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Interventions to prevent adverse fetal programming due to maternal during pregnancy

Peter W Nathanielsz, Stephen P Ford, Nathan M Long, Claudia C Vega, Luis A Reyes-Castro, and Elena Zambrano

Maternal obesity is a global epidemic affecting both developed and developing countries. Human and animal studies indicate that maternal obesity adversely programs the development of offspring, predisposing them to chronic diseases later in life. Several mechanisms act together to produce these adverse health effects. There is a consequent need for effective interventions that can be used in the management of human pregnancy to prevent these outcomes. The present review analyzes the dietary and exercise intervention studies performed to date in both altricial and precocial animals, rats and sheep, with the aim of preventing adverse offspring outcomes. The results of these interventions present exciting opportunities to prevent, at least in part, adverse metabolic and other outcomes in obese mothers and their offspring. © 2013 International Life Sciences Institute

INTRODUCTION diseases through fetal programming.11 In order to gain a better understanding of such developmental program- Worldwide,nearly 1.5 billion people are overweight (body ming, investigation of the various factors involved in its mass index [BMI] >25 kg/m2) or obese (BMI >30 kg/m2),1 challenges, mechanisms, and outcomes is required. and the distribution among countries is broad. For Reports of experimental interventions in animal models example, in Mexico, 32% of women of reproductive years in the setting of obesity are scarce.12,13 In some experi- are obese2,3; in the United States, 35% of women of repro- mental animal models, the use of nutritional or targeted ductiveyearsareobese4; in Brazil,50% of the population is therapeutic interventions during windows of develop- overweight or obese5,6; in the United Kingdom, 33% of mental programming has shown the potential to reverse pregnant women are overweight or obese7;in India,26% of unwanted metabolic outcomes in offspring.13 For women of reproductive years are overweight and 8% are example, in neonatal female rats born to undernourished obese8; in China, 16% of women are overweight or obese9; mothers, treatment with prevented development of and in Ghana, 64.7% of women are either overweight or metabolic compromise in adulthood14; maternal antioxi- obese.10 The World Health Organization has declared dant supplementation in rats fed a Western diet partially obesity one of the top ten adverse health risk conditions in prevented adiposity and normalized glucose tolerance in the world and one of the top five in developed nations. offspring.15 In other studies, genistein supplementation in As noted in another review in the present supple- mice during gestation was shown to protect offspring ment, animal studies indicate maternal obesity predis- from susceptibility to obesity.16 This review focuses on poses offspring to a wide variety of chronic, later-life animal studies in which interventions were designed to

Affiliations: PW Nathanielsz is with the Center for Pregnancy and Newborn Research, Department of Obstetrics, University of Texas Health Sciences Center San Antonio, San Antonio, Texas, USA. SP Ford is with the Department of Animal Science, University of Wyoming Laramie, Laramie, Wyoming, USA. NM Long is with the Department of Animal and Veterinary Sciences, Clemson University, Clemson, South Carolina, USA. CC Vega, LA Reyes-Castro, and E Zambrano are with the Departamento de Biología de la Reproducción, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, México City, D.F., México. Correspondence: E Zambrano, Reproductive Biology, Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán, 14000 México City, D.F., México. E-mail: [email protected]. Phone: +52-55-5487-0900 ext 2417. Fax: +52-55-5655-9859. Key words: diet intervention, exercise intervention, fetal programming, maternal obesity

doi:10.1111/nure.12062 S78 Nutrition Reviews® Vol. 71(Suppl. 1):S78–S87 illuminate mechanisms by which a change in maternal PREPREGNANCY DIETARY INTERVENTION STUDIES diet or level of exercise may act to improve maternal and IN THE OBESE RAT offspring outcomes. There are many reasons why animal intervention studies are needed. Importantly, animal studies are much Methods more controllable than human clinical interventions, which is the parallel human approach to hypothesis- Investigations of adverse offspring programming due to driven animal research. In addition, a greater depth of maternal obesity requires that investigators ensure mechanistic interrogation is possible,resulting from tissue initial phenotypic homogeneity within the different retrieval and multiple rounds and forms of testing, and groups of mothers studied, i.e., controls, obese mothers, results are obtained much more quickly than in human and mothers in which interventions are introduced. studies. Reproducibility and independent confirmation, Care is necessary to achieve this important goal when the indispensable requirements of scientific certainty, are females who will be the study mothers are purchased also generally easier to achieve in animal studies. from commercial vendors. Specific information should Carefully designed clinical trials to determine the be obtained as to the lineage of all females purchased to effects of interventions and to improve maternal health in avoid the inclusion of sibling females in the same sub- pregnancy and offspring outcomes are now in progress.17 group. The following procedures used in previous However, in addition to the length of time needed to studies can help to avoid this and related problems. The obtain the required data, clinical trials have to contend first requirement is to maintain a colony of nonpreg- with multiple confounds related to the mother’s socio- nant females, which are then bred to deliver the female economic status and prepregnancy health; this not only pups that will be recruited as mothers into future makes analysis and interpretation difficult, it may also studies. All rats should be maintained on the same labo- limit the usefulness of findings for determining mecha- ratory chow unless they are being exposed to an experi- nisms. There is a pressing need, as a recent report from mental diet.25 At delivery (postnatal day [PND] 0), litters the Institute of Medicine indicates, for the development should be culled to 10 pups, with each litter containing of evidence-based interventions that both inform and at least four female pups. This standardization is impor- motivate pregnant women to adopt a healthy lifestyle tant since programming effects have been shown in off- before and during pregnancy.18 Currently, there is much spring according to the different sizes of litters being interest in both maternal diet and exercise as potentially reared by mothers during lactation.26 modifiable factors to target through interventions.19–21 At weaning (PND 21), female offspring were ran- The optimal timing and extent to which the adverse domly assigned either a control (C) group fed normal effects of the maternal metabolic phenotype, resulting laboratory chow or to a maternal obesity group (MO) from maternal obesity and associated high-calorie diets, fed a high-energy, obesogenic diet containing 23.5% can be prevented and/or possibly reversed by these inter- protein, 20% animal lard, 5% fat, 20.2% polysaccharide, ventions remain to be determined, and are of consider- 20.2% simple sugars, 5% fiber, 5% mineral mix, 1% able physiological interest and importance in clinical vitamin mix (w/w), and energy 4.9 Kcal/g. Only one obstetric management. Most authorities believe that female from any one litter was assigned to any study interventions introduced before conception will have the group. At PND 90, 1 month before breeding, half of the best results. However, it should always be born in mind obese females were selected at random for the dietary that poor maternal nutrition also programs adverse off- intervention (DINT) group and placed back on the C spring outcomes22–24 and sudden and excessive restriction diet for the rest of the study, including during preg- of maternal and fetal nutrient availability may well intro- nancy and lactation. The remaining obese females con- duce new dangers. Thus, firm scientific data are needed to tinued on the high-fat diet during pregnancy and guide interventions. lactation. Females were bred at 120 days as it has been When considering the goals of specific interventions shown that at younger breeding ages the mothers are to beneficially impact developmental programming out- still growing, albeit not as fast as earlier in life, and key comes, a distinction must always be made between inter- components of offspring outcomes, such as growth, tri- ventions designed to prevent negative offspring outcomes glyceride levels, and leptin levels, are affected by mater- and interventions conducted at later stages of an off- nal age as well as the nutritional challenge (unpublished spring’s life to reverse adverse health outcomes. Clearly, data). At PND 120, all three groups, C, MO, and DINT, prevention is a better strategy than reversal. The present were bred and fed their prepregnancy diet throughout review focuses on animal studies that have evaluated pregnancy and lactation. All mothers delivered by spon- maternal interventions to prevent negative offspring out- taneous vaginal delivery. Day of delivery was considered comes due to maternal obesity. as PND 025,27 (Figure 1).

Nutrition Reviews® Vol. 71(Suppl. 1):S78–S87 S79 Group MATERNAL DIET PUP DIET

PND PND growth 21-90 90-120 Pregnancy Lactation Weaning PND 21 Adult life Control (C) Chow diet

Maternal obesity High-fatHigh-fat ddietiet Chow diet (MO)

High-High- Dietary intervention Chow diet fatfat (DINT)

Figure 1 Feeding schedule for dietary intervention studies in obese maternal rats.

Changes in maternal and offspring phenotypes diet. Thus, there was no opportunity for any post- resulting from maternal obesity and weaning increase in offspring dietary intake to act as a dietary intervention second hit in addition to the developmental program- ming that had already occurred. In one study that followed the procedures outlined above, MO females were 16% heavier than controls, which is equivalent to a pregnant woman increasing her PREPREGNANCY EXERCISE INTERVENTION STUDIES BMI from 25 (the top of the normal BMI range) to 30.5 IN THE OBESE RAT (the lower end of the obese range). DINT females were 9% heavier than controls (equivalent to BMI in the mid- Methods overweight range) at breeding. Maternal serum leptin at the end of lactation was higher in the MO group than Recently, we have published the effects of an exercise the C group. Leptin levels in the DINT group were intervention in mothers and offspring of obese and similar to controls.28 control rats. General management of the pregnancies The effects of MO and DINT have only been and lactation were as described above for the dietary reported in male offspring.28 No differences in body intervention. At PND 90, i.e., 1 month before breeding, weight were seen between pups at birth and at weaning. one half of the C group of non-pregnant females and At weaning, MO offspring had more subcutaneous fat half of the MO female groups were selected at random to tissue and higher serum triglyceride and leptin levels than continue on their diet and begin wheel-running exercise C offspring, showing dysregulation of lipid metabolism; (C exercise intervention, CEx; MO exercise intervention, offspring from the group receiving prepregnancy mater- MOEx) (Figure 2). Mothers continued to be placed in nal DINT did not show the increases observed in MO the wheel throughout pregnancy. All females continued offspring. This important finding shows the limitations of on their respective diets. A training session lasted weight alone at any age as an assessment of outcomes. 15 min, which was established as the optimum running Body composition is much more important for predict- schedule that was always completed, and it was followed ing future offspring health. Serum glucose did not differ by a 15 min rest period and a second 15 min run. Rats among the three offspring groups; however, serum were allowed to rest for 2 days per week according to the insulin was elevated in MO offspring but not in C or following regimen: 2 days running, 1 day resting, 3 days DINT offspring, indicating the presence of insulin resis- running, 1 day resting. Before pregnancy, all rats com- tance in MO offspring.28 pleted the 30-min total running regimen, while during At PND 120, male MO offspring had elevated resting pregnancy rats were placed in the wheel for only one serum glucose and insulin and increased insulin resis- 15-min session per day, and the amount of voluntary tance compared with C offspring. Insulin remained exercise completed varied among the animals, especially elevated in DINT compared with C offspring, while blood in late gestation. During lactation, mothers nursed their glucose in the DINT group did not differ significantly pups and did not exercise. Therefore, lactating mothers from either the C or MO groups.28 It is important to were maintained on their pregnancy diet and not placed note that all offspring were on the same post-weaning in the wheel.29

S80 Nutrition Reviews® Vol. 71(Suppl. 1):S78–S87 GROUPMATERNAL DIET AND EXERCISE PUP DIET

21-90 90-120 PND

Pregnancy Lactation Weaning Adult life days days 21

Control (C) Chow diet

Chow diet Control exercise intervention Exercise (CEx) Chow diet

Maternal obesity (MO) High-fat diet

High-fat diet Maternal obesity exercise intervention Exercise (MOEx)

Figure 2 Exercise schedule for intervention studies in obese maternal rats.

Changes in maternal phenotype and fertility resulting random, fasted for 4 h, and euthanized by decapitation; from maternal exercise prior to and during pregnancy trunk blood samples were obtained and fat depots were excised and weighed. Litter size, litter weight, individual Calorie and food intake per day were similar in all four pup body weight, and litter sex ratio at birth were not groups and exercise did not affect calorie or food intake affected by either MO or exercise. In male offspring, body in any group. Exercise had no effect on maternal weight at weight, cholesterol, and insulin were not different at PND any stage except for in the CEx group in which exercise 36 among the four groups. Maternal obesity increased decreased body weight in comparison with the C group at offspring leptin, triglycerides, and fat mass in males. In the parturition. There were no differences among the four MOEx group, maternal exercise prevented the leptin groups in average distance run per session before preg- increase seen in male offspring of MO mothers who did nancy or in the first 15 days of pregnancy but, interest- not exercise and it partially prevented the increase in ingly, MOEx ran further than CEx rats in the last few days triglycerides. In the CEx group, maternal exercise reduced of pregnancy. This difference is hypothesized to result glucose and HOMA in the male offspring. The impor- from lower circulating estrogen levels in the MOEx tance of paying attention to the phenotype of study group, since a negative correlation has been shown to mothers is shown by the interesting observation that exist between estrogen levels and physical activity.30 maternal exercise decreased weight and cholesterol in As in the DINT study mentioned above, at the end of control offspring, indicating that even animals recruited lactation, maternal insulin, glucose, HOMA, leptin, as controls may be affected by experimental protocols.29 triglycerides, and cholesterol were all elevated in MO Maternal voluntary exercise intervention has been mothers. Exercise did not alter these variables in C previously reported in lean pregnant rats in two different mothers but it prevented changes from occurring in all of models: male, but not female, offspring of exercised the variables except leptin in MOEx mothers. mothers showed increases in percent lean mass and decreases in fat mass percent compared to male offspring Effect of maternal obesity and exercise on male from controls, showing that maternal exercise can affect offspring metabolism at postnatal day 36 offspring.31,32 These effects on the metabolic phenotype of offspring show similarities to the effects observed in Offspring outcomes were evaluated since the goal of the control mothers in the study described above. In another interventions in MO pregnancy was to improve both study, normal, lean, pregnant rats performed voluntary maternal and offspring outcomes. At offspring PND 36, exercise,33,34 training from 42 days before pregnancy and one male offspring from each litter (n = 8) was chosen at continuing on to day 19 of gestation, with the result that

Nutrition Reviews® Vol. 71(Suppl. 1):S78–S87 S81 A B CD

1000 1500 1500 1000 b b b 800 b 1200 1200 800 c a c ab 600 a a 900 900 600 a a a a a a 400 600 600 400

200 300 300 200 Corticosterone (ng/mL) Corticosterone (ng/mL) Corticosterone (ng/mL) Corticosterone (ng/mL)

C MO DINT MOEx C MO DINT MOEx C MO DINT MOEx C MO DINT MOEx

Figure 3 Comparison of corticosterone levels in rat serum: A) maternal: prepregnancy; B) maternal: end of lactation; C) male and female neonate: postnatal day 2; and D) young adult male offspring: postnatal day 110. Values are mean ± SEM; n = 6; P < 0.05 for groups not sharing at least one letter. Abbreviations: C, control diet; MO, maternal obesity; DINT, maternal dietary intervention; MOEx, maternal obesity exercise intervention.

maternal plasma antioxidant status was improved. Both increases in glucose, insulin, HOMA, fat, and fat cell size, of these studies provide important data for designing and it completely prevented leptin increases in MO off- future studies in obese mothers. spring. The maternal exercise intervention partially pre- vented increases in fat and insulin and completely Comparison of diet intervention and exercise models prevented increases in glucose, HOMA, and fat cell size in MO offspring. One of the important differences between the DINT and For both models, the data indicate there were differ- the exercise intervention model is the maternal weight. ent changes in metabolism in various tissues, since no In the DINT model,28 the increased maternal body differences in food intake and body weight were found in weight of the DINT group at breeding was partially pre- the young adult offspring. The two intervention models vented, and there were no differences in maternal body appear to benefit offspring metabolism in diverse ways, weight during pregnancy and lactation between the suggesting dissimilar maternal mechanisms. Excessive DINT and C groups. In contrast, maternal exercise gestational weight gain has been associated with adverse intervention did not modify the maternal body weight at maternal pregnancy outcomes, and Catalano has demon- any stage.29 The weight of MOEx mothers was the same strated that maternal prepregnancy BMI is a major factor as MO mothers before and during pregnancy as well as in determining maternal and offspring outcomes.35 One during lactation. However, in both models, the mothers important finding of the exercise intervention study was undertaking the intervention presented a better meta- that the adverse offspring outcomes produced by MO bolic and hormonal maternal environment with regard were the result of maternal metabolic changes and/or to offspring outcomes than the MO mothers not receiv- increased maternal corticosterone and not maternal ing an intervention. body weight, since MOEx prevented many of the adverse In a completely independent study, maternal dietary MO offspring outcomes without producing any change and exercise interventions were applied to subsets of in maternal calorie intake or body weight. This finding MO and C groups and all groups were compared. again shows that outcomes are related more to body Corticosterone was found to be increased in serum of composition than to body weight. The overwhelming evi- MO mothers prior to breeding. Maternal DINT and exer- dence in favor of the importance of body composition cise interventions before pregnancy decreased maternal clearly indicates that the most successful interventions corticosterone concentration, but values in the MOEx will contain at least a component of prepregnancy inter- group did not return to those of the C group (Figure 3A). vention. Additional interventions during pregnancy will A similar picture was seen at the end of lactation further build on the interventions performed prior to (Figure 3B) and in the neonate and young adult male pregnancy. offspring (Figure 3C,D). These changes in corticosterone In previous reports on the effects of maternal dietary levels may be protective mechanisms to help prevent intervention on offspring outcomes in the setting of future metabolic problems in the MO offspring. obesity the following was written, which statement bears: Both types of maternal intervention resulted in “There is a need to determine optimal timing, nature and reductions in the adverse metabolic outcomes caused by extent of interventions. We have taken the view – as MO in offspring, but the degree and type were different in others have done – that the optimal time for recuperation the two models. Maternal DINT partially prevented would be prior to pregnancy and have sought to develop

S82 Nutrition Reviews® Vol. 71(Suppl. 1):S78–S87 ABC

800 b 60 b 8 b 600 a a 6 a 40 a a a 400 a a a 4 Fat (g) 20 200 2 Adiposity Index Body weight (g)

CMODINTMOEx CMODINTMOEx C MO DINT MOEx

Figure 4 Comparison of three measures in rat male offspring from a diet and exercise intervention study at postnatal day 650: (A) body weight, (B) fat, and (C) adiposity index. Values are mean ± SEM; n = 6; P < 0.05 for groups not sharing at least one letter. Abbreviations: C, control diet; MO, maternal obesity; DINT, maternal dietary intervention; MOEx, maternal obesity exercise intervention. a model to show the ability and extent of the simplest of interventions, reducing global intake, to produce benefi- cial results. . . . The available evidence indicates that women do not spontaneously alter their dietary patterns when they discover they are pregnant.36 Interventions in pregnancy, as in any other major health area, therefore need to be based on firm, reproducible scientific evidence.”28 Obese women contemplating pregnancy need to be C MO DINT provided with firm information as to the benefits that Figure 5 Representative pictures of male offspring from accrue from decreasing their BMI both before and during dietary intervention study at postnatal day 650. pregnancy for at least two reasons. First, they need to be Abbreviations: C, control diet; MO, maternal obesity; and aware of the biological reasons that maternal obesity is DINT, maternal dietary intervention. harmful to themselves and their baby in many ways. Second, they need to be confident that appropriately low- ering their BMI and food intake will provide significant benefit to themselves and their children.

Influence of interventions on offspring aging

Maternal low-protein diets accelerate aging in rat off- spring.37 For example, increased adiposity index and leptin, and triglyceride levels have been found in male offspring of non-intervention MO mothers during young C CEx MO MOEx adult life (PND 110),28 but these were not accompanied Figure 6 Representative pictures of male offspring from by statistically significant differences in body weight. exercise intervention study at postnatal day 650. However, by PND 650, more rapid aging was evident in Abbreviations: C, control diet; CEx, control diet + maternal some metabolic indices, such as body weight (Figures 4– exercise intervention; MO, maternal obesity; and MOEx, 6), fat, and adiposity index, while such increases were not maternal obesity + maternal exercise intervention. apparent in the offspring of MO mothers that received a maternal dietary and exercise intervention (Figure 4). One good example of positive features of program- STUDIES ON DIETARY INTERVENTION IN OBESE ming is seen in the offspring of CEx mothers, which had PREGNANT SHEEP a better metabolic phenotype at an early stage of aging (PND 650) than the rest of the groups, including the As discussed in another review of developmental pro- control group. gramming in the present supplement,there are differences

Nutrition Reviews® Vol. 71(Suppl. 1):S78–S87 S83 between pregnancy in altricial,polytocous mammals,such studies have demonstrated that maternal undernutrition as the rat, and precocial, monotocous species, such as (50% global undernutrition) starting at day 28 of gestation humans, sheep, and nonhuman primates.11 The pregnant resulted in delivery of offspring that exhibited metabolic sheep has been extensively investigated to determine the disturbances as adults (i.e., they were hyperphagic, insulin impacts of decreased maternal nutrition,but fewer studies resistant, and obese).53 It was, therefore, hypothesized that have been conducted on the effects of maternal a dietary intervention in which the obesogenic diet is overnutrition/obesity on fetuses and offspring in this reduced from 150% to 100% of NRC requirements (MO important, precocial, experimental species.38–46 Although intervention [MOI]) beginning on day 28 of gestation there are differences in some capabilities, such as locomo- would be early enough to, at least in part, prevent the tion, both sheep and pregnant women produce well- negative impacts of maternal overnutrition/obesity on the developed precocial offspring, exhibit similar newborn- fetus and resulting offspring. Further, day 28 of gestation to-maternal weight ratios, and have a temporal pattern of in the sheep is equivalent to approximately day 50 in fetal tissue and organ development. Further, investigators human pregnancy, which is about the time when women worldwide have utilized the fetal sheep as a biomedical confirm they are pregnant and early enough for their model to design studies of human pregnancy,such as fetal obstetrician to provide overweight/obese women with a behavior, heart rate, and sleep states.47–50 corrective dietary regimen if deemed necessary. MOI eliminated MO-induced fetal macrosomia at Methods midgestation, and either reduced (right ventricular weight, liver weight) or prevented MO-induced increases Some studies on the impact of maternal overnutrition/ in organ weight (left ventricular weight, total kidney obesity in the ewe on fetal growth and development and weight, pancreatic weight, and total perirenal fat weight). offspring health have been conducted with animals from At day 135, while fetal weight was similar among the C, a well-characterized, closed flock at the Center for the MO, and MOI fetuses, the MO fetuses exhibited greater Study of Fetal Programming, University of Wyoming.11 left ventricular weights and thicknesses, right ventricular For those studies, ewes of similar size and breeding were thicknesses, total kidney weight, and total perirenal fat, as maintained in the source flock developed from lambs well as reduced pancreatic weight, in comparison with C born within the flock whose mothers were fed according fetuses. The weights and thicknesses of these organs and to National Research Council (NRC) feed requirements tissues in the MOI fetuses returned to C levels.54 These throughout pregnancy and lactation. The ewe lambs were data provide the first indication that alterations in fetal then maintained on the same diet and used as the organ and tissue growth as well as endocrine changes (see mothers in all studies; they were housed together and fed below) can, at least in part, be prevented by early preg- only NRC-compliant feed from weaning to maturity.This nancy MOI in the face of maternal obesity. management policy provides assurance that animals have To date, changes in cortisol levels have only been not been exposed to highly variable environments prior evaluated in the MOI sheep model in order to observe any to any investigation and thus limits the chance of mark- similarities with findings from the obese rat model edly different environmental (epigenetic) influences on described above (Figure 3). MO increased both maternal study results, as well as other problematic influences, such and fetal cortisol at 50% and 90% gestation, and this as sibships within groups. increase was prevented by MOI at both timepoints. Inter- A model of maternal overnutrition/obesity (MO) has estingly, while the maternal increases in cortisol were been developed and characterized, whereby ewes are fed a accompanied by increased ACTH, this was not so in the highly palatable pelleted diet at 150% of NRC require- fetus where cortisol, but not ACTH, was higher in the MO ments from 60 days before conception throughout preg- group than the C group at both ages (Figure 7). Two nancy. On this diet, ewes become obese by the time possible mechanisms for this finding are hypothesized: 1) they are bred and continue to gain additional weight MO may change adrenal sensitivity toACTH;and 2) much throughout pregnancy; their fetuses show a definitive of the fetal cortisol in the setting of maternal obesity is endophenotype.38–41,45,46,51,52 In humans, overweight and produced in peripheral fetal tissues by increased activity of obesity at conception in pregnant women has been shown 11BHSD1,converting inactive cortisone to active cortisol. to have the greatest impact on increasing adiposity of It has been shown that the 11BHSD1 system is upregulated infants at birth, which leads to insulin resistance and exhi- infetalfemaleperirenalfatandfetalmaleliverinthe bition of obesity in later life.35 In our model of diet-induced setting of maternal undernutrition, which supports a MO, lambs are born with increased adiposity, and by 19 potential role for increased 11BSD1 activity in response to months of age they exhibit hyperphagia, glucose and maternal dietary challenges.55 Importantly, the extent to insulin dysregulation, and increased adiposity compared which inhibition of the increase in fetal cortisol will to offspring of ewes fed only to requirements.40 Previous prevent adverse side effects of MO on offspring remains to

S84 Nutrition Reviews® Vol. 71(Suppl. 1):S78–S87 A B 600 50 *

500 40 400 30 300 20 200 *

Fetal ACTH Fetal ACTH (pg/mL) 100 10 ** (ng/mL)Fetal Cortisol 0 0 C MO MOI C MO MOI C MO MOI C MO MOI Day75 Day 135 Day75 Day 135 C D 350 100 * * 300 * 250 75 200 50 150 *

100 25 50 Maternal ACTH ACTH Maternal (pg/mL) Maternal Cortisol Maternal Cortisol (ng/mL) 0 0 C MO MOI C MO MOI C MO MOI C MO MOI Day75 Day 135 Day75 Day 135

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).

be seen. These findings illustrate clearly the value of com- behaviors can be modified when firm, incontrovertible paring results of studies performed in precocial and information on the benefits of modification is provided. It altricial species. Current studies in sheep are evaluating C, has been over 50 years since Sir Richard Bradford Doll MO, and MOI offspring to determine whether reducing demonstrated the connection between cigarette smoking maternal nutrition to recommended levels in early preg- and lung cancer.56 Changing this self-destructive behav- nancy of overnourished/obese ewes prevents endocrine ior has taken decades, but the eventual decrease in and metabolic disturbances in offspring in adult life. smoking is estimated to have saved thousands of lives. One of the most persuasive pieces of scientific evidence in Communicating the need for interventions to the the antismoking campaign was the demonstration that general public: Lessons from antismoking campaigns while smoking from early adult life tripled mortality rates, giving up smoking at age 50 halved the mortality Improved women’s health and, especially, the institution risk, and stopping at age 30 removed virtually all mortal- of effective corrective measures is vitally important for ity risk.56 Human studies indicate that elevated maternal obtaining optimal obstetric outcomes in the face of the prepregnancy BMI in women is a major determinant of current epidemic of obesity in women of reproductive adverse offspring metabolic outcomes resulting from years. There may be lessons that can be learned from the maternal obesity.57 The parallel between smoking and success in the developed world in decreasing the inci- MO would be the potential to avoid a likely negative dence of smoking through antismoking campaigns. This outcome through behavior and lifestyle modification. For success suggests that even the strongest of compulsive MO, the persuasive message would be the evidence given

Nutrition Reviews® Vol. 71(Suppl. 1):S78–S87 S85 here that lifestyle adjustments aimed at reducing obesity 11. Zambrano E, Nathanielsz PW. Mechanisms by which maternal obesity programs offspring for obesity: evidence from animal studies. Nutr Rev. 2013;71:present would have the potential to prevent adverse maternal and issue. offspring outcomes. 12. Gavard JA, Artal R. Effect of exercise on pregnancy outcome. Clin Obstet Gynecol. 2008;51:467–480. 13. Vickers MH, Sloboda DM. Strategies for reversing the effects of metabolic disor- ders induced as a consequence of developmental programming. Front Physiol. CONCLUSION 2012;3:242. 14. Vickers MH, Gluckman PD, Coveny AH, et al. Neonatal leptin treatment reverses Epidemiological studies have shown that once a woman developmental programming. Endocrinology. 2005;146:4211–4216. 15. Sen S, Simmons RA. Maternal antioxidant supplementation prevents adiposity in knows she is pregnant, she does not typically modify her the offspring of Western diet-fed rats. . 2010;59:3058–3065. lifestyle.36 Thus, the earlier a positive lifestyle intervention 16. Dolinoy DC, Weidman JR, Waterland RA, et al. Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fetal is undertaken, the better the outcome. As the important epigenome. Environ Health Perspect. 2006;114:567–572. IOM report58 and reviews by several clinical and basic 17. Nelson SM, Poston L. Intervention strategies to improve outcome in obese pregnancies: insulin resistance and gestational diabetes. In: Gillman MW, Poston science leaders indicate, studies such as those described Led.Maternal Obesity. New York: Cambridge University Press; 2012:179– here are essential for determining the mechanistic targets 198. 18. Rasmussen KM, Catalano PM, Yaktine AL. New guidelines for weight gain during in the mother that can guide the development of predic- pregnancy: what obstetrician/gynecologists should know. Curr Opin Obstet tive and clinical tools for use in human pregnancy.59 Gynecol. 2009;21:521–526. 19. McCance RA, Widdowson EM. Fat. Pediatr Res. 1977;11:1081–1083. Other potential interventions remain to be investigated to 20. Oken E, Gillman MW. Intervention strategies to improve outcome in obese permit evidence-based changes in clinical management. pregnancies: focus on gestational weight gain. In: Gillman MW, Poston L, ed. Maternal Obesity. New York: Cambridge University Press; 2012:151–178. These include diets supplemented with polyunsaturated 21. Stern JS, Johnson PR. Spontaneous activity and adipose cellularity in the geneti- fatty acids or antioxidants. Different interventions to cally obese Zucker rat (fafa). Metabolism. 1977;26:371–380. 22. Armitage JA, Khan IY, Taylor PD, et al. 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Plagemann A, Heidrich I, Gotz F, et al. Obesity and enhanced diabetes and car- México, Sociedad Mexicana de Nutrición y diovascular risk in adult rats due to early postnatal overfeeding. Exp Clin Endocrinología and HD 21350 from the National Institute Endocrinol. 1992;99:154–158. 27. Zambrano E, Bautista CJ, Deas M, et al. A low maternal protein diet during preg- of Child Health and Human Development. nancy and lactation has sex- and window of exposure-specific effects on off- spring growth and food intake, glucose metabolism and serum leptin in the rat. Declaration of interest. The authors have no relevant J Physiol. 2006;571:221–230. 28. Zambrano E, Martinez-Samayoa PM, Rodriguez-Gonzalez GL, et al. Dietary inter- interests to declare. vention prior to pregnancy reverses metabolic programming in male offspring of obese rats. J Physiol. 2010;588:1791–1799. 29. Vega C, Reyes-Castro L, Bautista C, et al. 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