The ability to store calories as fat would have helped our ancestors to survive periods of prolonged caloric restriction, and would have enhanced the ability of women to breast feed their offspring and provide greater energy stores to nourish mother and fetus during pregnancy. Thus, it is likely that the human genome is enriched with genes favoring the storage of calories as adipose tissue.1 In contrast, there would have been little evolutionary pressure to favor genotypes that are defending body thinness prior to the industrial revolution. Our ancestors rarely had the opportunity to consume calories to the point that they experienced significant adiposity-related morbidity, nor did they frequently survive to an age when the cumulative effects of morbidities, such as diabetes and cardiovascular disease, would have a significant effect on their health or reproductive capacity. In an environment that favors the consumption of calorically dense foods and a sedentary lifestyle, any "defense" against further weight gain is stretched to the limit, while opposition to sustaining weight loss remains potent and viable. Thus, we are confronted with a tendency for our own metabolic systems to be "biased" toward further weight gain and biased against attempts to sustain weight loss.
The consequences of the interactions of a rapidly changing environment that favors the storage of calories as fat with a relatively static and highly cooperative genotype also favors increasing fatness. Our environment includes a burgeoning population of adults and children who are overweight or obese. This is particularly ominous in children, because there is an increasing body of evidence that children will accrue adiposity-related comorbidities as fast as or faster than people who become overweight or obese as adults. Therefore, our already overburdened health care system (in which 5% to 9% of annual health care costs are directly related to obesity and its comorbidities2'3) will soon see an alarmingly disproportionate increase in diabetes, hypertension, renal failure, blindness, and limb amputations among adults in their 30s and 40s as our current population of overweight children ages into adulthood.
DEFINITION OF PEDlATRlC OVERWEIGHT AND OBESITY
The ideal measure of pediatrie obesity would include some assessment of the risk of current and future morbidity by incorporating factors such as family history of growth patterns and adiposityrelated morbidities. This ideal is not yet available, and current definitions of both pediatrie and adult obesity rely on surrogate measures of body fatness. The most widely accepted of these is body mass index (BMI = weight (kg)/[height (m)]p 2) that correlates quite well with direct measures of body fatness within a populatioa4 In adults, it is feasible to use a generalized standard of BMI > 25 kg/mp 2 as overweight or "at-risk" for adiposity-related morbidity and BMI > 30 kg/mp 2 as obese.5 Because normative values for BMI are highly age-dependent and BMI values in children are significantly lower than in adults at the same level of adiposity6 (see Table 1, page 91), a classification system based on percentiles for BMI in children has been suggested. Children with BMI in the 85th to 95th percentile for age and gender based upon National Health and Nutrition Education Survey I (NHANES I, 1971 to 1974) data are defined as "atrisk" for overweight while those with BMI greater than the 95th percentile are defined as overweight7 Growth charts of age/sex specific BMI percentiles are now available and can be downloaded directly from the Centers for Disease Control (http://www. cdc.gov/nchs/data/ad/ad3 14.pdf).
HERITABILITY OF BODY FATNESS
Heritability, defined as the percentage of the variance in a given trait (in this case, body fatness) that is attributable to genetics, is usually calculated from studies of identical versus fraternal twins or by comparison of trait similarities between children who are adopted with their biological versus their adoptive parents. Heritability calculated from twin studies assumes that each member of a monozygotic or dizygotic pair is gestated and reared in the same environment and that the degree to which body fatness is more similar within mono- than dizygotic twin pairs is due to the additional 50% of the genotype shared by identical versus non-identical twins. Studies comparing adopted children with their adoptive and their biological parents assume that each child shares none of the environment, but 50% of their genotype, with each biological parent, and that the degree to which body fatness is more similar between children and their biologic versus adoptive parents is primarily due to genetic effects. Twin and adoption studies indicate that the heritability of body fatness and of body fat distribution in adulthood is 30% to 70%.8 This range of heritability is similar to that for height and suggests that there are more potent genetic influences on body fatness than on schizophrenia, hypertension, and other diseases that are commonly thought of as strongly heritable. There are also significant genetic influences (heritability greater than 30%) on multiple behaviors and physiological measures of energy expenditure relating to body weight homeostasis, including resting metabolic rate, feeding behavior, food preferences, and changes in energy expenditure, which occur in response to overeating.9'10
Heritability of body fatness refers to an assessment of the fraction of the variance in body fatness that is attributable to genetics, not to absolute values of weight and food intake. If both parents of a child weigh 100 kg, this does not mean that the child is also destined to achieve a similar weight What is heritable is the rank order of body fatness within a given population. Thus, if both parents are at the 75th percentile for body fatness of a population of people with a similar lifestyle, then it is more than likely that their offspring will also be at approximately the 75th percentile for body fatness among their similar lifestyle peers. What that dietary and exercise habits of that peer group is and therefore, what the absolute level of body fatness is at any given percentile within that group can be influenced by multiple environmental factors. The rapidly increasing prevalence of pediatrie overweight and obesity illustrates these gene x environment interactions.
The potent interactions between genetic predisposition toward obesity and the environment in which they are expressed are evidenced by the ethnic and geographic differences in obesity prevalence in the United States. Obesity is more prevalent among African-, Mexican, and Asian-Americans; among certain geographic regions (more prevalent in the northeast, midwest, south, west, urban, and rural areas); and among certain socioeconomic classes (poorer, less educated families, families with less access to recreational areas, or single parent/older parent families).11'12
The prevalence of pediatrie obesity is increasing at the rate of approximately 30% per decade (see Table 2). For example, between 1988 and 1991, the prevalence of overweight (defined as BMI 85th percentile based on data obtained in the 1976 to 1980 survey) rose from 15% (by definition) to 21%.12 The prevalence of obesity (defined as BMI > 95th percentile) among children ages 6 to 17 years has risen from approximately 3.7% in NHANES I (1971 to 1974) to 6% in NHANES II (1976 to 1980) to 10.5% in NHANES III (1998 to 1994).13 Changes in the mean BMI of children ages 6 to 17 from NHES II or III to NHANES III are indicated in Table 2.
The current demographics of obesity and the large increase in the prevalence of obesity over a single decade must reflect major changes innongenetic factors. The interaction of genetic factors favoring storage of calories as fat and an environment that is permissive to the clinical expression of this genetic tendency is thus evident in the increasing prevalence of pediatrie (and adult) obesity. Such secular trends may also be taken as tacit evidence that some instances/aspects of obesity are responsive to, and therefore, preventable by, environmental manipulation (eg, diet, physical activity, improved pre- and perinatal care).
85th to 95th Percentile BMI (kg/rn2) of Children Enrolled in NHANES 1(1971 to 1974)7
Mean BMI (kg/m2) of Children Enrolled in NHES II or III (1963 to 1970) or NHANES III(1988 to 1994)6
ENVIRONMENTAL INFLUENCES ON ADIPOSITY AND COMORBIDITIES
Obesity and adiposity-related comorbidities result from the interactions of genetic susceptibility to store excess calories as fat, as well as heritable predilections toward insulin resistance, impaired betacell function, dyslipidemia, hypertension, etc., with an environment that favors the "expression" of these susceptibilities. The intrauterine environment and the patterns of energy intake and expenditure that are laid down in childhood influence later patterns of energy storage, feeding behavior, and morbidity risk. As discussed below, it is clear that the interactions between the fetus and the environment that will influence subsequent body fatness and comorbidity risk begin at the moment of conception.
Low birthweight - defined in various studies as full term newborns weighing less than 2,500 to 3,000 g, or small for gestational age (SGA) defined as birthweight > 2 SD below the mean for gestational age - is associated with an increased risk of obesity and, to an even greater extent, adiposity-related comorbidities, including the "metabolic syndrome" (defined as three of the following: 14'15 waist circumference > 90th percentile for age and gender,16'17 hypertension,16 hypertriglyceridemia,18'20 low HDL-cholesterol,18 or hyperglycemia19'21"23) by two- to threefold.24 In a study to examine the long-term effects of prenatal undernutrition at different points in gestation, Ravelli et al25·26 examined adults conceived during the Nazi-imposed Dutch famine ("the Winter Hunger" of 1944 to 1945) versus those conceived before or after the famine. They found that the prevalence of impaired glucose tolerance was highest in low birthweight infants who were in utero while mothers were exposed to the famine during the last two trimesters of pregnancy. Associations of low birthweight with type 2 diabetes and impaired glucose tolerance have been reported in adults through the seventh and eighth decades of life,22·27'28 including negative correlations of insulin sensitivity and insulin secretory capacity with birthweight, even corrected for age, sex, gestational age at delivery, and current weight.23
A "thrifty genotype" hypothesis and a "catch-up growth" hypothesis have been proposed as mechanistic explanations for the association of low birthweight and the increased risk of adiposity-related comorbidities at any given level of body fatness. Briefly, the thrifty genotype hypothesis proposes that intrauterine undernutrition invokes neuroendocrine changes in the form of insulin resistance and islet cell dysfunction, which result in delivery of nutrients to vital organs, such as the heart and brain, rather than somatic growth.29 This tendency to optimize the efficiency of storing calories in the setting of insulin resistance results in obesity, diabetes, and dyslipidemia in the nutrientrich extrauterine environment, as opposed to the nutrient-poor environment in which these traits were encouraged.
The catch-up growth view proposes that intrauterine undernutrition provokes decreased insulin and insulinlike growth factor production.30 When the production of these molecules increases during the calorically rich postnatal catch-up growth phase, tissues respond by becoming insulin and insulin-like growth-factor resistant to protect against hypoglycemia.31 Frayling and Hattersley32 have suggested that impaired fetal growth and type 2 diabetes may represent two distinct phenotypes of a single thrifty genotype.33 In this case, resistance to the insulin's inability to synthesize an essential compound and the effect of other growth-promoting factors (eg, insulin-like growth factors) on somatic and organ growth maximizes energy storage at the expense of growth in the setting of an unstable food supply. Additionally, genes that reduce insulin secretion or increase insulin resistance predispose infants to low birthweights. Once adequate nutrients are available, the phenotypes that minimized energy expenditure in growth predispose the person to obesity and type 2 diabetes.
Although these formulations focus on somatic effects of intrauterine dysnutrition, it is certainly possible - even likely - that such effects also influence brain development, which could also predispose the person to neuroendocrine and behavioral phenotypes and which could result in increased adiposity and comorbidities. More recently, maternal smoking in the first trimester of pregnancy has been associated with increased body fat and blood pressure in childhood,34 perhaps via the effects on blood flow to the developing fetus.
Prenatal overnutrition exemplified by the macrosomic infant of a mother with diabetes (IDM), like prenatal undernutrition, is associated with increased risk of obesity and its comorbidities. Fetal overnutrition is associated with increased deposition of body fat in childhood and increased risk of obesity in adulthood and, like the SGA baby, with all of the phenotypes associated with the metabolic syndrome even when corrected for pre- and perigravid maternal adiposity.35'36 The IDM pancreas is exposed to high glucose levels, especially if the mother's diabetes control is poor, resulting in fetal hyperinsulinism and macrosomia, as well as altering the developing neuroendocrine systems to deposition of stored calories as fat (increased cortisol, resistance to insulin-mediated glucose transport but not lipogenesis) as well as insulin resistance.37
Early Feeding Practices
A number of recent well-designed studies have suggested that predominantly breastfeeding for at least six months is associated with an approximately 20% to 30% reduction in the prevalence of obesity (defined as BMI > 95th percentile for age and sex) through early adolescence, even when controlled for other adiposity-risk variables such as socioeconomic status and maternal adiposity.38 However, although associations have been reported between breastfeeding and diminution of some risk factors for adult cardiovascular disease, breastfed infants do not appear to be less fat as adults than their bottlefed counterparts.26 These data suggest that breastfeeding in infancy may have an independent effect on adiposity in childhood. However, it is also possible that this association is reflective of other factors in the environment in which the child is raised,38'39 which may influence both subsequent adiposity and the likelihood that an infant is breast fed.
Neither the age at which specific foods are introduced into the diet nor the proportions of fat, carbohydrate or protein in the diet significantly influence subsequent adult adiposity.40'41 The lack of association of diet composition per se with subsequent adiposity is also relevant to adiposity-related morbidities. In the Women's Health Initiative Randomized Controlled Dietary Modification Trial, prospective analyses of diet found no statistically significant associations between consumption of a low fat diet and the incidence of cardiovascular disease,42 colorectal cancer,43 or breast cancer,44 although trends toward beneficial effects on some of these morbidities were noted. Therefore, the institution of a well-balanced diet in childhood may form the basis for long-term healthy dietary habits that will persist into adulthood and over time may translate into significant reductions in body fat.
Early physical activity and dietary patterns track into adolescence and correlate with adolescent adiposity. These patterns also emphasize the potential benefits of early regular exercise and a healthy diet. Significant negative correlations have been reported between physical activity and body fatness in preschool children, whereas positive correlations have been noted between adiposity and the amount of time spent watching television in adolescence.45'46 More than 60% of television commercials during children's programs are food-related, and television watching promotes both inactivity and increased caloric intake.47 In addition, physical activity exerts independent beneficial effects on risks for adiposity-related morbidities (including cardiovascular disease, dyslipidemia, and type 2 diabetes mellitus) even if body fatness is not reduced.48'49
BODY FAT DISTRIBUTION
Body fat distribution, usually defined on the basis of waist circumference or the ratio of waist-to-hip circumference, is heritable.50 Central distribution of body fat is an independent predictor of insulin resistance and dyslipidemia in prepubertal and pubertal children51'52 and of type 2 diabetes, cardiovascular disease, stroke, and death in adults. 53'54 Free fatty acids (FFA) from omental fat drain directly into the portal circulation, exposing the liver to circulating FFA concentrations, which result in increased hepatic glucose production and decreased insulin clearance and which in turn lead to insulin resistance and dyslipidemia.53 In addition to central body fat distribution, intramyocellular lipid content (IMLC) has recently been identified as a strong heritable correlate of insulin resistance in adults and children and the possible cause of the impaired glucose transport resulting in lipodystrophy-associated type 2 diabetes mellitus.55
CHILDHOOD OBESITY AS A RISK FACTOR FOR ADULT OBESITY AND MORBIDITY
The age at which a child is noted to be obese and the family history of growth are both relevant risk factors for the persistence of childhood obesity or overweight into adulthood. The risk of persistence of pediatrie obesity into adulthood increases with age, independent of the length of time that the child has been obese.56'57 In large epidemiologie studies, if neither of a child's parents is obese, the likelihood of childhood obesity persisting into adulthood may be less than the risk for a non-obese child of the same age with one or two obese parents.58 Because growth patterns are also heritable, a mildly overweight child with a family history of excessive weight gain in adulthood may be at greater risk for subsequent obesity than a more severely overweight child with a negative family history of obesity and/or adiposity-related morbidity in adulthood.59'60
Obesity in childhood constitutes a risk factor for adiposity-related adult morbidity and mortality, even if childhood obesity does not persist. In adults, their fatness in adolescence has been reported to be a powerful predictor of mortality, cardiovascular disease, colorectal cancer, gout, and arthritis, irrespective of body fatness at the time that the morbidity was diagnosed.61 There is a further independent effect of family history of adiposity-related morbidity on the level of body fatness where morbidity becomes evident in an overweight child or adult.58'62 Also, adiposity-related morbidities, such as hyperlipidemia, which are evident in childhood, track well into adulthood63 as do the precursors of coronary artery disease, including elevated circulating concentrations of inflammatory markers and hypertension.64
Until recently, type 2 diabetes was thought of as an "adult" disease and constituted fewer than 2% of the new cases of diabetes in children as recently as a decade ago. Now, however, between 25% and 50% of newonset childhood diabetics are type 2. Thus, over the past decade and along with the increasing prevalence of obesity among children, type 2 diabetes has become a "pediatric" disease, and children with type 2 diabetes suffer the same morbidities as adults.65 Adiposity accounts for approximately 55% of the variance in insulin sensitivity in children66 and, as in adults, 50% to 90% of children with type 2 diabetes have a BMI >85* percentile, making obesity the primary risk factor for type 2 diabetes. This is especially true in black and Mexican-American adolescents, who have experienced the greatest increase in the prevalence of adolescent obesity over the past generation.6'12'67 The prevalence of obesity in blacks relative to other ethnic groups increases specifically during puberty.68
The increase in type 2 diabetes among adolescents may reflect an "unmasking" of an underlying genetic susceptibility to diabetes by the increased demand for insulin associated with the combined metabolic stresses of increased adiposity and puberty.62 The observation that those ethnic groups experiencing the greatest increase in the prevalence of overweight and obesity are also experiencing disproportionate increases in the adolescent type 2 diabetes69 supports this hypothesis.
The rapid increase in prevalence of obesity in the U.S. pediatrie population during the past 25 years demonstrates the effect of environment on adiposity. The environment has changed progressively to favor consumption of calorically dense foods through availability of fest foods, "super sizing," lower prices for fattier foods, and increased advertising for less healthful foods. Also, the environment has changed to an increasingly sedentary lifestyle via increased media and computer availability, as well as decreased availability of safe recreational areas in many neighborhoods. Improved prenatal and postnatal care has resulted in improved survival of infants suffering from intrauterine growth retardation who are more prone to obesity and its comorbidities.
Many other factors also may affect body fatness and may contribute to the increasing prevalence of obesity. These factors include getting less sleep, the disruption of endocrine function through the addition of artificial aromatase inhibitors and other "endocrine disruptors" to the environment, increased time spent in thermoneutral environments due to exogenous heaters and air conditioners, increased smoking, increased use of pharmaceuticals (anti-depressants, anti-psychotics, anti-diabetics, anti-histamines, and protease inhibitors) that promote weight gain, increased representation of ethnic groups who are more predisposed to obesity in the U.S. population (eg, Hispanics and blacks), and increasing grávida age.70
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85th to 95th Percentile BMI (kg/rn2) of Children Enrolled in NHANES 1(1971 to 1974)7
Mean BMI (kg/m2) of Children Enrolled in NHES II or III (1963 to 1970) or NHANES III(1988 to 1994)6