MetroHealth Medical Center, Department of Reproductive Biology Case Western Reserve University Cleveland, Ohio 44109
Address all correspondence and requests for reprints to: Patrick M. Catalano, M.D., MetroHealth Medical Center, Department of Obstetrics/Gynecology, 2500 MetroHealth Drive, Suite A-219, Cleveland, Ohio 44109. E-mail: pcatalano{at}Metrohealth.org.
"Obesity is a chronic disease, prevalent in both developed and developing countries, and affecting children as well as adults. Indeed, it is now so common that it is replacing the more traditional public health concerns, including undernutrition and infectious disease as one of the most significant contributors to ill health" (1). In the United States, the adult age-adjusted prevalence of obesity [body mass index (BMI) 30] was 30.5% in 2000, compared to 22.9% from 19981994. The prevalence of overweight (BMI
25%) increased from 55.964.5% during the same period of time (2). Potentially more important is that the prevalence of obesity in adolescents has also increased, particularly among Hispanic and African-American populations. In the United States, the prevalence of obesity, defined as weight greater than the 95th percentile of the sex-specific BMI for age, was 15.3% among 611 yr olds, an 11.3% increase since 198894 (3).
In the last decade, there has been a plethora of data relating to the fact that adipose cells are not just a storage depot for excess calories, but rather a metabolically active tissue. Leptin and, more recently, a number of additional cytokines have been reported to have paracrine as well as endocrine effects on a variety of target tissues. Relative to the issue of cytokines and insulin resistance, TNF- has been reported to modify the insulin signaling pathway via serine phosphorylation of insulin receptor substrate-1, one primary substrate of insulin receptor (4). How then do these data relate to pregnancy and the increased prevalence of obesity in the past decade?
Human pregnancy is an insulin-resistant condition. Although there is a 4- to 5-fold range of insulin resistance in the general population, there is a relatively uniform 4050% increase (from the pregravid condition) in insulin resistance during pregnancy (5). These alterations in insulin resistance have been previously ascribed to a variety of reproductive hormones such as human placental lactogen, but more recent data suggest that cytokines, in particular TNF-, possibly from the placental sources, may be a significant factor (6). Hence, the degree of insulin resistance during late gestation appears to be dependent primarily on pregravid maternal insulin resistance, which is quite variable, and secondarily on the 4050% increases mediated through placental factors.
Hence, it is not surprising that Retnakaran et al. (7) reported in this issue of JCEM that C-reactive protein (CRP) levels in late pregnancy relate to pregravid BMI and not to gestational diabetes mellitus (GDM) per se. Assuming that the CRP concentrations in late gestation are a marker of insulin resistance, then a womans pregravid BMI may be the strongest clinical marker of the degree of her insulin resistance, even in late gestation. The lack of relationship of CRP to GDM may reflect the wide variation of pregravid BMI to inflammation/insulin resistance rather than the relative uniform decreases observed during pregnancy. It is of interest that in the study of Retnakaran et al., the mean pregravid BMI of the obese controls was greater (29.3 kg/m2) as compared with the GDM subjects (24.7 kg/m2). Therefore, based on their study, pregravid obesity represents a state of chronic inflammation and insulin resistance as estimated by CRP levels. The relationship between obesity and inflammation/insulin resistance has been noted by others using CRP as well as other markers of inflammation, such as IL-6 (8). Although in the United States most women with GDM are obese, these women not only represent a condition of insulin resistance but also, because of the inability to maintain normal glycemia during the metabolic stress of pregnancy, have defects in pancreatic ß-cell function.
Multiple factors have been associated with fetal overgrowth or macrosomia. Although maternal demographic factors such as age and weight gain play a significant role, they explain only a small fraction of the variance in fetal growth. In contrast, increased maternal pregravid weight and decreased pregravid insulin sensitivity are the strongest correlates with fetal growth, in particular fat mass at birth (9). The mechanisms are not as yet well defined, but in early pregnancy increased maternal insulin resistance may be related to altered placental function as well as to increased fetoplacental availability of nutrients in late gestation, not only glucose but also free fatty acids and amino acids. Therefore, although women with GDM (even those who are treated and are under tight metabolic control) are at increased risk of having a macrosomic infant, women who are obese with normal glucose tolerance are potentially at twice the risk of having a macrosomic baby (10). More important is the fact that the increase in birth weight or macrosomia may represent an increase in fat compared with fat free mass. We recently reported that there is a significant increase in neonatal fat mass but not total body weight or fat free mass in appropriate birth weight infants of women with GDM as compared with a matched control group (11). Hence, the risk of neonatal macrosomia/obesity may be a specific risk for adolescent/adult obesity.
Does obesity beget obesity? Barker et al. (12) have been strong proponents of the fetal origin of adult disease hypothesis. Based on their work, low birth weight may impact the lifelong metabolic function of the organism. In their studies, low birth weight was a significant factor for the development of the metabolic syndrome in adulthood; although obesity was not a hallmark of their diabetic population, it was an independent risk factor. However, others have pointed out that the risk of developing obesity and type 2 diabetes is also a risk factor for infants born at the upper end of the birth weight curve, i.e. the risk is U-shaped (13). On the basis of these observations, one could hypothesize that increased maternal pregravid obesity is a state of increased insulin resistance and inflammation as estimated by CRP. During gestation, obese women make available increased nutrients to the fetus, resulting in increased placental growth in early gestation and increased somatic growth, particularly fetal adipose tissue in late gestation. The worldwide increase in maternal pregravid weight may help explain why a recent study from Denmark reported that mean birth weight at term had increased 62 g over the past decade, and the percentage of babies born with a birth weight of over 4,000 g has increased from 16.720.0% (14)!
If greater than 30% of the population is obese, whereas the prevalence of GDM is currently in the range of 38%, then on the basis of numbers alone at this time, maternal obesity is the greater issue relative to the short- and long-term risks of adolescent and possible adult obesity. Unfortunately, the increase in adolescent obesity is associated with the increase in adolescent type 2 diabetes, compounding the problem. In the last decade, the prevalence of type 2 diabetes increased 33% in children. Eighty-five percent of children diagnosed with type 2 diabetes are obese (15). Additionally, in a recent study, impaired glucose tolerance/insulin resistance was diagnosed in 25% of obese children 410 yr old (16).
In summary, the worldwide epidemic of adolescent and adult obesity may not only be a result of our lifestyle of inadequate activity and poor diet; it may also be propagated and enhanced at a much earlier stage in life because of an abnormal metabolic milieu in utero during gestation (Fig. 1). Because we know that lifestyle treatment of obesity is rarely successful in the long term, we need to give serious consideration to prevention. The potential of in utero therapy, possibly through lifestyle measures during gestation, should become a research focus of considerable interest relative to the short- and long-term prevention of obesity.
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Footnotes
Abbreviations: BMI, Body mass index; CRP, C-reactive protein; GDM, gestational diabetes mellitus.
Received June 17, 2003.
Accepted June 26, 2003.
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