The Biology of Obesity

	Tweet

Adipocyte Development
The adipocyte is derived from preadipocytes in the pericapillary endothelium. Differentiation factors, including peroxisome proliferator-activated nuclear hormone receptor, CCAAT enhancer-binding protein, and adipocyte determination and differentiation-dependent factor 1 (ADD1/SREPB1), control the expression of adipocyte-specific genes and the differentiation of adipocytes. Insulin, glucocorticoids, some prostaglandins, and various medications all can affect this process. Adipocytes increase in size during infancy, but this hypertrophy ceases in nonobese children at about 2 years of age. Among obese children, hypertrophy continues until adolescence. Hyperplasia of fat cells occurs at a greater rate among obese than among nonobese children. Although there appears to be a genetic basis for these differences, weight loss among obese children may decrease the rate of adipocyte hyperplasia.

Control of Appetite
Many central nervous system factors affect dietary intake in mammals in a redundant and complex manner to provide a failure-proof mechanism to ensure adequate energy intake. The ventromedial hypothalamus is one of the hypothalamic centers that regulates appetite and feeding behavior. Destruction by trauma or a brain tumor greatly increases intake and decreases metabolic rate, leading to massive obesity. Agents that stimulate appetite include drugs such as ß-adrenergic agents, cyproheptadine, glucocorticoids, orexins, and neuropeptide Y. Agents that suppress appetite include ß²-adrenergic agents, ACTH-releasing factor, dopamine, serotonin, glucagon-like peptide-1, and leptin.

Leptin is a highly conserved protein hormone produced by adipocytes. It interacts with its hypothalamic receptor to regulate feeding through a leptin-melanocortin pathway in the hypothalamus. Serum leptin concentrations are mainly determined by white fat mass (as opposed to brown fat), but other factors such as sex hormones and nutritional factors also modulate levels. Abnormalities in five of the genes found in the leptin-melanocortin pathway are known to cause obesity among humans. A few consanguineous kindreds have autosomal-recessive genetic defects in the production of leptin or in the receptor for leptin: affected children have exceptional weight gain starting in infancy. One 9-year-old child with leptin deficiency had 50% body fat, an insatiable appetite, and low gonadotropin secretion despite an advanced bone age of 13 years. Recombinant human leptin treatment decreased weight and appetite and increased pulsatile gonadotropin secretion, indicating the onset of pubertal activity. The average obese human has increased leptin secretion because of increased fat mass, but appetite is not reduced, suggesting a degree of resistance to leptin. Leptin treatment does not promote weight loss in common forms of obesity among humans.

Genetics of Obesity
The obesity gene map (http://www.obesity.chair.ulaval.ca/genemap.html) lists at least 98 chromosomal loci for body weight, body fat, fat-pad weight (white adipose tissue), and other obesity-related traits in animal models and 59 traits in humans. Twenty-six mendelian disorders include obesity as a phenotype, including Prader-Willi and Bardet-Biedl syndromes, among others. Thirty-nine genes have associations with BMI, body fat, or other obesity-related phenotypes (Table 24-47).

A genetic tendency toward obesity is strongly suggested by epidemiologic observations. If either parent is obese, the likelihood that the child will be an obese adult increases fivefold. The BMIs of monozygotic twins are closer than those of dizygotic twins. The weights of monozygotic twins reared apart are similar, again indicating that genetic factors have a major effect on weight. The BMIs of adopted children are closer to those of their biological parents than to those of their adoptive parents. There is little effect of environment. Combining the results of studies leads to an estimate that at least 40% of obesity is heritable.

Environment
Several observations suggest that the intrauterine environment can affect ultimate weight control. Infants of mothers with diabetes have a higher prevalence of obesity by 10 years of age, but because diabetes is more common among obese mothers, it is possible that this can be explained as a genetic trend. Mothers who starve during the first and second trimesters but have adequate nutrition thereafter have had infants of normal weight who had an increased tendency to obesity 20 years later. The effect of the intrauterine environment on weight remains uncertain.

There is little doubt that the extrauterine environment can alter ultimate weight. Learned habits in regard to diet and activity affect the weight achieved. This likely explains the increased tendency toward obesity in the United States. An excess of only 50 kcal/d (eg, an additional pat of butter), all other thing being equal, leads to a gain of 5 pounds (2.25 kg) per year. For a person with a genetic susceptibility to obesity, an alteration in dietary habits can lead to obesity. A good example is provided by the Pima Indians of Mexico and Arizona, who have the same genetic background. The Arizona Pima once had a higher incidence of obesity than did the Mexican Pima, likely because of the high caloric density they ingested and reduced activity. As the diet and activity of the Mexican Pima change so that they are more similar to those of the Arizona Pima, the incidence of obesity is approaching that of the Arizona Pima.

Childhood activity is decreased in many developed nations, and television watching is increased. A relation between the prevalence of obesity and the amount of time watching television has been demonstrated in numerous studies. An average US child watches 20 hours of television per week and by the end of high school has watched 3 years of television. This decreases the time engaged in other physical activities and exposes them to numerous commercials that encourage the intake of high-calorie, low-fiber foods. Activity decreases with increasing age among children, more among girls than boys. Social factors further decrease activity in childhood; examples are concerns over safety of parks, limited family activity time, and after-school jobs. Participation in physical education decreases with advancing grade; by 11th and 12th grade, fewer than half of students have gym class.

Possibly because of lack of adequately sensitive techniques, there is no proof that overweight children expend less energy than do average-weight children. A 4-year longitudinal study of children showed that sex, initial adiposity, and parental adiposity were related to weight gain in childhood but found no evidence that reduced energy expenditure had a role. However, one study in which recording pedometers were used showed that nonobese children had a higher intensity of activity than did obese children, although total time spent in activity was the same.

Differences in activity level may affect overall energy expenditure, basal energy expenditure (basal metabolic rate) being altered by activity. Increased activity may increase resting energy expenditure as well. Resting energy expenditure decreases during weight loss; thus it becomes more difficult to lose weight as weight decreases.

Endocrine Changes and Obesity
Secretion of GH decreases in obesity, so an incorrect diagnosis of GH deficiency might be entertained. Paradoxically, the level of IGF-I in the serum is normal in obesity. This is the reverse of starvation or Anorexia Nervosa, in which the level of GH increases and that of IGF-I is low. Serum values of GH-binding protein are directly proportional to BMI and are high in obesity. Increased binding sites for GH may explain the normal serum level of IGF-I and excellent growth among obese children despite low GH secretion. IGFBP1 is suppressed by insulin, and serum values are low in obesity because of increased insulin secretion.

Hypothyroidism often is thought to be a cause of obesity. However, even among untreated children with hypothyroidism, weight gain is modest, and massive obesity rarely is explained by hypothyroidism. Treatment does produce modest weight loss. Most obese children are euthyroid. Adrenal function is normal in most cases of obesity, although cortisol secretion rate and urinary levels of 17OHCs may be elevated, incorrectly suggesting Cushing disease as a cause of obesity. Cushing disease can be differentiated from uncomplicated obesity because obese patients have normal urinary levels of free cortisol and normal diurnal rhythms of serum levels of cortisol. An overnight or low-dose dexamethasone suppression test can be useful for the differential diagnosis of obesity and Cushing disease if a question remains.

RELATED STORIES:
Treatment of Obesity   Mother knows best? Feeding styles and child obesity   Childhood Obesity   Obesity Prevention   Preventing Childhood Obesity: Tips for Child Care Professionals   Obesity as a Major Public Health Threat   Obesity may complicate surgery in children   Obesity Associated with Psychiatric Disorders, Decreased Odds of Substance Abuse   Blacks With Diabetes Are Under-Diagnosed for Obesity   Pregnancy and Obesity   Treatment of obesity   Morbidity and mortality associated with obesity

Comments

[ + Post Your Own ]

Now you're in the public comment zone. What follows is not Armenian Medical Network's stuff; it comes from other people and we don't vouch for it. A reminder: By using this Web site you agree to accept our Terms of Service. Click here to read the Rules of Engagement.

There are no comments for this entry yet. [ + Comment here + ]