Etiology and Pathophysiology of Obesity in Children

Etiology and Pathophysiology of Obesity in Children
Obesity is the most prevalent nutritional disorder among children and adolescents in the United States. Approximately 21-24% of American children and adolescents are overweight, and another 16-18% is obese; the prevalence of obesity is highest among specific ethnic groups.

Childhood obesity predisposes to insulin resistance and type 2 diabetes, hypertension, hyperlipidemia, liver and renal disease, and reproductive dysfunction. This condition also increases the risk of adult-onset obesity and cardiovascular disease. 

Obesity in children is a complex disorder. Its prevalence has increased so significantly in recent years that many consider it a major health concern of the developed world. The National Health and Nutrition Examination Survey (NHANES) indicates that the prevalence of obesity is increasing in all pediatric age groups, in both sexes, and in various ethnic and racial groups. Many factors, including genetics, environment, metabolism, lifestyle, and eating habits, are believed to play a role in the development of obesity. However, more than 90% of cases are idiopathic; less than 10% are associated with hormonal or genetic causes.


Genetic syndromes associated with childhood obesity include the following:

  • Prader-Willi syndrome
  • Pseudohypoparathyroidism
  • Laurence-Moon-Biedl (Bardet-Biedl) syndrome
  • Cohen syndrome
  • Down syndrome
  • Turner syndrome

    Hormonal disorders associated with childhood obesity include the following:

    • Growth hormone deficiency
    • Growth hormone resistance
    • Hypothyroidism
    • Leptin deficiency or resistance to leptin action
    • Glucocorticoid excess (Cushing syndrome)
    • Precocious puberty
    • Polycystic ovary syndrome (PCOS)
    • Prolactin-secreting tumors

    Medications that may cause weight gain in children and adolescents include the following:

    • Cortisol and other glucocorticoids
    • Megace
    • Sulfonylureas
    • Tricyclic antidepressants (TCAs)
    • Monoamine oxidase inhibitors (MAOIs), such as phenelzine
    • Oral contraceptives
    • Insulin (in excessive doses)
    • Thiazolidinediones
    • Risperidone
    • Clozapine
    • Energy imbalance

      During childhood and adolescence, excess fat accumulates when total energy intake exceeds total energy expenditure. This energy imbalance can result from excessive energy intake and/or reduced energy expenditure, the latter is usually a consequence of a sedentary lifestyle. This is particularly associated with excessive television viewing, excessive computer use, and insufficient physical activity. In infancy, excess fat deposition occurs when excess energy is provided, especially when the protein-to-energy ratio is altered. This is often seen when feedings are supplemented with additives such as carbohydrates or fat and protein content remains the same. In addition, one study reported an increased incidence of obesity at age 3 years in infants weaned to solid foods by 4 months. 

      Ghrelin/leptin hormonal pathway dysfunction

      • In individuals who are obese, dysfunction in the gut-brain-hypothalamic axis via the ghrelin/leptin hormonal pathway has been suggested to have a role in abnormal appetite control and excess energy intake. See the image below.
      • Central nervous system (CNS) neurocircuitry for satiety and feeding cycles. AGRP = Agouti-related protein; CB = cannabinoid; CCK = cholecystokinin; CRH = corticotropin-releasing hormone; GLIP = glucagonlike peptide; Mc-3 and 4 = melanocortin-3 and 4; MCH = melanin concentrating hormone; α-MSH = alpha–melanocyte-stimulating hormone; POMC = pro-opiomelanocortin; TNF = tumor necrosis factor.
      • Studies indicate that dysfunction in this hormonal axis may be the causative factor in as many as 10% of obese subjects, with emphasis particularly on those individuals who appear to manifest familial morbid obesity. In these families, several reports have shown a dramatic, weight loss response to hormone replacement therapy in patients with leptin deficiency. Reductions in energy expenditure characterize other hormonal deficiency states, including hypothyroidism and growth hormone deficiency. Increases in energy intake are observed in genetic syndromes, such as Prader-Willi syndrome, Cushing syndrome, and drug-induced obesity.

      Weight gain factors

      • Despite observations of an etiologic role for genetic and hormonal disorders, these factors alone do not explain the excess weight gain observed in most patients who have obesity and are referred to physicians for evaluation and treatment. Although most overweight children have a familial form of obesity, with 1 or 2 obese parents, excess weight gain in obese children clearly depends on both genetic and environmental factors. Correlations between parent and child habitus likely reflect, at least in part, the familial patterns of food intake, exercise, and selection of leisure activity (including amount of television watching), as well as familial and cultural patterns of food selection. Nevertheless, evidence from twin, adoption, and family studies suggests that genetic factors also play a considerable role in the development of childhood obesity.

      Genetics

      • Concordance rates for obesity and type 2 diabetes mellitus are higher in monozygotic twins than in dizygotic twins, and measures of total body fat (TBF) correlate nearly as strongly in monozygotic twins reared apart as in monozygotic twins reared together. Still, genetic factors cannot explain the increased prevalence of obesity observed among American adolescents over the past generation.

      Insulin resistance, dyslipidemia, and hypertension

      • The accumulation of body fat, particularly in a visceral distribution, reduces the sensitivity to insulin in skeletal muscle, liver tissue, and adipose tissue; this “insulin resistance” predisposes to glucose intolerance and hypertriglyceridemia. Low levels of high-density lipoprotein (HDL), observed both genetically and in association with a sedentary lifestyle, likely contribute to the increase of premature coronary artery disease observed in adults with obesity. Increases in circulating levels of insulin and insulin-like growth factor I may increase blood pressure (BP) and may stimulate the production of androgens from ovarian and adrenocortical cells, with consequent dysmenorrhea and virilization in females. Aromatization of adrenal androgens to estrone leads to gynecomastia in males. The insulin resistance, dyslipidemia, and hypertension predispose to type 2 diabetes and cardiovascular disease, reducing life expectancy.
      • In a study by D’Adamo et al that evaluated the role of fatty liver in the alteration of insulin sensitivity and β-cell function in obese patients, the investigators concluded that fatty liver, independent of visceral fat and intramyocellular lipid content (ICML), has a central role in insulin resistance in obese adolescents. [11] Patients were divided into 2 groups: 23 obese adolescents with and 20 obese adolescents with low HFF were matched for age, Tanner stage, BMI score, and percentage of body fat, visceral fat, and IMCL. The group with a high hepatic fat fraction (HFF) had lower whole-body insulin sensitivity index and lower estimates of insulin secretion, as well as a significantly lower glucose disposal rate, than the group with low HFF.
      • While insulin resistance represents an important associated finding in adolescents with steatosis, a recent study reported that in younger children with fatty liver, markers for oxidative stress (eg, oxidized glutathione) were the most significant, independent risk factors.
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