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Head: Jack Yanovski
yanovskj@mail.nih.gov

Functional Statement | Objectives | Introduction | Results

Functional Statement for the SGO

The primary goal of the Section on Growth and Obesity is to elucidate the genetic underpinnings of the metabolic and behavioral endophenotypes that contribute to the development of obesity in children. Using an integrated program of basic and clinical translational research, our ongoing studies of patients with monogenic and polygenic obesity aim to advance our understanding of energy balance regulation during childhood. Using our unique longitudinal cohort of children at-risk for adult obesity who have undergone intensive metabolic and behavioral phenotyping, we examine genetic and phenotypic factors predictive of progression to adult obesity in children who are in the “pre-obese” state, allowing characterization of phenotypes unconfounded by the impact of obesity itself. Once identified as linked to obesity, genetic variants that impair gene function are studied intensively. These approaches are expected to improve our ability to predict which children are at greatest risk for obesity and its comorbid conditions and to lead to more targeted, etiology-based prevention and treatment strategies for pediatric obesity.

Child's Drawing
Eat Well, by Robbie Kraff. Reproduced with permission.

Objectives

  1. To investigate the genetic, physiologic, metabolic, behavioral, and environmental characteristics leading to obesity in diverse US populations.
  2. To devise population-specific risk predictors to enable identification of children and adults at risk for the development of obesity and its complications.
  3. To use this information to develop rational interventions specifically targeted to prevent and treat obesity.

Introduction

For children in the US, the prevalence of overweight has more than tripled during the past four decades. 17.1 percent of children and adolescents are overweight, and an additional 16.5 percent are classified as at-risk for overweight (BMI 85-95th percentile). Racial and ethnic minority populations, especially African American, Hispanic/Latina, and American Indian women, are at particular risk for the development of obesity. While adult obesity has also increased dramatically, the increase in obesity prevalence among children is particularly alarming. Obesity-related diseases rarely seen in children previously, including obesity-associated sleep apnea, non-alcoholic fatty liver disease with resultant cirrhosis and type 2 diabetes, are increasingly diagnosed in pediatric patients. The earlier onset of chronic health conditions such as type 2 diabetes in childhood has been shown to lead to an earlier onset of related medical complications such as end-stage renal disease. Pediatric obesity also has a tremendous impact on later health, independent of adult weight. In the absence of effective strategies to prevent and treat childhood obesity, millions of children will enter adulthood with the physical and psychological consequences of excess adiposity. The current U.S. childhood obesity epidemic also has the potential to reverse the improvements in life-expectancy that have been seen during the 20th century in the U.S. and to result in more functional disability and decreased quality of life in those who survive to old age.

The alarming rise in obesity in both children and adults has occurred at a time when the current environment affords easy access to large portions of calorie-dense foods and requires less voluntary energy expenditure. However, this environment leads to obesity only in those individuals whose body weight regulatory systems are not able to control body adiposity with sufficient precision in our high calorie/low activity environment. Indeed, the most marked increases in BMI are found in children at the greatest BMI percentiles, and it is clear there is variability within the U.S. population in susceptibility to weight gain that is not fully explained by sociocultural or environmental factors. Even today, 60-80% of the variance in pediatric body weight can be attributed to genetic factors.

Effective prevention and treatment of obesity-related disorders requires a better understanding of the key elements for body weight regulation. The Section on Growth and Obesity carries out an integrated program of basic and clinical translational research aimed at: 1) elucidating genetic underpinnings of the metabolic and behavioral endophenotypes involved in energy homeostasis during childhood, and 2) identifying effective strategies for the prevention and treatment of obesity and its comorbid conditions.

Results

Brain-Derived Neurotrophic Factor (BDNF) and Obesity in the Wilms Tumor Aniridia Genito-Urinary Anomialies and Mental Retardation (WAGR) syndrome:

BDNF and Obesity

Subjects were categorized as BDNF haploinsufficient by comparative genomic hybridization. Subject A has a large deletion on chromosome 11 that removes one copy of the BDNF gene. Subject B has a smaller deletion that does not remove BDNF.

Adjusted BMI-Z Score Telomeric End Deletion

Patients with WAGR Syndrome who have haploinsufficiency for Brain-Derived Neurotrophic Factor (BDNF) had higher BMI standard deviation score (BMI Z-Score) than children and adults with WAGR Syndrome who retained two copies of BDNF. Deletions that extended into exon 1 of BDNF were associated with 100% risk of childhood-onset obesity.

Overweight children with the greatest hyperinsulinemia eat more at meals than equally heavy children who have less insulin resistance. One physiological factor that may stimulate children’s food intake is skeletal muscle insulin resistance. Because adipose tissue remains sensitive to insulin, nutrients may then be stored as fat when hyperinsulinemia is present. Using a cohort of overweight children, we found a relationship between the degree of hyperinsulinemia and insulin resistance identified using hyperglycemic clamp studies and food intake at a meal. Ongoing natural history studies explore the etiology and consequences of differences in body composition and hormone levels for the development of obesity.

The greater susceptibility for weight gain of African Americans may result from differences in metabolic efficiency: We have found that resting energy expenditure is approximately 90 kcal/d less in African American than in Caucasian children. Ongoing studies explore the role of these differences in energy expenditure in predicting future weight gain.

A pair of melanocortin 3 receptor polymorphisms are associated with childhood body weight. Among 355 overweight and non-overweight children, 8.2% were double homozygous for a pair of missense MC3R sequence variants (Thr6Lys and Val81Ile). Such children were significantly heavier (BMI and BMI SD score: p < 0.0001), had more body fat (body fat mass and percentage fat mass; p < 0.001) and had greater plasma leptin (p < 0.0001) and insulin concentrations (p < 0.001) and greater insulin resistance (p < 0.008) than wild type or heterozygous children. Both sequence variants were more common in African American than Caucasian children. In vitro expression studies found the double mutant MC3R was partially inactive, with significantly fewer receptor binding sites, decreased signal transduction and less protein expression. Diminished MC3R expression in this double MC3R variant may be a predisposing factor for excessive gain in body weight in children.

cAMP accumulation

Immunofluorescence of MC3R –GFP fusion proteins
Immunofluorescence of MC3R –GFP fusion proteins

Typical Winter Holiday weight gain in adults is only 0.37 kg (0.8 lb). In a study of 200 Caucasian, African American, Hispanic, and Asian adults in which subjects did not know that the primary outcome measure was body weight, we found that weight gain from Thanksgiving Day to New Year's Day was only 0.37 kg, far less than the 2.27 kg (5 lb) commonly believed. Winter holiday weight gain may be a major contributor to annual weight gain in adults.

Binge eating in children is associated with greater food intake as well as high body weight and adiposity. Children who report episodes of loss of control over eating weigh more and have more body fat than those who do not report such episodes, gain weight more rapidly over time, and eat more during laboratory test meals.

Body Fat Mass
Gain of fat mass
Energy intake

Orlistat treatment in the context of a behavioral modification program may help significantly overweight adolescents lose weight. Over a 6-month treatment period, 200 adolescents randomized to take orlistat or placebo capsules (with a multivitamin) decreased their body weight more when treated with orlistat than when taking the placebo.

Metformin Treatment in the context of a behavioral modification program may help significantly overweight children lose weight. Over a 6-month treatment period, 100 children randomized to take metformin or placebo capsules (with a multivitamin) decreased their body weight more when treated with metformin than when taking the placebo.

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