-matched controls (age, sex and BMI matched; P=0.29) or 20 GOF subjects versus 20 GOF-matched controls (P=0.40). Serum BDNF was significantly associated with genotype for BDNF rs12291186 (P=0.006) and rs6265 (P=0.009), but not rs7124442 (P=0.99); BDNF SNPs did not interact with MC4R status to predict serum BDNF. In the Hispanic cohort, plasma BDNF was not significantly different among 21 LOF subjects, 20 GOF subjects and 28 controls (P=0.79); plasma BDNF was not predicted by BDNF genotype or BDNF-x-MC4R genotype interaction. Circulating BDNF concentrations were not significantly associated with MC4R functional status, suggesting that peripheral BDNF does not directly reflect hypothalamic BDNF secretion and/or that MC4R signaling is not a significant regulator of the bulk of BDNF expression in humans.

Obesity is a major public health problem that increases the risk for a broad spectrum of co-morbid conditions. Despite evidence for a strong genetic contribution to susceptibility to obesity, previous efforts to discover the relevant genes using positional cloning have failed to account for most of the apparent genetic risk variance.Deploying a strategy combining analysis of exome sequencing data in extremely obese members of four consanguineous families with segregation analysis, we screened for causal genetic variants. Filter-based analysis and homozygosity mapping were used to identify and prioritize putative functional variants.Two novel frameshift mutations in the leptin receptor in two of the families were identified.These results provide proof-of-principle that whole-exome sequencing of families segregating for extreme obesity can identify causal pathogenic mutations. The methods described here can be extended to additional families segregating for extreme obesity and should enable the identification of mutations in novel genes that predispose to obesity.

Brain pathways, including those in hypothalamus and nucleus of the solitary tract, influence food intake, nutrient preferences, metabolism and development of obesity in ways that often differ between males and females. Branched chain amino acids, including leucine, can suppress food intake, alter metabolism and change vulnerability to obesity. The SLC6A15 (v7-3) gene encodes a sodium-dependent transporter of leucine and other branched chain amino acids that is expressed by neurons in hypothalamus and nucleus of the solitary tract. We now report that SLC6A15 knockout attenuates leucine's abilities to reduce both: a) intake of normal chow and b) weight gain produced by access to a high fat diet in gender-selective fashions. We identify SNPs in the human SLC6A15 that are associated with body mass index and insulin resistance in males. These observations in mice and humans support a novel, gender-selective role for brain amino acid compartmentalization mediated by SLC6A15 in diet and obesity-associated phenotypes.

In animal studies, brain-derived neurotrophic factor (BDNF) is an important regulator of central nervous system development and synaptic plasticity. WAGR (Wilms tumour, Aniridia, Genitourinary anomalies, and mental Retardation) syndrome is caused by 11p13 deletions of variable size near the BDNF locus and can serve as a model for studying human BDNF haploinsufficiency (+/-). We hypothesized that BDNF+/- would be associated with more severe cognitive impairment in subjects with WAGR syndrome. Twenty-eight subjects with WAGR syndrome (6-28 years), 12 subjects with isolated aniridia due to PAX6 mutations/microdeletions (7-54 years), and 20 healthy controls (4-32 years) received neurocognitive assessments. Deletion boundaries for the subjects in the WAGR group were determined by high-resolution oligonucleotide array comparative genomic hybridization. Within the WAGR group, BDNF+/- subjects (n = 15), compared with BDNF intact (+/+) subjects (n = 13), had lower adaptive behaviour (p = .02), reduced cognitive functioning (p = .04), higher levels of reported historical (p = .02) and current (p = .02) social impairment, and higher percentage meeting cut-off score for autism (p = .047) on Autism Diagnostic Interview-Revised. These differences remained nominally significant after adjusting for visual acuity. Using diagnostic measures and clinical judgement, 3 subjects (2 BDNF+/- and 1 BDNF+/+) in the WAGR group (10.7%) were classified with autism spectrum disorder. A comparison group of visually impaired subjects with isolated aniridia had cognitive functioning comparable to that of healthy controls. In summary, among subjects with WAGR syndrome, BDNF+/- subjects had a mean Vineland Adaptive Behaviour Compose score that was 14-points lower and a mean intelligence quotient (IQ) that was 20-points lower than BDNF+/+ subjects. Our findings support the hypothesis that BDNF plays an important role in human neurocognitive development.

A previous study has shown that allicin produces changes in aqueous humor dynamics, and this study was conducted to examine possible cellular mechanisms. In rabbit nonpigmented ciliary epithelial cells, basal levels of [Ca 2+ ], were determined to be 164 ± 34 nM. Allicin, a sulfhydryl-reactive agent, induced Ca 2+ transients at 0.01 mM and at 0.2 mM, the Ca 2+ transient peaked at 732 ± 35 nM. Allicin-induced Ca 2+ transients were prevented by pretreatment with dithiothreitol which did not affect the basal Ca 2+ levels. Allicin had only a slight, insignificant, effect on L-type Ca 2+ currents, and allicin-induced Ca 2+ transients were also present under extracellular Ca 2+ -free conditions. These data suggest that intracellular Ca 2+ stores are the most probable source of allicin's effect. Pretreatment of cells with ryanodine, an inhibitor of Ca 2+ -induced-Ca 2+ -release, inhibited allicin-induced Ca 2+ transients, but the basal Ca 2+ levels were unaffected by ryanodine. Thus, allicin-induced Ca 2+ transients are most likely mediated through ryanodine-sensitive intracellular Ca 2+ stores.

The intent of this work was to examine the actions of allicin on 1) intraocular pressure (IOP) in normal and unilaterally sympathectomized (SX) rabbits; 2) cAMP accumulation in the rabbit iris-ciliary body (ICB) and cultured nonpigmented epithelial (NPE) ciliary body cells; and 3) 3H-norepinephrine (NE) release by calculating fractional tritium overflow in response to electrical field stimulation (EFS, 5 Hz, 12 V/cm) in isolated, perfused rabbit ICBs. Allicin, one of the active compounds produced by garlic, was evaluated on IOP and it was determined that allicin (1, 2.5, or 10 micrograms), topically, but not the precursor, alliin (10 micrograms), lowered the IOP unilaterally in normal rabbits. Allicin (10 micrograms) reduced the IOP by 6 +/- 1 mmHg (n = 4) in normal rabbits at 2 hrs (maximum response) whereas no change occurred in sympathectomized rabbit eyes. Moreover, allicin (0.01, 0.1, or 1 microM) caused 40, 40, or 52% inhibition, respectively, of 3H-NE overflow in response to EFS. Isoproterenol (ISO, 1 microM) stimulated cAMP accumulation by 3.6 and 9 fold in isolated rabbit ICB and cultured NPE cells, respectively. Allicin (1 microM) had no effect on basal cAMP level while it inhibited ISO-stimulated cAMP accumulation by 40% and 23% in ICB and NPE cells, respectively. This study suggests that allicin lowered IOP, in part, by dual actions at the neuroeffector junction.

To examine whether supplemental nutrition augments the anabolic actions of growth hormone (GH) in boys with constitutional delay of growth and maturation (CDGM).We conducted a randomized, controlled trial at an outpatient clinical research center. Subjects were 20 prepubertal boys (age, 9.3 ± 1.3 years) with CDGM (height standard deviation score, -2.0 ± 0.5; bone age delay, 1.8 ± 0.8 years; body mass index standard deviation score, -1.2 ± 1.0; peak stimulated GH, 15.7 ± 7.7 ng/mL), who were randomized (n = 10/group) to 6 months observation or daily nutritional supplementation, followed by additional daily GH therapy in all for another 12 months. t tests and repeated measures analyses of variance compared energy intake, total energy expenditure (TEE), growth, hormones, and nutrition markers.Energy intake was increased at 6 months within the nutrition group (P = .04), but not the observation group, and TEE was not statistically different within either group at 6 months. Addition of 6 months GH resulted in higher energy intake and TEE in the GH/nutrition group at 12 months (P.01), but not in the GH group versus baseline. Height, weight, lean body mass, hormones, and nutrition markers increased comparably in both groups throughout 18 months.Boys with CDGM use energy at an accelerated rate, an imbalance not overcome with added nutrition. GH therapy increases growth comparably with or without added nutrition in these patients.

Low insulin sensitivity is a major physiological precursor to type 2 diabetes and an important risk factor for the development of cardiovascular disease [1]. One of the primary pathways by which decreased insulin sensitivity develops is through excessive gain of body fat. Overweight youth have decreased insulin sensitivity compared to their non-overweight counterparts, placing them at heightened risk for negative health consequences including type 2 diabetes [2]. However, evidence from adult studies suggests that psychological factors may also affect insulin sensitivity [3–11]. In overweight and non-overweight adults, sub-clinical and clinical threshold depressive symptoms are correlates of, and potential risk factors for, the development of decreased insulin sensitivity [3, 6–10], type 2 diabetes [5, 12, 13], and other aspects of the metabolic syndrome [4, 11]. The degree of psychosocial stress and anxiety symptoms in a large community sample of women also has been shown to be significantly related to measures of insulin sensitivity, even after accounting for body mass index [4]. From a psychophysiological theoretical perspective, depression or anxiety are believed to impact insulin sensitivity through physiological mechanisms such as altered insulin signaling in the brain, pro-inflammatory activation, and/or distress-induced upregulation of counterregulatory hormone systems [14, 15]. In addition, from a behavioral psychology perspective, depression and stress may affect insulin sensitivity, in theory, through their impact on lifestyle factors such as physical inactivity. Given the possible role that adult studies suggest for depression and anxiety in the development of decreased insulin sensitivity, understanding how these factors are linked to glucose homeostasis during adolescence may be important for identifying early risks for potentially adverse health outcomes. Parents’ perceptions of their children’s negative emotionality have been found to be associated with children’s fasting insulin, particularly among boys, in a large study of Finnish youth ages 6 to 18 years [16]. To our knowledge, however, no studies to date have examined the links between depressive or anxiety symptoms and fasting insulin or measures of insulin sensitivity in youth. Adolescence represents an important developmental stage for understanding the links between psychological symptoms and insulin sensitivity. During adolescence, normative endocrine changes associated with puberty produce decreased insulin sensitivity relative to childhood. Moreover, adolescence marks a peak time for the onset of depressive symptoms, particularly among girls. Thus, these marked psychological and biological shifts render adolescence an important developmental stage for understanding how symptoms of depression are associated with insulin sensitivity. We, therefore, investigated whether symptoms of depression and anxiety were associated with insulin sensitivity among adolescents. Based upon prior data, we hypothesized that symptoms of depression and anxiety would be associated with higher fasting insulin and decreased insulin sensitivity. Since previous literature has indicated that sex may act as a moderator of the association between psychological symptoms and insulin sensitivity [9, 16], we expected that sex might interact with depression or anxiety and their association with insulin measures, such that the effects would be stronger for girls than for boys.

We report on a patient with trisomy 21, microophthalmia, neonatal diabetes mellitus, hypopituitarism, and a complex structural brain anomaly who was a member of a large bilineal family with eye anomalies. The patient inherited a different mutation in PAX6 from each parent and is the only known living and second reported patient with compound heterozygosity for mutations in PAX6. PAX6 is a transcription factor involved in eye and brain development, and has roles in pancreatic and pituitary development. Clinical evaluation of the propositus and his parents demonstrated the effects of mutations of differing severity in multiple individuals.

Brain-derived neurotrophic factor (BDNF) has been found to be important in energy homeostasis in animal models, but little is known about its role in energy balance in humans. Heterozygous, variably sized, contiguous gene deletions causing haploinsufficiency of the WT1 and PAX6 genes on chromosome 11p13, approximately 4 Mb centromeric to BDNF (11p14.1), result in the Wilms' tumor, aniridia, genitourinary anomalies, and mental retardation (WAGR) syndrome. Hyperphagia and obesity were observed in a subgroup of patients with the WAGR syndrome. We hypothesized that the subphenotype of obesity in the WAGR syndrome is attributable to deletions that induce haploinsufficiency of BDNF.We studied the relationship between genotype and body-mass index (BMI) in 33 patients with the WAGR syndrome who were recruited through the International WAGR Syndrome Association. The extent of each deletion was determined with the use of oligonucleotide comparative genomic hybridization.Deletions of chromosome 11p in the patients studied ranged from 1.0 to 26.5 Mb; 58% of the patients had heterozygous BDNF deletions. These patients had significantly higher BMI z scores throughout childhood than did patients with intact BDNF (mean [+/-SD] z score at 8 to 10 years of age, 2.08+/-0.45 in patients with heterozygous BDNF deletions vs. 0.88+/-1.28 in patients without BDNF deletions; P=0.03). By 10 years of age, 100% of the patients with heterozygous BDNF deletions (95% confidence interval [CI], 77 to 100) were obese (BMIor = 95th percentile for age and sex) as compared with 20% of persons without BDNF deletions (95% CI, 3 to 56; P0.001). The critical region for childhood-onset obesity in the WAGR syndrome was located within 80 kb of exon 1 of BDNF. Serum BDNF concentrations were approximately 50% lower among the patients with heterozygous BDNF deletions (P=0.001).Among persons with the WAGR syndrome, BDNF haploinsufficiency is associated with lower levels of serum BDNF and with childhood-onset obesity; thus, BDNF may be important for energy homeostasis in humans.