Sheila M. Brady

Orthopedic Complications of Overweight in Children and Adolescents

OBJECTIVE. Few studies have quantified the prevalence of weight-related orthopedic conditions in otherwise healthy overweight children. The goal of the present investigation was to describe the musculoskeletal consequences of pediatric overweight in a large pediatric cohort of children that included severely overweight children. METHODS. Medical charts from 227 overweight and 128 nonoverweight children and adolescents who were enrolled in pediatric clinical studies at the National Institutes of Health from 1996 to 2004 were reviewed to record pertinent orthopedic medical history and musculoskeletal complaints. Questionnaire data from 183 enrollees (146 overweight) documented difficulties with mobility. In 250, lower extremity alignment was determined by bilateral metaphyseal-diaphyseal and anatomic tibiofemoral angle measurements made from whole-body dual-energy x-ray absorptiometry scans. RESULTS. Compared with nonoverweight children, overweight children reported a greater prevalence of fractures and musculoskeletal discomfort. The most common self-reported joint complaint among those who were questioned directly was knee pain (21.4% overweight vs 16.7% nonoverweight). Overweight children reported greater impairment in mobility than did nonoverweight children (mobility score: 17.0 ± 6.8 vs 11.6 ± 2.8). Both metaphyseal-diaphyseal and anatomic tibiofemoral angle measurements showed greater malalignment in overweight compared with nonoverweight children. CONCLUSIONS. Reported fractures, musculoskeletal discomfort, impaired mobility, and lower extremity malalignment are more prevalent in overweight than nonoverweight children and adolescents. Because they affect the likelihood that children will engage in physical activity, orthopedic difficulties may be part of the cycle that perpetuates the accumulation of excess weight in children.

Effects of Metformin on Body Weight and Body Composition in Obese Insulin-Resistant Children A Randomized Clinical Trial

OBJECTIVE Metformin can decrease adiposity and ameliorate obesity-related comorbid conditions, including abnormalities in glucose homeostasis in adolescents, but there are few data evaluating the efficacy of metformin among younger children. Our objective was to determine whether metformin treatment causes weight loss and improves obesity-related comorbidities in obese children, who are insulin-resistant. RESEARCH DESIGN AND METHODS This study was a randomized double-blind placebo-controlled trial consisting of 100 severely obese (mean BMI 34.6 ± 6.6 kg/m2) insulin-resistant children aged 6–12 years, randomized to 1,000 mg metformin (n = 53) or placebo (n = 47) twice daily for 6 months, followed by open-label metformin treatment for 6 months. All children and their parents participated in a monthly dietitian-administered weight-reduction program. RESULTS Eighty-five percent completed the 6-month randomized phase. Children prescribed metformin had significantly greater decreases in BMI (difference −1.09 kg/m2, CI −1.87 to −0.31, P = 0.006), body weight (difference −3.38 kg, CI −5.2 to −1.57, P < 0.001), BMI Z score (difference between metformin and placebo groups −0.07, CI −0.12 to −0.01, P = 0.02), and fat mass (difference −1.40 kg, CI −2.74 to −0.06, P = 0.04). Fasting plasma glucose (P = 0.007) and homeostasis model assessment (HOMA) insulin resistance index (P = 0.006) also improved more in metformin-treated children than in placebo-treated children. Gastrointestinal symptoms were significantly more prevalent in metformin-treated children, which limited maximal tolerated dosage in 17%. During the 6-month open-label phase, children treated previously with placebo decreased their BMI Z score; those treated continuously with metformin did not significantly change BMI Z score further. CONCLUSIONS Metformin had modest but favorable effects on body weight, body composition, and glucose homeostasis in obese insulin-resistant children participating in a low-intensity weight-reduction program.

Adiposity and human regional body temperature

BACKGROUND Human obesity is associated with increased heat production; however, subcutaneous adipose tissue provides an insulating layer that impedes heat loss. To maintain normothermia, therefore, obese individuals must increase their heat dissipation. OBJECTIVE The objective was to test the hypothesis that temperature in a heat-dissipating region of the hand is elevated in obese adults. DESIGN Obese [body mass index (in kg/m(2)) > or = 30] and normal-weight (NW; body mass index = 18-25) adults were studied under thermoneutral conditions at rest. Core body temperature was measured by using ingested telemetric capsules. The temperatures of the third fingernail bed of the right hand and of abdominal skin from an area 1.5 cm inferior to the umbilicus were determined by using infrared thermography. Abdominal skin temperatures were also measured via adhesive thermistors that were placed over a prominent skin-surface blood vessel and over an adjacent nonvessel location. The groups were compared by analysis of covariance with age, sex, race, and room temperature as covariates. RESULTS Core temperature did not differ significantly between the 23 obese and 13 NW participants (P = 0.74). However, infrared thermography-measured fingernail-bed temperature was significantly higher in obese subjects than in NW subjects (33.9 +/- 0.7 degrees C compared with 28.6 +/- 0.9 degrees C; P < 0.001). Conversely, infrared thermography-measured abdominal skin temperature was significantly lower in obese subjects than in NW subjects (31.8 +/- 0.2 degrees C compared with 32.8 +/- 0.3 degrees C; P = 0.02). Nonvessel abdominal skin temperatures measured by thermistors were also lower in obese subjects (P = 0.04). CONCLUSIONS Greater subcutaneous abdominal adipose tissue in obese adults may provide a significant insulating layer that blunts abdominal heat transfer. Augmented heat release from the hands may offset heat retention in areas of the body with greater adiposity, thereby helping to maintain normothermia in obesity. This trial was registered at clinicaltrials.gov as NCT00266500.

The Stability of Metabolic Syndrome in Children and Adolescents

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.

Targeted prevention of excess weight gain and eating disorders in high-risk adolescent girls: a randomized controlled trial

BACKGROUND The high prevalence and incidence of obesity and eating disorders in US adolescent girls are serious health problems. Because of the shared risk factors for obesity and eating disorders, a targeted prevention of both conditions is a priority. OBJECTIVE We determined whether an adapted interpersonal psychotherapy prevention program is more efficacious for reducing excess weight gain and worsening disordered eating than health education in adolescent girls at high risk of obesity and eating disorders. DESIGN A parallel-group, randomized controlled trial was conducted between September 2008 and January 2013 in a university-based laboratory and a federal research hospital. The study included 113 adolescent (12-17-y-old) girls deemed at high risk of adult obesity and eating disorders because of a body mass index (BMI) between the 75th and 97th percentiles and reports of episodes of a loss of control over their eating. Girls were randomly assigned to participate in an adapted interpersonal psychotherapy or a health-education group program for 12 weekly 90-min group sessions. Follow-up assessments occurred immediately after group programs and at 6 and 12 mo. RESULTS Participation in both conditions was associated with decreases in expected BMI gain, age-adjusted BMI metrics, the percentage of fat by using dual-energy X-ray absorptiometry, symptoms of depression and anxiety, and the frequency of loss-of-control eating over 12 mo of follow-up (Ps < 0.001) with no group difference. In follow-up analyses, interpersonal psychotherapy was more efficacious than health education at reducing objective binge eating at the 12-mo follow-up (P < 0.05). CONCLUSIONS The intervention with adolescent girls with loss-of-control eating is associated with lower age-adjusted BMI and percentage of adiposity as well as improved mood symptoms over 1 y. Interpersonal psychotherapy further reduced objective binge eating. Additional research is needed to elucidate the mechanisms by which physical and psychological improvements were observed. This trial was registered at clinicaltrials.gov as NCT00680979.

Psychological Symptoms and Insulin Sensitivity in Adolescents

Shomaker LB, Tanofsky‐Kraff M, Young‐Hyman D, Han JC, Yanoff LB, Brady SM, Yanovski SZ, Yanovski JA. Psychological symptoms and insulin sensitivity in adolescents.

Effects of Interrupting Children's Sedentary Behaviors With Activity on Metabolic Function: A Randomized Trial

CONTEXT Limited data suggest that interrupting sedentary behaviors with activity improves metabolic parameters in adults. OBJECTIVE We tested whether interrupting sitting with short, moderate-intensity walking bouts improved glucose tolerance in children. DESIGN Participants underwent two experimental conditions in random order on different days: continuous sitting for 3 hours or sitting interrupted by walking (3 min of moderate-intensity walking every 30 min). Insulin, C-peptide, glucose, and free fatty acids were measured every 30 minutes for 3 hours during an oral glucose tolerance test. Area under the curve (AUC) was calculated from hormone and substrate measurements. Children were given a buffet meal after each condition. SETTING The study was conducted at the National Institutes of Health Hatfield Clinical Research Center. PARTICIPANTS Twenty-eight normal-weight 7-11 year olds participated. MAIN OUTCOMES Patterns of substrate/hormone secretion and AUC, as well as energy intake, were examined by experimental condition. RESULTS Interrupting sitting resulted in a 32% lower insulin AUC (P < .001), 17% lower C-peptide AUC (P < .001), and 7% lower glucose AUC (P = .018) vs continuous sitting. Mixed model results indicated that insulin (P = .036) and free fatty acid concentrations (P = .009) were significantly lower in the interrupted vs the continuous sitting condition. Lunchtime buffet meal energy intake did not significantly differ between the conditions (975 ± 387 vs 963 ± 309 kcal; P = .85). CONCLUSIONS Interrupting sedentary time with brief moderate-intensity walking improved short-term metabolic function in non-overweight children without increasing subsequent energy intake. These findings suggest that interrupting sedentary behavior may be a promising prevention strategy for reducing cardiometabolic risk in children.

Association of brain-derived neurotrophic factor (BDNF) haploinsufficiency with lower adaptive behaviour and reduced cognitive functioning in WAGR/11p13 deletion syndrome.

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.

Effects of metformin on energy intake and satiety in obese children

To investigate the effects of metformin on appetite and energy intake in obese children with hyperinsulinaemia.

Attentional Bias to Food Cues in Youth with Loss of Control Eating

Emerging data indicate that adults with binge eating may exhibit an attentional bias toward highly palatable foods, which may promote obesogenic eating patterns and excess weight gain. However, it is unknown to what extent youth with loss of control (LOC) eating display a similar bias. We therefore studied 76 youth (14.5 ± 2.3 years; 86.8% female; BMI-z 1.7 ± .73) with (n = 47) and without (n = 29) reported LOC eating. Following a breakfast to reduce hunger, youth participated in a computerized visual probe task of sustained attention that assessed reaction time to pairs of pictures consisting of high palatable foods, low palatable foods, and neutral household objects. Although sustained attentional bias did not differ by LOC eating presence and was unrelated to body weight, a two-way interaction between BMI-z and LOC eating was observed (p = .01), such that only among youth with LOC eating, attentional bias toward high palatable foods versus neutral objects was positively associated with BMI-z. These findings suggest that LOC eating and body weight interact in their association with attentional bias to highly palatable foods cues, and may partially explain the mixed literature linking attentional bias to food cues with excess body weight.