As discussed in another review of developmental programming in the present supplement, there are differences between pregnancy in altricial, polytocous mammals, such as the rat, and precocial, monotocous species, such as humans, sheep, and nonhuman primates. The pregnant sheep has been extensively investigated to determine the impacts of decreased maternal nutrition, but fewer studies have been conducted on the effects of maternal overnutrition/obesity on fetuses and offspring in this important, precocial, experimental species.[38-46] Although there are differences in some capabilities, such as locomotion, both sheep and pregnant women produce well-developed precocial offspring, exhibit similar newborn-to-maternal weight ratios, and have a temporal pattern of fetal tissue and organ development. Further, investigators worldwide have utilized the fetal sheep as a biomedical model to design studies of human pregnancy, such as fetal behavior, heart rate, and sleep states.[47-50]
Some studies on the impact of maternal overnutrition/obesity in the ewe on fetal growth and development and offspring health have been conducted with animals from a well-characterized, closed flock at the Center for the Study of Fetal Programming, University of Wyoming. For those studies, ewes of similar size and breeding were maintained in the source flock developed from lambs born within the flock whose mothers were fed according to National Research Council (NRC) feed requirements throughout pregnancy and lactation. The ewe lambs were then maintained on the same diet and used as the mothers in all studies; they were housed together and fed only NRC-compliant feed from weaning to maturity. This management policy provides assurance that animals have not been exposed to highly variable environments prior to any investigation and thus limits the chance of markedly different environmental (epigenetic) influences on study results, as well as other problematic influences, such as sibships within groups.
A model of maternal overnutrition/obesity (MO) has been developed and characterized, whereby ewes are fed a highly palatable pelleted diet at 150% of NRC requirements from 60 days before conception throughout pregnancy. On this diet, ewes become obese by the time they are bred and continue to gain additional weight throughout pregnancy; their fetuses show a definitive endophenotype.[38-41, 45, 46, 51, 52] In humans, overweight and obesity at conception in pregnant women has been shown to have the greatest impact on increasing adiposity of infants at birth, which leads to insulin resistance and exhibition of obesity in later life. In our model of diet-induced MO, lambs are born with increased adiposity, and by 19 months of age they exhibit hyperphagia, glucose and insulin dysregulation, and increased adiposity compared to offspring of ewes fed only to requirements. Previous studies have demonstrated that maternal undernutrition (50% global undernutrition) starting at day 28 of gestation resulted in delivery of offspring that exhibited metabolic disturbances as adults (i.e., they were hyperphagic, insulin resistant, and obese). It was, therefore, hypothesized that a dietary intervention in which the obesogenic diet is reduced from 150% to 100% of NRC requirements (MO intervention [MOI]) beginning on day 28 of gestation would be early enough to, at least in part, prevent the negative impacts of maternal overnutrition/obesity on the fetus and resulting offspring. Further, day 28 of gestation in the sheep is equivalent to approximately day 50 in human pregnancy, which is about the time when women confirm they are pregnant and early enough for their obstetrician to provide overweight/obese women with a corrective dietary regimen if deemed necessary.
MOI eliminated MO-induced fetal macrosomia at midgestation, and either reduced (right ventricular weight, liver weight) or prevented MO-induced increases in organ weight (left ventricular weight, total kidney weight, pancreatic weight, and total perirenal fat weight). At day 135, while fetal weight was similar among the C, MO, and MOI fetuses, the MO fetuses exhibited greater left ventricular weights and thicknesses, right ventricular thicknesses, total kidney weight, and total perirenal fat, as well as reduced pancreatic weight, in comparison with C fetuses. The weights and thicknesses of these organs and tissues in the MOI fetuses returned to C levels. These data provide the first indication that alterations in fetal organ and tissue growth as well as endocrine changes (see below) can, at least in part, be prevented by early pregnancy MOI in the face of maternal obesity.
To date, changes in cortisol levels have only been evaluated in the MOI sheep model in order to observe any similarities with findings from the obese rat model described above (Figure 3). MO increased both maternal and fetal cortisol at 50% and 90% gestation, and this increase was prevented by MOI at both timepoints. Interestingly, while the maternal increases in cortisol were accompanied by increased ACTH, this was not so in the fetus where cortisol, but not ACTH, was higher in the MO group than the C group at both ages (Figure 7). Two possible mechanisms for this finding are hypothesized: 1) MO may change adrenal sensitivity to ACTH; and 2) much of the fetal cortisol in the setting of maternal obesity is produced in peripheral fetal tissues by increased activity of 11BHSD1, converting inactive cortisone to active cortisol. It has been shown that the 11BHSD1 system is upregulated in fetal female perirenal fat and fetal male liver in the setting of maternal undernutrition, which supports a potential role for increased 11BSD1 activity in response to maternal dietary challenges. Importantly, the extent to which inhibition of the increase in fetal cortisol will prevent adverse side effects of MO on offspring remains to be seen. These findings illustrate clearly the value of comparing results of studies performed in precocial and altricial species. Current studies in sheep are evaluating C, MO, and MOI offspring to determine whether reducing maternal nutrition to recommended levels in early pregnancy of overnourished/obese ewes prevents endocrine and metabolic disturbances in offspring in adult life.
Figure 7. Comparison of cortisol and ACTH levels in obese maternal sheep and their offspring at 75 and 135 days gestation: A) fetal ACTH, B) fetal cortisol, C) maternal ACTH, and D) maternal cortisol. Values are mean ± SEM; n = 6; P < 0.05 ** vs C and MO, * vs C and MOI. Abbreviations: C, control (open); MO, maternal obesity (solid); MOI, maternal obesity dietary intervention (striped).
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Communicating the need for interventions to the general public: Lessons from antismoking campaigns
Improved women's health and, especially, the institution of effective corrective measures is vitally important for obtaining optimal obstetric outcomes in the face of the current epidemic of obesity in women of reproductive years. There may be lessons that can be learned from the success in the developed world in decreasing the incidence of smoking through antismoking campaigns. This success suggests that even the strongest of compulsive behaviors can be modified when firm, incontrovertible information on the benefits of modification is provided. It has been over 50 years since Sir Richard Bradford Doll demonstrated the connection between cigarette smoking and lung cancer. Changing this self-destructive behavior has taken decades, but the eventual decrease in smoking is estimated to have saved thousands of lives. One of the most persuasive pieces of scientific evidence in the antismoking campaign was the demonstration that while smoking from early adult life tripled mortality rates, giving up smoking at age 50 halved the mortality risk, and stopping at age 30 removed virtually all mortality risk. Human studies indicate that elevated maternal prepregnancy BMI in women is a major determinant of adverse offspring metabolic outcomes resulting from maternal obesity. The parallel between smoking and MO would be the potential to avoid a likely negative outcome through behavior and lifestyle modification. For MO, the persuasive message would be the evidence given here that lifestyle adjustments aimed at reducing obesity would have the potential to prevent adverse maternal and offspring outcomes.