Journal of Developmental Origins of Health and Disease (2012), 3(3), 140–152. & Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2012 doi:10.1017/S2040174412000062

REVIEW

Effects of in utero conditions on adult feeding preferences A. K. Portella1, E. Kajantie2,3, P. Hovi2,3, M. Desai4, M. G. Ross4, M. Z. Goldani1, T. J. Roseboom5 and P. P. Silveira1* 1

Nu´cleo de Estudos da Sau´de da Crianc¸a e do Adolescente (NESCA), Hospital de Clı´nicas de Porto Alegre, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul, Brazil 2 Children’s Hospital, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland 3 Department of Chronic Disease Prevention, Diabetes Prevention Unit, National Institute for Health and Welfare, Helsinki, Finland 4 Department of Obstetrics and Gynecology, Harbor-UCLA Medical Center, Los Angeles Biomedical Research Institute at Harbor-UCLA, David Geffen School of Medicine at UCLA, Torrance, California, USA 5 Department of Clinical Epidemiology and Biostatistics and Department of Obstetrics and Gynaecology, Academic Medical Center, University of Amsterdam, Amsterdam, The Netherlands

The fetal or early origins of adult disease hypothesis states that environmental factors, particularly nutrition, act in early life to program the risks for chronic diseases in adult life. As eating habits can be linked to the development of several diseases including obesity, diabetes and cardiovascular disease, it could be proposed that persistent food preferences across the life-span in people who were exposed to an adverse fetal environment may partially explain their increased risk to develop metabolic disease later in life. In this paper, we grouped the clinical and experimental evidence demonstrating that the fetal environment may impact the individual’s food preferences. In addition, we review the feeding preferences development and regulation (homeostatic and hedonic pathways, the role of taste/olfaction and the reward/pleasure), as well as propose mechanisms linking early life conditions to food preferences later in life. We review the evidence suggesting that in utero conditions are associated with the development of specific food preferences, which may be involved in the risk for later disease. This may have implications in terms of public health and primary prevention during early ages. Received 15 August 2011; Revised 2 January 2012; Accepted 1 February 2012; First published online 6 March 2012 Key words: DOHaD, feeding preferences, fetal programming, thrifty behavior

Introduction

Could food preferences also be programmed?

Developmental origins of adult disease – fetal programming

As eating habits can be linked to the development of several of the diseases mentioned above,17–20 it could be proposed that persistent small nutrient imbalances across the life-span in people who were small at birth may explain, in part, their increased risk to develop metabolic disease later in life. In other words, fetal adversity may drive the individual to prefer specific foods during the life course, increasing their ingestion and ultimately leading to disease. As such, a better understanding of the mechanisms contributing to these imbalances is essential to address the pathogenesis of the metabolic syndrome epidemic. Although ‘hunger/appetite’ is a major determinant of caloric intake, ingestive responses are significantly mediated by hedonistic mechanisms (i.e. reward), food preferences and social behavior. In this review, we synthesize clinical and experimental evidence from independent research groups demonstrating that the fetal environment may also affect the offspring’s food preferences in adulthood and that programming of these preferences may contribute to the development of metabolic disturbances later in life. Other early life events also impact food preferences in the offspring, such as early nutrition/ overfeeding,21,22 maternal diet,22 neonatal handling,23 etc., but the focus of this review lies on the fetal life events ability to

The early life environment is now well recognized to contribute importantly to health and disease predisposition later in life. The fetal or early origins of adult disease hypothesis stated that environmental factors, particularly nutrition, act in early life to program the risks for chronic diseases in adult life. In addition to the risks of adult obesity, hypertension,1 and type II diabetes,2,3 infants small at birth are at increased risk of atherogenic lipid profiles,4,5 reduction of bone mass and possibly bone mineral content,6–9 differential stress responses,10,11 less elastic arteries,12 specific patterns of hormonal secretion13,14 and higher incidence of depression11,15,16 in adult life. Extensive studies in animal models have confirmed that disease risk and behavior later in life can be influenced or ‘programmed’ dependent upon the fetal and early postnatal environment. *Address for correspondence: P. P. Silveira, Departamento de Pediatria, Faculdade de Medicina, Universidade Federal do Rio Grande do Sul. Ramiro Barcelos, 2350, Largo Eduardo Zaccaro Faraco, 90035-903 Porto Alegre, Brazil. (Email [email protected])

Effects of in utero conditions on adult feeding preferences program the offspring food preferences. Prior reviews have addressed the programming of appetite regulation.24–28 Physiological, cellular and molecular basis of hedonic feeding behavior Essential to survival and homeostasis maintenance, feeding behavior is finely regulated through an intricate and complex mechanism. Basically, ingestive behavior may be divided into several phases29–32: in the initiation phase, the value of an available food objective or the internal state attracts the individual’s attention to feeding. Once the selective attention is reached and the motivation to food ingestion is present, it begins the procurement phase, which requires planning, learning and memory, depending exclusively on cortical cognitive processes. The consummatory phase begins when the food is finally available and involves stereotypical behavioral sequences, but also is characterized by the formation of associations between the different sensorial characteristics of the food. Thereafter, satiety mechanisms lead to the meal termination, including the postabsorptive sensations and storing of this information in the form of associative memory for posterior comparison. Brain afferent systems regarding food intake include external stimuli (visual, olfactory, auditory and tactile information) and internal stimuli, which is divided into pregastric (essentially taste), gastric (distention), postgastric (or preabsorptive stimuli) and postabsorptive stimuli (gastric hormonal release; nutrient, metabolites and hormonal action at liver or brain receptors).32 The individual response to any of these stimuli could potentially be subjected to developmental programming, as well as the learning and reinforcement/extinction of the consequences of the consummatory behavior. Taste/olfaction Research suggests that food preferences and behavior develop early in infancy33,34 and track further on until adulthood.33,35,36 Taste bud development is observed at around 11 weeks gestation in humans.37 Using radiographic techniques on pregnant women, it was possible to demonstrate fetal swallowing as early as 12 weeks gestation.38 Early studies describe that fetus can be induced to swallow amniotic fluid if saccharine is introduced into the amniotic cavity39 suggesting that fetal taste buds are functional. Of note, maternal hyperglycemia influences amniotic fluid glucose levels,40 with increased amniotic fluid glucose concentrations observed in pregnant diabetics. Interestingly, researchers showed that prenatal flavor experiences enhance the acceptance and enjoyment of similarly flavored foods during weaning in human babies.41 Infants who had exposure to the flavor of carrots in either amniotic fluid or breast milk exhibited fewer negative facial expressions in response to that flavor than did non-exposed control infants. Hence, it seems that the sensory environment in which the fetus lives, the amniotic sac,

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changes as a function of the food choices of the mother as dietary flavors are transmitted and flavor the amniotic fluid.42 Therefore, the pregnant female’s diet may be involved in the programming of the offspring’s feeding behavior. The development of food preferences continues when the infant is exposed to maternal milk, itself containing a variety of flavors dependent upon the foods ingested by the mother.43–45 From an early age it is possible to detect an early attraction to sweet and salty tastes, which might later drive the appetite for sweet and salty foods.46 These varied flavor exposures during the nursing period provide the infant with opportunities to learn new flavors, which impacts on the response to similarly flavored solid foods.41 Whether maternal food ingestion during pregnancy also influences offspring food preferences is controversial. With weaning, several factors promote the acceptance of solid foods, including introduction of a variety of solid foods,47,49 repeated exposure to the specific food and previous breastfeeding experience;48 in particular, when the foods consumed when the child was being breastfed had the same flavor.41 Infants exposed to a variety of solid foods accept new foods more readily than do infants exposed to a monotonous solid diet.49 Besides repeated exposure,50 taste development is promoted by other mechanisms such as flavor and nutrient learning. Parental attitudes also play an important role in the development of their child’s food preferences.51 Later on and into adulthood, food preferences are influenced by several other factors such as personal experiences, cultural adaptations and perceived health benefits.51 The sensory and hedonic evaluation of the majority of the food-related flavors is influenced by the olfactory perception. Odor perception is initiated in the chemosensory olfactory neurons in the nasal epithelium, where the chemical signal is converted into electrical impulses. This information is transmitted to the olfactory bulb, and decoded in the olfactory cortex, leading to the perception of distinct flavors.52 Interestingly, even imagined odors can to some extent induce changes in perceived taste intensity comparable to those elicited by perceived odors.53 Because there is no evidence for innate odor preferences, most of our food preferences are probably acquired by learning.54,55 Food odors rated as pleasant have the ability to stimulate appetite, as evidenced by increased ratings of hunger following exposure to food-related odors,56 as well as stimulate other responses such as insulin release57,58 and gastric acid secretion.59 At least partial olfactory, as well as taste, sensory-specific satiety does not require food to enter the gastrointestinal system, and does not depend on the ingestion of calories.60 Although children usually eat more of the foods they like best in terms of taste,61,62 the impact that taste factors have on the food intakes of adults is much less clear, for their taste preferences and aversions are not always direct predictors of food consumption.63–65 Therefore, the general assumption that taste preferences predict food preferences does not always hold true.66

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Reward/pleasure The hypothalamus is the key brain structure involved in the homeostatic food intake regulation. However, even in the absence of hunger, the pleasure and reward sensations associated to the food can also stimulate feeding behavior (hedonic food intake). Thus, the perceived pleasantness of foods can modulate food intake indirectly by influencing the preference for certain foods. Among healthy individuals, eating beyond homeostatic needs when facing caloric-rich palatable foods evidences the fact that a significant proportion of consumption is driven by pleasure, rather than energy supply. The brain extracts information about quality, intensity and hedonic value from gustatory neuronal responses; thus all of these psychological attributes must be coded by the neural activity in the taste pathways. Therefore, appetite for specific foods and nutrients is under complex neuroregulatory control. For instance, in animal studies, fat intake is increased by opioids,67–69 whereas carbohydrate intake is increased by neuropeptide Y (NPY).70 The forebrain plays a prominent role in the hedonic value that the brain attaches to gustatory activity originating from the oral cavity. The nucleus accumbens has been related to directive behaviors and appetitive instrumental learning71,72 and may provide an interface between motivation and behavioral action. Neuroimaging studies strongly support a role for central dopamine in food reward processes. Studies in humans reveal that food-related cues activate areas of the brain associated with the processing of information related to the pleasurable features of stimuli (i.e. the brain reward system), such as the ventral tegmental area (VTA) and substantia nigra, amygdala and orbitoprefrontal cortex73,74; these areas are either involved in the synthesis and release of dopamine or are targets for dopamine projections. Recent evidence suggest that dopaminergic neuronal activity in the VTA that projects to the nucleus accumbens can be modulated by peripheral energy status signals including leptin, insulin and ghrelin,75–77 revealing the potential importance of the integration between the peripheral signaling and the central mesolimbic system in food preference regulation. Therefore, besides their well-known role in altered regulation of appetite control in the field of developmental programming when acting at the hypothalamic level,24,28,78,79 these hormones also appear to modulate the pleasure associated with the ingestion of palatable food and could be involved in the programming of feeding preferences. As a corollary to reward-mediated ingestion, studies in humans demonstrate that emotional experience can lead to an increase in food intake, especially sweets and calorie dense foods.80 Periods of workload are associated with a higher consumption of calories and fat, especially in people who practice dietary restraint.81–83 Individual variation in the hypothalamus–pituitary–adrenal (HPA) stress response intensity correlates with the degree of stress influence on food choices.84 It has been proposed that glucocorticoids and insulin stimulate the consumption of highly dense caloric

foods (‘comfort foods’), which in turn would protect the HPA axis from potential dysfunction.85 Intrauterine growth restricted (IUGR) individuals are also reported to have an increased adrenal response to acute stress,11 a feature that combined with their known insulin resistance could set the stage for altered feeding behaviors, especially increased consumption of palatable, ‘comfort’ foods. Finally, the prefrontal cortex may be involved in the conscious perception of some types of flavors86 particularly in the integration of the valuation and comparison processes (coding of rewards relative to other available rewards, general and specific satiety, temporal discounting and negative valuations such as negative health consequences) that impact food selection.87 Obese children react to food stimuli with increased prefrontal activation;88 one could propose that reduced inhibitory control may also be suggested as playing a role in excessive feeding behavior. Infants who were growth restricted have poorer executive functioning,89,90 and increased vulnerability to addictive disorders91 and attention deficit hyperactivity disorder,92 therefore, alterations on brain frontal regions could also play a role in their food choices. Proposed mechanisms linking early life conditions to food preferences later in life A possible mechanism by which the early environment could impact the individual’s food choices permanently is the programming of the sensitivity to the reward (i.e. pleasure) associated with the ingestion of a palatable food. In adult rodents, prenatal protein malnutrition alters the response to reward.93 In addition, both leptin and insulin are associated with a decrease in the response of the nucleus accumbens to food cues.94,95 Interestingly, several studies have shown that cord leptin levels are diminished in small for gestational age (SGA) infants,96,97 increase during the catch-up growth98 and decrease again in adulthood in the context of an excess of adipose tissue when corrected for body fat mass, gender and fasting insulin,99 suggesting an altered adipocyte function and leptin resistance in these individuals. Low birth weight also is related to impaired insulin secretion,100,101 decreased glucose tolerance in later life13,102 and diabetes.1,103 Besides the potential implication of abnormal adipose/pancreatic tissue development in the long-term metabolic consequences associated with in utero undernutrition. Potentially, leptin/insulin modulation of central dopamine is altered in SGA individuals, leading to an altered reward response to food, consequent increased palatable food ingestion and the development of obesity. These alterations could make these individuals prone to ‘food addiction’, a recent concept proposed by some researchers. Although addictive behavior is generally associated with drugs, alcohol or sexual behavior, it is becoming apparent that certain food substances may cause similar physiological and psychological reactions in vulnerable people.104–106 Avena et al.107 classified sugar as an addictive substance because it follows the typical addiction pathway that consists of bingeing,108

Effects of in utero conditions on adult feeding preferences

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Peripheral signalling (leptin, insulin, ghrelin, glucocorticoids, etc.)

Pleasure/Reward (Mesolimbic system)

Homeostatic regulation (Hypothalamus)

FOOD CHOICES

Judgement/value (Prefrontal cortex)

Peripheral sensation (taste, olfaction, texture)

Culture

Socioeconimic status

Exposure

Fig. 1. Brief schematic outlining the regulation of food preferences. Red – predominantly centrally mediated influences. Green – predominantly peripherally mediated (adipose tissue, pancreas, gastrointestinal tract and hypothalamus–pituitary–adrenal axis) influences. Blue – environmental influences. Fetal life adversities can affect any of the pathways, except for environmental factors (although they could be a cause of fetal adversity).

withdrawal,109 craving110 and cross-sensitization.111 The seeking behavior is motivated and reinforced not only by a food’s positive effects but also the negative state or ‘antireward’ that accompanies abstinence from its use,112 ultimately leading to obesity and related metabolic consequences. In addition, peripheral hormones, within subsets of taste cells and structures of the olfactory system, have also been proposed as modulators of olfaction/taste perception. Vasoactive intestinal peptide, cholecystokinin, leptin receptor and NPY, are found within type II taste cells, whereas glucagon-like peptide-1 is found in both type II and type III taste cells. The interplay between these systems modulates not only gustatory and olfactory function but also whole-body physiological functions, such as metabolic control and energy homeostasis.113 Flavor–taste learning also involves brain dopamine signaling.114 Therefore, fetal adversities could program the functioning of such systems modulating food preferences (Fig. 1).

Evidences for the fetal programming of feeding behavior Experimental (animal) studies Animal studies have confirmed the potential for developmental programming of obesity. Low birth weight sheep have a higher relative fat mass as neonates compared with higher birth weight offspring.115 There is also evidence that a maternal protein-restricted (50%) diet during pregnancy programs offspring susceptibility to adult obesity in rats and mice, with the difference apparent already by 7 days of age.116,117 Moderate (50%) and severe (70%) maternal prenatal caloric restriction is also associated with greater fat

deposition in offspring when presented with a hypercaloric or high-fat diet.118,119 Importantly, animal studies have consistently demonstrated increased caloric intake among low birth weight offspring, a result in part of reduced anorexigenic responses, neural pathways and neuronal signaling.119–121 Several animal models aid in understanding the effects of early life events upon behavioral and metabolic outcomes in adulthood. A study using a low protein (LP) diet during gestation describes specific food preferences for high-fat food in both male and female adult offspring when compared with the control animals. If offered at discrete periods during gestation (early, mid and late gestation), the LP-diet programs the offspring feeding behavior in a gender-specific and timingdependent manner, in which the females exposed to LP diet in early gestation prefer to eat more carbohydrates over the other macronutrients in adult life, as compared with controls.122 Interestingly, the addition of high levels of folate to the LP diet during gestation prevents the LP effects on offspring food preferences, possibly a result of epigenetic effects.123 However, folate added to a normal protein diet also alters offspring’s feeding behavior similarly to the LP diet exposure alone. Therefore, it seems that the role for potential folate-influenced DNA methylation in programming of food preference is likely to be gene-specific rather than genome-wide. Manipulation of the dietary fat content during pregnancy also leads to altered offspring food preferences. Pups nursed by dams fed low fat diet during pregnancy and lactation show an increased preference for fat as compared with controls.124 However, if the obesogenic diet is offered to the dams before mating, it results in hyperphagia, decreased locomotor activity, increased adiposity, endothelial dysfunction and hypertension in the adult offspring.125 Hyperphagia is also a consequence of

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prenatal nutritional disturbance. Subjecting pregnant rats to severe food restriction (feeding 30% to 50% of ad libitum intake) promotes profound intrauterine growth retardation in their offspring118,119 with decreased newborn plasma leptin and increased ghrelin.118 These growth-retarded pups become hyperphagic, and when provided with a hypercaloric diet from weaning, develop pronounced central adiposity.119 Cross fostering the IUGR offspring to dams receiving ad libitum chow induces a rapid catch-up growth and results in increased weight, percent body fat and plasma leptin levels.118 In fetuses at term, the exposure of the pregnant rodent to chronic stress reduces body, adrenal and pancreas weight as well as plasma corticosterone and glucose levels.126 Long-term effects of this intervention include the induction of a rebound and basal hyperphagia when the offspring is on chow diet, with an exacerbated effect when put on a high-fat diet.126,127 Moreover, these animals display hyperglycemia, glucose intolerance and decreased basal leptin levels.126 It has not been determined whether the hyperphagia is mediated via appetite or reward mechanisms. These combined observations suggest that early life events can lead to alterations in the feeding patterns of the adult offspring. It is intriguing to note that, although the metabolic disarrangements following these diverse interventions may be very distinct depending on the type of model used, feeding behavior (higher caloric consumption or specific food preferences) seems to be consistently found in the different protocols. Epidemiologic and clinical observations The epidemiologic observations that inadequate availability of nutrients to the fetus during gestation is associated with altered feeding preferences in adult life come from populations throughout the world in mainly three different settings: severe maternal undernutrition during a famine, intrauterine growth retardation and severely preterm birth. Severe maternal undernutrition (Famine studies) The Dutch Famine Birth Cohort has provided evidence that prenatal nutrition may affect dietary preferences later in life.128 During the final months of the World War II, there was a period of extreme food shortage in the west of the Netherlands, known as the ‘Dutch Famine’. The Dutch famine birth cohort includes men and women who were born around the time of the Dutch famine as term singletons in one of the main hospitals of Amsterdam. In this study, periods of 16 weeks were used to differentiate between persons who were exposed in late gestation, mid-gestation and early gestation. Persons born before and persons conceived after the period of famine were used as the control group. Food frequency of intake and physical activity and detailed clinical examinations of cardiovascular and metabolic disease were made at the ages of 50 and 58. Although the mean percentage of protein, carbohydrate and fat in the diet did not

differ among the exposure groups, participants exposed to famine in early gestation were more likely to consume a highfat diet (defined as the highest quartile of fat in the diet or .39% of energy from fat). The relative risk of participants with early exposure to famine consuming a high-fat diet remained significantly higher even after adjustment for confounding factors. This finding may explain in part the finding that the group of participants exposed to famine in early gestation had more pronounced hypercholesterolemia and hypertriglyceridemia than the other groups (after exclusion of participants using lipid-lowering medication). Importantly, offspring exposed to famine in early gestation had a two-fold prevalence of coronary heart disease. In another study,129 involving a different sample of individuals exposed to the Dutch Famine during or immediately preceding the pregnancy period was compared with a sample of births from the previous or following year (1943 and 1947) as hospital time controls and to same-sex siblings. Food frequency and physical activity data was acquired using questionnaires at a mean age of 58 years. Individuals exposed to famine in the first half of gestation (i.e. week 20) had higher reported absolute intakes of energy, fat and protein and lower reported absolute intakes of carbohydrate than did the controls. Using time controls as a comparison, gestational famine exposure was associated with higher energy intake due to higher fat density in the diet. In addition, lower levels of physical activity were found in the exposed group. In sexstratified analyses, protein intakes were higher for exposed men and lower for exposed women compared with unexposed men and women, respectively. In a further comparison to sibling controls, gestational famine exposure was still associated with higher energy intake, higher fat density and lower physical activity score. However, using a sex-stratified analysis, energy intake was lower in exposed men and higher in exposed women compared with their unexposed siblings. Carbohydrate density was lower in individuals exposed to famine at any point in gestation compared with their siblings, and exposed and unexposed siblings did not differ in protein intake. There was no evidence for heterogeneity by sex for any macronutrient. Hence, independently of the control chosen for interpretation of the study, these results confirm that there is a specific food preference pattern associated with exposure to undernutrition during gestation, with increased caloric content mainly due to fat preference, as well as a diminished propensity to physical exercise. Intrauterine growth restriction In a cross-sectional evaluation of a prospective, longitudinal cohort of subjects born in the municipality of Ribeira˜o Preto (state of Sa˜o Paulo, southeast of Brazil), it was investigated if IUGR was associated with offspring macronutrient ingestion and food preferences.130 Food intake was measured by a food frequency questionnaire and the data was shown in a carbohydrate to protein ratio (preference). IUGR was determined based on the birth weight ratio (BWR; the ratio between the

Effects of in utero conditions on adult feeding preferences newborn’s weight and the population’s sex-specific mean birth weight for each gestational age). Individuals were classified as non-restricted (BWR > 0.85), moderately restricted (BWR , 0.85 and >0.75) and severely growth restricted (BWR , 0.75). At the age of 24 years, offspring women born severely growth restricted ate more carbohydrates than the women born non-growth restricted, and this finding persisted after adjustment for several confounders (maternal income, smoking and schooling at the time of delivery, and participants’ smoking, schooling, current body mass index (BMI) and physical activity). This effect was accompanied by a decreased ingestion of protein. Rather than an absolute BWR cut-off, regression analysis showed a continuous association between growth restriction and adult carbohydrate to protein ratio consumption, meaning that the more growth restricted at birth (lower BWR), the more these women prefer to eat carbohydrates over protein in adult life. The increased carbohydrate to protein consumption was distributed across different types of foods, and not associated with over or under consumption of any one food. In addition to the carbohydrate preference, women born IUGR exhibited increased waist to hip ratio (WHR), though the prevalence of risk factors for metabolic syndrome (plasma fasting insulin, glucose, high-density lipoprotein (HDL), triacylglycerol) did not differ between the groups. Using the NCEP-ATP III diagnostic criteria,131 there were no differences in the prevalence of metabolic syndrome between the groups. As studies were performed at 24 years of age, the increased WHR may suggest a predisposition to subsequent metabolic syndrome, which may be evident with follow-up. It is interesting to note that protein ingestion seems to be more tightly controlled than other macronutrients,132 being set to around 15% of the total calories. In this cohort, despite the fact that individuals from the different groups eat protein at that percentage, IUGR girls prefer comparatively less protein, and more carbohydrates. This probably means that the set point of the carbohydrate to protein ratio was changed to a different level in this group. As carbohydrates are more effective in releasing insulin (known for its anabolic actions), this may explain their increased central adiposity, and could be interpreted as an early sign of the thrifty phenotype. Severely preterm birth Another interesting model of an early adverse environment is birth at very low birth weight (VLBW; ,1500 g) or very low gestational age (VLGA; ,32 weeks), which comprise , 1% to 1.5% of live births in countries with available statistics.133–134 Following birth, these infants experience a period characterized by immaturity-related neonatal illness frequently requiring neonatal intensive care, accompanied by inadequate nutrition and slow growth, sometimes referred to as ‘extrauterine growth restriction (EUGR)’. Moreover, during infancy, VLGA infants frequently suffer from eating difficulties including selective eating, which may be related to neurodevelopmental impairments. A recent study in

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6-year-olds born extremely preterm suggested that feeding problems are present in those born most immature although not solely explained by neurodevelopmental delay.135 As young adults, VLBW/VLGA offspring exhibit increased cardiovascular risk factors such as higher blood pressure,136,137 impaired glucose regulation138 and lower rates of leisure-time physical activity139,140 as compared with their counterparts born at term with normal birth weight. A paradox is that adults born as small preterms are not more obese but, if anything, tend to have on average a lower BMI than those born at term.138,141 Much of this difference is attributable to lower lean body mass.138 Although VLBW adults have a higher basal metabolic rate per unit lean body mass, their lower lean body mass results in a lower total basal metabolic rate142 and, accordingly, lower energy intake.143 Although a preliminary report from the same cohort showed no difference in energy-adjusted macronutrient intakes, intakes of calcium and vitamin D were lower in VLBW adults. This argues for the possibility of altered food preferences, although we are unaware of any published reports on the analyses of intake and preference of specific foods in this context. In general, although VLGA infants constitute a promising model of early programming of food preferences, it remains relatively understudied. When comparing these studies, it is important to take into account several facts. Firstly, Barbieri et al. evaluated the cohort at 24 years of age, while the Dutch Famine studies evaluated middle-aged individuals. It is known that food preferences vary according to ageing,46,144,145 and the apparent diversity in the findings may simply reflect that these specific feeding preferences in low birth weight subjects transit from high carbohydrates to high fat as the individuals age. Moreover, although all of these studies may reflect the effects of stress exposure during fetal life, the Dutch Famine cohort was exposed to both the nutritional and environmental (war conditions) stress, while the Brazilian cohort was primarily nutritional deprivation and stress exposure. As different types of stress induce specific physiological responses,146 one could argue that different adverse events occurring in utero lead to particular effects on feeding behavior later in life, depending on the type of the insult (Fig. 2). Specific food preferences may be involved in the development of later disease To date, several studies have shown that feeding preferences during adulthood are related to physical health, impact the risk for future disease and play a role in the prevention of overweight. For example, rates of incident verified non-fatal myocardial infarction, coronary death and diabetes are lower among people following a general healthy eating pattern in midlife (high consumption of fruit and vegetables, polyunsaturated oils and high-fiber bread and breakfast cereals and a low consumption of red meats, saturated fats and refined carbohydrate foods).147 Large cohort studies point to the fact

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A. K. Portella et al. IUGR programs the hedonic response to sweet food

IUGR girls are impulsive towards sweet food

IUGR women have a higher preference for carbohydrates

Individuals exposed to undernutrition during fetal life prefer to eat more fat

IUGR = overweight, metabolic syndrome

Newborns at 27 weeks of gestational age

3 years of age

24 years of age

50 years of age

Adult life

Ayres et al., 2010192

Silveira et al., 2012190

Barbieri, Portella, Silveira et al., 2009130

Lussana et al., 2008128

Barker et al and many others

Fig. 2. Conceptual framework depicting the fetal programming of food preferences proposal. Human evidence of feeding preferences in individuals exposed to fetal adversities suggests that the choices for specific types of foods at different times during the life course may play an important role in the increased risk for disease largely described in these subjects. IUGR, intrauterine growth restricted.

that a western dietary pattern is associated with a substantially increased risk for type 2 diabetes,147–150 incident heart failure,151 coronary heart disease,150,152 stroke,153 chronic obstructive pulmonary disease,153 colon cancer,154,155 altered markers of inflammation and endothelial dysfunction156 and altered plasma biomarkers of cardiovascular disease risk and obesity.157 Although the issue is still debated,158,159 a systematic review of 37 published cohort studies showed that low glycemic index and/or low glycemic load diets are associated with a reduced risk of chronic diseases such as type 2 diabetes, coronary heart disease, gallbladder disease and breast cancer, suggesting that higher postprandial glycemia is a mechanism for disease progression.159 Whole-grain as well as fruits and vegetables intake have been associated with lower risk of cardiovascular disease,160–163 ischemic stroke164 and hypertension,165 improvements in glycemic control,166,167 and lower levels of inflammatory biomarkers.168 Dietary fiber may also affect fibrinolysis and coagulation,169,170 which may be important in the setting of established atherosclerotic plaques. With regard to polyunsaturated fatty acid (PUFA) consumption, n-3 PUFAs from both seafood and plant sources may reduce cardiovascular risk,171 whereas eating even limited quantities of fish may reduce the risk of ischemic stroke in men.172 Not simply the food choices, but feeding behavior per se is also associated with human health. For instance, men eating takeaway foods twice a week or more are significantly less likely to meet the dietary recommendation for vegetables, fruits, dairy, breads and cereals, and have a higher prevalence of moderate abdominal obesity.173 On the other hand, young adults who report frequent food preparation have less frequent fast-food use and are more likely to meet dietary objectives for different macro and micronutrients.174 Feeding frequency may also affect health outcomes, as a high daily eating frequency is associated with a healthy lifestyle and dietary pattern in both men and women.175 Finally, there is a well-known association between

television viewing and abdominal obesity in young adults, which is partially explained by food and beverage consumption while watching television.175 While this review focuses on early programming of nutrient intake and preferences, it is important to keep in mind that the biological effects of specific nutrients also may be programmed early in life. Not all people are equally sensitive to health effects of specific nutrients. For example, lipid responses to dietary interventions176 and blood pressure responses to alterations in salt intake177 vary widely between people, with genetic mechanisms explaining only a small proportion of the differences.178–180 Few human studies have explored this area, although a study from Hertfordshire, England, showed that among 59- to 71-year-old men, high intakes of total and saturated fat were associated with reduced HDL-cholesterol and HDL/LDL (low-density lipoprotein) ratio only in men with low birth weight.181 A Dutch study of healthy adults showed a strong inverse correlation between birth weight and salt sensitivity of blood pressure.182 All of the above behaviors and preferences could potentially be affected by early life events. Future studies may clarify the particular behavioral facets of individuals exposed to specific insults in order to identify their possible health risks. Medical and public health implications The worldwide rise in chronic diseases in children and adolescents is challenging for the health assistance, financial resources administration and biomedical research. These disorders may be a consequence of a long process of epidemiological and demographic transition, occurring during the last century. The decrease in infant mortality and longer life-span has created a new pattern of health and disease, in which chronic and degenerative disorders have overcome acute conditions and infectious diseases. In this scenario, the identification of vulnerability and proposals for chronic

Effects of in utero conditions on adult feeding preferences diseases prevention is of extreme significance and importance. Knowledge about behavioral traits that could be linked to specific health risks may alert health professionals to promote early intervention and assistance. Education, support and long-term follow-up may be required to assist children exposed to fetal insults to make lifestyle changes essential to a healthy lifestyle, such as wise dietary choices. For instance, interventions that promote reduced amount of added sugar and increased intake of dietary fiber improve insulin action and reduce visceral adipose tissue in youth.183–187 The efficacy of these interventions remains to be established for this population. Importantly, prenatal care and preconception counseling is critical for developing preventive strategies in terms of public health. For instance, findings suggest that pre-pregnancy dietary patterns may affect womens’ risk of developing gestational diabetes mellitus.188 A healthy diet before and during the pregnancy promotes a better fetal environment, preventing diseases in future generations. Women of reproductive ages, especially those who are planning a pregnancy, should be counseled to consume a well-balanced diet, and may be more easily prone to engage in healthy life choices. We propose that a prudent diet style before and during pregnancy affects the newborn’s food preferences in a positive way, as well as its future food choices in adulthood and is a promising new way of preventing chronic degenerative disease in future generations. This may be a transgenerational model of health programming. Conclusions In conclusion, evidence from experimental and clinical studies demonstrate that early life events are linked to specific feeding preferences in adulthood. Although these studies have somewhat divergent final findings, they consistently demonstrate that a metabolic or environmental stress during gestation that impacts fetal growth results in altered offspring adult feeding behavior, with a preference for highly palatable, energy dense foods (either rich in carbohydrates or fat or both). The chronic, persistent alteration in feeding preferences in these individuals likely starts in early life189,190,192 and contributes to the development of obesity and altered lipid profile reported in this group.128,130 This seems to be another facet of the ‘thrifty phenotype’,191 what could be called ‘thrifty behavior’. Future studies are warranted to understand the mechanisms by which specific insults lead to specific behavioral preferences, as well as to establish the validity of preventive measures in humans. References 1. Barker DJ, Eriksson JG, Forsen T, et al. Fetal origins of adult disease: strength of effects and biological basis. Int J Epidemiol. 2002; 31, 1235–1239. 2. Eriksson JG, Forsen T, Tuomilehto J, et al. Effects of size at birth and childhood growth on the insulin resistance syndrome in elderly individuals. Diabetologia. 2002; 45, 342–348.

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