Obesity, defined as a body mass index (BMI) >30kg/m2, is a significant health problem. Obesity has reached epidemic proportions globally, and the World Health Organization estimates that there are more than 1 billion overweight adults, of which at least 300 million are obese. Societal changes and the worldwide nutrition transition have driven the obesity epidemic over recent decades. Economic growth as well as modernization, urbanization and globalization of food markets are some of the elements that have contributed to the obesity epidemic. Significant shifts toward less physically demanding work have been observed worldwide. Decreased physical activity has also been associated with increasing opportunities to use automated transport, have technology in the home, and engage in more passive leisure pursuits.
Obesity is associated with premature death through increasing the risk of many chronic diseases, including type 2 diabetes, cardiovascular disease, and certain cancers. In addition, obesity is associated with respiratory difficulties, chronic musculoskeletal problems, lumbago, skin problems, and infertility. Most of the evidence proposing obesity-associated health problems has been obtained from epidemiological analyses of human subjects; the precise molecular mechanisms of obesity-associated health problems have not yet been determined.
Genetics of Obesity
The obesity gene map 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).
The obese lack willpower; they overeat and underexercise - or so believe a majority of Americans. A 2012 online poll of 1143 adults conducted by Reuters and the market research firm Ipsos found that 61% of U.S. adults believed that “personal choices about eating and exercise” were responsible for the obesity epidemic. A majority of Americans, it seems, remain unaware of or unconvinced by scientific research suggesting that “personal choices” may not account for all cases of obesity.
Yet for more than a century, physicians have been proposing that some cases of obesity are a function of innate biologic mechanisms or heredity. In 1907, the German pathologist Carl von Noorden delineated two types of obesity: exogenous and endogenous (1953; see Historical New England Journal of Medicine Articles Cited). Exogenous obesity, which accounted for most cases, was the consequence of external culprits - namely, food consumption in excess of energy expenditure. But some people had endogenous obesity, caused by hypometabolism or other thyroid disorders.
Some early-20th-century doctors bluntly dismissed the idea of endogenous obesity. George Van Ness Dearborn, a neuropsychiatrist who had been on the faculty at Harvard and Tufts, declared in 1917 that “the great and culpable majority of the obese achieve their uncomplimentary fatness.” Nonetheless, a survey of medical journal articles on obesity in the 1910s and 1920s reveals that even physicians who might have shared Dearborn’s sentiments conceded that dietary excess and lack of exercise could not account for all cases of overweight. And although the hypometabolic thesis had fallen out of favor by 1930, when more accurate calculations of body-surface area indicated that the metabolic rates of the obese were normal, researchers in the second half of the 20th century continued to make the case that some people were predisposed to obesity.
In the 1950s, for instance, the work of Rockefeller University’s Jules Hirsch showed that for obese people, long-term weight loss is a lifelong struggle. Hirsch found that although obese subjects could shed a substantial amount of weight through drastic calorie restriction, their metabolic rates would dip in response to calorie reductions. This effect meant, for example, that if an obese woman dropped down from 200 lb to 130 lb, she would have to consume fewer calories to remain at 130 lb than would a 130-lb counterpart whose weight had always held steady. The previously obese woman, then, required more “willpower” to maintain her reduced weight than someone who had never been obese. Decades later, in 1995, Hirsch and his former Rockefeller colleagues Rudolph Leibel and Michael Rosenbaum observed that just as the metabolism of subjects who had lost 10% of their body weight decelerated, the metabolism of those who had gained 10% of their body weight revved up (1995). These findings suggested that the body has built-in mechanisms that resist attempts to resize it for the long term.
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.
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 β-adrenergic agents, cyproheptadine, glucocorticoids, orexins, and neuropeptide Y. Agents that suppress appetite include β2-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.
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.
It has long been axiomatic that obesity is fundamentally a problem of energy balance. Put simply, obesity can only develop when energy intake is in excess of energy expenditure, differences in input and output being buffered primarily by changes in the fat stores. Understanding the basis of how the balance between intake and expenditure is regulated has been a longstanding challenge in fundamental biology. The simplicity of the energy balance equation has led to an inappropriate focus on obesity as being either a problem of food intake control or of energy expenditure; in practice, a rather more holistic and integrative approach is required.
There are two immutable “Laws of Obesity”: (1) that for obesity to develop intake must be in excess of expenditure; (2) obese subjects have a higher energy expenditure, and therefore a higher average energy intake, than lean subjects.
The first is a reflection of the Laws of Thermodynamics, while the second is the result of energy expenditure studies carried out from the late 1970s (Prentice et al. 1986, 1996; Bandini et al. 1990). These studies demonstrate that obese subjects have a higher 24 h energy expenditure than lean subjects, indicating that their habitual intake is greater when they are weight stable or in energy balance (Prentice et al. 1986, 1996). The higher expenditure reflects, of course, the additional energy costs associated with a greater body mass.
The difficulty in undertaking in man long-term energy balance studies with the required degree of precision has been a key reason for the extensive focus on animal models, and on laboratory rodents in particular. A number of such models are available, including those in which obesity is induced by dietary manipulation (e.g. high-fat diet), endocrinologically (e.g. by administration of corticosteroids or neuropeptide Y), surgically (lesions of the ventromedial hypothalamus), chemically (e.g. gold thioglucose administration) or through transgenics (e.g. uncoupling protein 1, 11b-hydroxysteroid dehydrogenase-1 and melanocortin-4 receptor knockouts; Lowell et al. 1993; Huszar et al. 1997; Masuzaki et al. 2001). In addition, several spontaneous mutations that lead to frank obesity have long been recognised (single gene mutants such as ob/ob and db/db mice), as well as physiologically-programmed fattening during the normal life cycle (e.g. pregnancy, and seasonal obesity in hibernators and migratory birds; see Trayhurn, 1984).
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.
Revision date: July 3, 2011
Last revised: by Janet A. Staessen, MD, PhD