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Perinatal Exposure to High-Fat Diet Programs Energy Balance, Metabolism and Behavior in Adulthood

Perinatal Exposure to High-Fat Diet Programs Energy Balance, Metabolism and Behavior in Adulthood At the Cutting Edge Received: July 19, 2010 Neuroendocrinology 2011;93:1–8 Accepted after revision: October 15, 2010 DOI: 10.1159/000322038 Published online: November 13, 2010 Perinatal Exposure to High-Fat Diet Programs Energy Balance, Metabolism and Behavior in Adulthood Elinor L. Sullivan M. Susan Smith Kevin L. Grove  Department of Neuroscience, Oregon National Primate Research Center, Beaverton, Oreg. , USA Key Words ders such as anxiety. Potential mechanisms for perinatal HFD Metabolic imprinting  Maternal high-fat diet  programming of neural pathways include circulating factors, Energy balance  Energy expenditure  Obesity  Anxiety  such as hormones (leptin, insulin), nutrients (fatty acids, tri- Inflammation glycerides and glucose) and inflammatory cytokines. As ma- ternal HFD consumption and obesity are common and rap- idly increasing, we speculate that future generations will be Abstract at increased risk for both metabolic and mental health disor- The perinatal environment plays an important role in pro- ders. Thus, it is critical that future studies identif y therapeutic gramming many aspects of physiology and behavior in- strategies that are effective at preventing maternal HFD-in- cluding metabolism, body weight set point, energy balance duced malprogramming. Copyright © 2010 S. Karger AG, Basel regulation and predisposition to mental health-related dis- orders such as anxiety, depression and attention deficit hy- peractivity disorder. Maternal health and nutritional status heavily influence the early environment and have a long- Introduction to Metabolic Imprinting term impact on critical central pathways, including the me- lanocortinergic, serotonergic system and dopaminergic sys- Only a minority of individuals living in the obesigen- tems. Evidence from a variety of animal models including ic environment currently encountered in developed na- rodents and nonhuman primates indicates that exposure to tions are able to maintain a healthy body weight [1] . For maternal high-fat diet (HFD) consumption programs off- example, in the USA, evidence from the latest National spring for increased risk of adult obesity. Hyperphagia and Health and Nutrition Examination Survey (collected in increased preference for fatty and sugary foods are impli- 2007–2008) indicates that 68% of adults are overweight or cated as mechanisms for the increased obesity risk. The ef- obese [1] . Given the health risks associated with obesity fects of maternal HFD consumption on energy expenditure (heart disease, diabetes, hypertension, cancer) [2] , this are unclear, and future studies need to address the impact of has important implications for global health, and in light perinatal HFD exposure on this important component of en- of the additional health-care costs associated with obe- ergy balance regulation. Recent evidence from animal mod- sity [3] , the global economy. Genome-wide association els also indicates that maternal HFD consumption increases studies have identified numerous loci associated with the risk of offspring developing mental health-related disor- obesity; however, their contribution to variation in body © 2010 S. Karger AG, Basel Elinor L. Sullivan, PhD 0028–3835/11/0931–0001$38.00/0 Department of Neuroscience, Oregon National Primate Research Center Fax +41 61 306 12 34 505 NW 185th Ave, Beaverton, OR 97006 (USA) E-Mail karger@karger.ch Accessible online at: Tel. +1 503 690 5510, Fax +1 503 690 5384 www.karger.com www.karger.com/nen E-Mail sullivel  @   ohsu.edu mass index and weight between individuals is estimated increased incidence of obesity and metabolic syndrome to be less than 2% [4] , suggesting that environmental in- in children [15] . Although this review focuses on the im- fluences, such as increased availability of energy-dense pact of maternal HFD consumption, it is important to food and an increasingly sedentary lifestyle, play a crucial note that maternal undernutrition during gestation also role. Accumulating evidence from epidemiologic studies increases the incidence of offspring obesity; thus, the re- and animal models indicate that maternal health and nu- lationship between birth weight and adult adiposity is tritional state during pregnancy and lactation play a crit- thought of as a ‘U’-shaped curve with both a very high ical role in programming the neural circuitry that regu- and a very low birth weight increasing the risk of obesity lates energy balance and behavior in offspring, having a in adulthood [16, 17] . The relationship between maternal sustained inf luence on their physiology and behavior. obesity and the development of offspring obesity appears Metabolic imprinting refers to the programming of an to be independent of gestational diabetes as women who offspring’s future metabolic responses by a stimulus oc- are obese, but able to maintain normal glycemia, also curring during a critical developmental period. As the have heavier offspring with increased adiposity [18] . type and amount of available nutrition are crucial deter- Although epidemiological studies implicate the intra- minants of survival and reproductive success, the evolu- uterine environment, including maternal diet and energy tionary purpose of metabolic imprinting is to enhance status, in programming offspring obesity, in these studies offspring survival by programming energy balance regu- it is not possible to directly link maternal diet and energy lation so that available metabolic fuels are most efficient- status with the offspring’s metabolic profile, as several ly utilized. Mammals are exposed to two environments other factors could contribute to the association between during development, the intrauterine and early postnatal maternal and offspring obesity, including genetics and environments, both of which are heavily impacted by ma- shared environment factors such as access to energy- ternal diet and adiposity. Perinatal nutrition has endur- dense foods and a sedentary lifestyle. Also, there is rela- ing effects on many aspects of physiology and behavior tively limited information on normal brain development including the regulation of energy balance, susceptibili- in humans, making it challenging to examine the impact ty to metabolic disorders [5, 6] , programming of body of maternal diet on offspring’s brain development. Fur- weight set point [7, 8] , stress response [9, 10] and mental thermore, it is difficult to accurately monitor and poten- health-related behaviors [11, 12] . In addition to perinatal tially unethical to manipulate the diet of pregnant wom- nutrition, a number of factors associated with maternal en. Thus, it is critical to use animal models to directly consumption of a high-fat diet (HFD), including mater- examine the effects of maternal overnutrition on subse- nal adiposity, hyperlipidemia, lipotoxicity, glucose levels quent generations and to develop effective therapeutic in- and insulin resistance, also have a long-term impact on tervention strategies. the developing offspring and are associated with in- creased risk of obesity, metabolic disorders, and mental health disorders [5, 11, 12] . As maternal obesity is associ- Animal Models of Maternal HFD Consumption/ ated with consumption of a HFD in humans and a HFD Overnutrition is used to promote maternal obesity in most animal mod- els, a major challenge faced by the field is the ability to Providing animals with a HFD during pregnancy and disassociate the effects of the HFD from the maternal lactation is a common method of inducing maternal obe- metabolic phenotype. sity. However, the duration of exposure to the diet (acute vs. chronic), the percent of calories from fat, and diet composition are variable across studies, hindering com- Maternal Obesity Is Associated with Increased Risk parisons. The diets commonly used to promote maternal of Offspring Obesity obesity are either a purified HFD with fat in place of car- bohydrates as an energ y source or a cafeteria diet in which The most common perturbation of maternal nutrition animals are provided with a selection of palatable food is nutritional excess and maternal obesity. In 2008, over items that have a high fat content along with their regular 64% of women of child-bearing age in the USA were over- diet. The cafeteria diet is most effective in promoting weight or obese [13] and the majority consume an excess obesity; however, as several food items are provided, it is amount of calories and fat [14] . Epidemiological studies difficult to calculate the amount and composition of the clearly indicate that maternal obesity is associated with diet consumed by each animal and the diet consumed by Neuroendocrinology 2011;93:1–8 2 Sullivan/Smith/Grove animals in the same group is variable. Several studies late feeding [17, 38] . Early postnatal overfeeding increases have used purified diets with different sources of fat to the orexigenic peptides neuropeptide Y and agouti-relat- compare the impact of maternal consumption of satu- ed peptide (AGRP) in the arcuate nucleus of the hypo- rated fat [19–22] , polyunsaturated fat [20, 23]  –3 [ 9, 21, thalamus (ARH) of juvenile rats [38] . Offspring of rat 22] or  –6 fatty acids [9, 22] on offspring physiology and dams fed a HFD during the perinatal period also display brain development. It is clear from these studies that the a long-term upregulation in the expression of orexigenic source of fat in the HFD matters. For example, a study in peptides including galanin, enkephalin, and dynorphin rodents determined that while a maternal diet high in in the paraventricular nucleus of the hypothalamus saturated fat programs hyperphagia in offspring, expo- (PVH), and orexin and melanin-concentrating hormone sure to a diet of equivalent percent of calories from fat as in the perifornical lateral hypothalamus [32] . Exposure to fish oil does not [21] . Thus, it is essential that future stud- HFD during gestation stimulates the proliferation of neu- ies determine which sources of fat in a mother’s diet are ronal and neuroepithelial cells of the embryonic third beneficial and which are detrimental to the developing ventricle of the hypothalamus and increases their migra- offspring in order for physicians and nutritionists to tion to hypothalamic regions resulting in an increase in make appropriate recommendations to expecting moth- the proportion of neurons expressing orexigenic peptides ers. [3 2] . Also, offspring from HFD mothers have reduced Most rodent studies report that offspring exposed to a sensitivity to the anorectic effects of leptin [33] . Thus, in HFD during gestation and lactation have increased body rodents it is postulated that perinatal exposure to overnu- weight and adiposity at weaning [24, 25] . However, sev- trition or maternal HFD consumption results in disrup- eral studies report that maternal HFD consumption re- tion of the homeostatic feedback regulation and nutrient sults in lighter offspring [26–28] which they speculate is sensing capabilities of the hypothalamic feeding circuits due to HFD/obesity-induced impairments in the initia- leading to hyperphagia. Though rodent models have sig- tion and production of milk by obese mothers [26, 29] . nificant advantages, such as a relatively short period of The differences in offspring’s body weight phenotypes gestation and the ability to manipulate genetics, the crit- across studies are likely due to differences in the duration ical periods for the development of energy balance regu- of HFD consumption and fatty acid composition of the latory systems differ between rodents and humans. In ro- diets. Using nonhuman primates, our group is examin- dents, the neural pathways regulating energy balance are ing the impact of chronic maternal HFD consumption on immature at birth and are not completely developed until offspring body weight regulation. Brief ly, infant offspring the third postnatal week (mice) [39] . In contrast, in hu- from HFD mothers are underweight at birth and display mans, nonhuman primates, pigs, and sheep, the hypo- rapid catch-up growth, so that by 6 months of age they thalamic circuitry that regulates feeding develops pri- are heavier and have increased adiposity [30] . This off- marily prenatally [38] . Thus, models of maternal over- spring phenotype appears to be independent of whether nutrition in which the development of energy balance the HFD-consuming mother is obese with insulin resis- regulation occurs prenatally are particularly relevant. In tance or lean with normal sensitivity to insulin. These the nonhuman primate model of maternal HFD-induced studies indicate that in primates, as in rodents, maternal obesity, our group has determined that fetal offspring HFD consumption, independent of maternal weight and also display alterations in the development of the hypo- metabolic status, predisposes offspring to increased risk thalamic melanocortin system that may contribute to of developing obesity and metabolic disorders early in disrupted homeostatic signaling [40] . life. In addition to hyperphagia, there is evidence that feed- ing behavior and food choice are also programmed by perinatal nutrition. Overweight children are reported to Programming of Food Intake and Feeding Behavior have increased preference for high-fat foods which is associated with increased parental adiposity [41] . Also, Rodents that experience an early environment in children with one or two overweight parents consume a which they are exposed to maternal HFD consumption larger percentage of energy from fat than children who [31 –33] or overnutrition [34–37] are consistently reported have two normal-weight parents [42] . In these studies it to be hyperphagic as adults. A number of studies have is unclear if the children’s increased fat preference is due found that maternal HFD consumption plays a critical to programming as a result of perinatal HFD exposure, role in programming hypothalamic pathways that regu- genetics or increased availability of high-fat food during Neuroendocrinology 2011;93:1–8 Maternal HFD Has a Long-Term Impact 3 on Offspring Physiology and Behavior childhood. Animal models in which offspring are ex- metabolic rate has not been examined. Thus, a major gap posed to a HFD during the perinatal period provide fur- in the knowledge of the field of metabolic programming ther evidence for an inf luence of perinatal HFD exposure is the impact of perinatal HFD exposure on the regula- on food choice. For example, adult rat offspring exposed tion of energy expenditure. Future studies are needed to junk food during either gestation or lactation displayed which examine not only the effects of perinatal exposure increased preference for fatty, sugary and salty foods [21, to HFD on average basal energy expenditure, but its im- 33, 43] . The source of fat in the perinatal diet inf luences pact on compensatory changes in energy expenditure in the programming of food preference, as rat pups from response to metabolic challenges, such as fasting, dieting mothers that consumed a HFD with lard as the main and chronic consumption of a HFD. source of fat displayed increased preference for the HFD, whereas offspring exposed to maternal consumption of HFD with fish oil as the fat source do not [21] . In rodents, HFD Programming of Mental Health Disorders there is evidence that maternal HFD consumption causes perturbation in the dopamine system of adult animals in In addition to being associated with metabolic disor- areas associated with the rewarding value of food such as ders, epidemiological data indicate that obesity is associ- the nucleus accumbens and ventral tegmental area [44] . ated with increased risk of behavioral/mental health dis- Preliminary findings from our studies examining the orders, such as depression [47] , anxiety [47] , and attention impact of exposure to maternal HFD consumption on the deficit hyperactivity disorder [48] . Moreover, anxiety and food preference of nonhuman primate offspring also in- depression influence the feeding behavior, food prefer- dicate that offspring display increased preference for di- ence and physical activity level. Depression and anxiety ets with a high sugar and fat content [Sullivan and Grove, are associated with increased craving for palatable food unpubl. observation]. Together, these studies provide items [49] and decreased physical activity level [50] . Vari- compelling evidence that perinatal nutrition has a long- ations in mood also alter food choice, with increased pref- term inf luence on dietary preference and feeding behav- erence for high-fat/high-sugar foods being reported dur- ior and may be an important contributing factor to the ing negative emotions [51] . Maternal nutrition has long- development of obesity. As differences in food preference term implications for the offspring’s risk of developing and diet consumption will have a long-term impact on mental health disorders. Perinatal exposure to a HFD may stress response and depressive behaviors of adult off- contribute to this association by altering the development spring [45] , future studies examining the impact of peri- of key pathways implicated in regulating mood and be- natal HFD exposure on food preference should include havior such as the serotonin system [52] . Recently, mater- the examination of stress response and behavioral disor- nal HFD consumption has been associated with increased ders. anxiety in rodent [12] and nonhuman primate offspring Although many studies have examined the impact of [1 1] . In a rat model, male adult offspring from mothers perinatal nutrition on food intake and food intake regu- exposed to either a diet high in saturated or trans fat dur- lation, the number of studies examining the other com- ing gestation and lactation displayed increased anxiety ponent of energy balance, energy expenditure, are limit- and deficits in spatial learning [12] . Using a nonhuman ed. Offspring from mothers undernourished during ges- primate model, our group recently demonstrated that tation are reported to be less active than offspring from perinatal exposure to a HFD causes a decrease in seroto- dams fed ad libitum [46] . Offspring exposed to maternal nergic tone perturbations in the serotonin system, which overnutrition have also been reported to be hypoactive predisposes female offspring to increased anxiety [11] . [31] or to have no difference in physical activity as com- The finding that female nonhuman primate offspring ex- pared to offspring exposed to a control diet [44]. T he ef- posed to maternal HFD consumption are more sensitive fect of maternal diet on physical activity level depends on to developing anxiety than male offspring is consistent the type of fat in the diet. Rat pups from dams fed a diet with evidence in humans which suggests that females are rich in polyunsaturated fat displayed increased locomo- more prone to anxiety than males and that the association tor activity when compared to offspring from dams fed a between obesity and anxiety is stronger in women than saturated fat or standard laboratory diet [20] . This study men [53] . Thus, nonhuman primates appear to be an ide- also reported increased locomotor response to stimulants al model in which to examine the impact of maternal HFD in offspring from dams that consumed a saturated fat diet consumption on the development of mental health disor- [20] . Currently, the impact of early exposure to HFD on ders such as anxiety and depression. Neuroendocrinology 2011;93:1–8 4 Sullivan/Smith/Grove Lipotoxicity Fig. 1. Maternal obesity and HFD con- sumption have an enduring impact on the developing fetal brain and the juvenile off- spring. A fetus from a HFD-consuming mother experiences a fetal environment in which levels of glucose, insulin, fatty acids, triglycerides and inf lammatory cytokines are elevated, leading to changes in the crit- ical neural circuitry for the regulation of physiology and behavior. Mechanism by Which Maternal HFD Programs tors such as hormones (leptin, insulin), nutrients (fatty Physiology and Behavior acids, triglycerides and glucose) and inf lammatory cyto- kines play important roles ( fig. 1 ). Maternal obesity and A lthough there is clear evidence from studies in both diabetes result in maternal hyperglycemia [54] , and as rodents and nonhuman primates that maternal HFD glucose can readily pass through the blood-placenta bar- consumption leads to increased risk of obesity and meta- rier, it is transferred to the fetus. However, the elevated bolic diseases, the mechanisms responsible are largely insulin levels associated with maternal obesity do not unknown. We have very limited information on the im- cross the placenta [15] ; thus, the fetal pancreas must se- pact of maternal HFD consumption on the brain and the crete increased levels of insulin to respond to the mater- complex neural circuitry that regulates physiology and nal hyperglycemia. This fetal hyperinsulinemia is postu- behavior. Recent evidence indicates that circulating fac- lated to be involved in the programming of obesity and Neuroendocrinology 2011;93:1–8 Maternal HFD Has a Long-Term Impact 5 on Offspring Physiology and Behavior diabetes in the developing offspring [55] . Administering the developing fetus to increased circulating cytokines insulin to rats during the last term of gestation produces has been proposed as a potential mechanism by which obesity in the offspring [6, 56] and administering insulin maternal HFD consumption impacts brain development. to the hypothalamus of rat pups during the time that The development of many neural systems that are critical projects from the ARH to the PVH results in elevations in regulating energy balance, such as the melanocorti- in body weight, insulin level, impaired glucose tolerance, nergic system, the serotonergic system, and the dopami- and increased vulnerability to diabetes [57] . Insulin is an nergic system, is sensitive to circulating cytokine levels important growth factor in the central nervous system [64] . Also, rodent studies report that AGRP [66] and pro- [55]; t hus, it is postulated that early exposure to hyperin- opiomelanocortin [67] neurons in the ARH are directly sulinemia alters the development of the brain circuitry impacted by cy tokines. A recent study by Bilbo and Tsang regulating energy balance and behavior. [1 2] reported that offspring from mothers consuming a The hyperleptinemia that offspring from obese moth- saturated fat diet had increased microglial activation in ers experience during development is also implicated in the hippocampus at birth that persisted into adulthood. metabolic imprinting. There is substantial evidence in We have recently observed that fetuses from nonhuman rodents that postnatal leptin is a critical factor in the de- primates consuming a HFD have increased circulating velopment of neural pathways in the hypothalamus [39, and hypothalamic cytokines [40] . We postulate that ex- 58] . Human studies report that leptin is elevated in obese posure to increased inf lammatory cytokines leads to the and diabetic mothers [59, 60] and lower in infants that perturbations in the melanocortin [40] and serotonin experienced intrauterine growth restriction at term [61] . system observed in fetal offspring [11] . Given the large However, in human and nonhuman primate gestation, number of neurotransmitter systems that are inf luenced circulating leptin levels do not rise until after hypotha- by inflammation, future research is needed to examine lamic development is mostly complete [61, 62] . Though the impact of maternal HFD-induced inf lammation on critical for brain development in rodents, there is limited each critical regulator of physiology and behavior. evidence for leptin’s role in the development of primate In summary, many common brain regions and neu- brains [63] . rotransmitters regulate energy balance, stress response Obesity has recently been described as a state of chron- and mental health disorders including the melanocorti- ic inflammation. Increased adiposity is associated with nergic system, serotoninergic system and dopaminergic elevations in peripheral markers of inflammation, such system ( fig. 1 ). Thus, it is not surprising that maternal as C-reactive protein, interleukin-6, interleukin-1 , and HFD consumption has a long-term impact on metabolic tumor necrosis factor-  [64] . These inf lammatory mark- and behavioral regulation. As maternal HFD consump- ers are associated with increased risk of cardiovascular tion and obesity are commonplace and rapidly increas- disease, heart disease, insulin resistance, type 2 diabetes ing, we speculate that future generations will be at in- mellitus and hypertension [64] . The association between creased risk for both metabolic and mental health disor- obesity and increased inf lammatory cytokines has been ders. Given the prevalence of maternal obesity, future confirmed in pregnant women such that obese pregnant studies need to identify therapeutic strategies that are ef- women have increased levels of inf lammatory cytokines fective at preventing maternal HFD-induced malpro- which lead to endothelial dysfunction [65] . Exposure of gramming. 1 Flegal KM, Carroll MD, Ogden CL, Curtin 5 Vickers MH, Breier BH, Cutfield WS, Hof- References LR: Prevalence and trends in obesity among man PL, Gluckman PD: Fetal origins of hy- US adults, 1999–2008. 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Neuroendocrinology 2011;93:1–8 8 Sullivan/Smith/Grove http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neuroendocrinology Pubmed Central

Perinatal Exposure to High-Fat Diet Programs Energy Balance, Metabolism and Behavior in Adulthood

Neuroendocrinology , Volume 93 (1) – Nov 13, 2010

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Pubmed Central
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Copyright © 2010 by S. Karger AG, Basel
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0028-3835
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1423-0194
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10.1159/000322038
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Abstract

At the Cutting Edge Received: July 19, 2010 Neuroendocrinology 2011;93:1–8 Accepted after revision: October 15, 2010 DOI: 10.1159/000322038 Published online: November 13, 2010 Perinatal Exposure to High-Fat Diet Programs Energy Balance, Metabolism and Behavior in Adulthood Elinor L. Sullivan M. Susan Smith Kevin L. Grove  Department of Neuroscience, Oregon National Primate Research Center, Beaverton, Oreg. , USA Key Words ders such as anxiety. Potential mechanisms for perinatal HFD Metabolic imprinting  Maternal high-fat diet  programming of neural pathways include circulating factors, Energy balance  Energy expenditure  Obesity  Anxiety  such as hormones (leptin, insulin), nutrients (fatty acids, tri- Inflammation glycerides and glucose) and inflammatory cytokines. As ma- ternal HFD consumption and obesity are common and rap- idly increasing, we speculate that future generations will be Abstract at increased risk for both metabolic and mental health disor- The perinatal environment plays an important role in pro- ders. Thus, it is critical that future studies identif y therapeutic gramming many aspects of physiology and behavior in- strategies that are effective at preventing maternal HFD-in- cluding metabolism, body weight set point, energy balance duced malprogramming. Copyright © 2010 S. Karger AG, Basel regulation and predisposition to mental health-related dis- orders such as anxiety, depression and attention deficit hy- peractivity disorder. Maternal health and nutritional status heavily influence the early environment and have a long- Introduction to Metabolic Imprinting term impact on critical central pathways, including the me- lanocortinergic, serotonergic system and dopaminergic sys- Only a minority of individuals living in the obesigen- tems. Evidence from a variety of animal models including ic environment currently encountered in developed na- rodents and nonhuman primates indicates that exposure to tions are able to maintain a healthy body weight [1] . For maternal high-fat diet (HFD) consumption programs off- example, in the USA, evidence from the latest National spring for increased risk of adult obesity. Hyperphagia and Health and Nutrition Examination Survey (collected in increased preference for fatty and sugary foods are impli- 2007–2008) indicates that 68% of adults are overweight or cated as mechanisms for the increased obesity risk. The ef- obese [1] . Given the health risks associated with obesity fects of maternal HFD consumption on energy expenditure (heart disease, diabetes, hypertension, cancer) [2] , this are unclear, and future studies need to address the impact of has important implications for global health, and in light perinatal HFD exposure on this important component of en- of the additional health-care costs associated with obe- ergy balance regulation. Recent evidence from animal mod- sity [3] , the global economy. Genome-wide association els also indicates that maternal HFD consumption increases studies have identified numerous loci associated with the risk of offspring developing mental health-related disor- obesity; however, their contribution to variation in body © 2010 S. Karger AG, Basel Elinor L. Sullivan, PhD 0028–3835/11/0931–0001$38.00/0 Department of Neuroscience, Oregon National Primate Research Center Fax +41 61 306 12 34 505 NW 185th Ave, Beaverton, OR 97006 (USA) E-Mail karger@karger.ch Accessible online at: Tel. +1 503 690 5510, Fax +1 503 690 5384 www.karger.com www.karger.com/nen E-Mail sullivel  @   ohsu.edu mass index and weight between individuals is estimated increased incidence of obesity and metabolic syndrome to be less than 2% [4] , suggesting that environmental in- in children [15] . Although this review focuses on the im- fluences, such as increased availability of energy-dense pact of maternal HFD consumption, it is important to food and an increasingly sedentary lifestyle, play a crucial note that maternal undernutrition during gestation also role. Accumulating evidence from epidemiologic studies increases the incidence of offspring obesity; thus, the re- and animal models indicate that maternal health and nu- lationship between birth weight and adult adiposity is tritional state during pregnancy and lactation play a crit- thought of as a ‘U’-shaped curve with both a very high ical role in programming the neural circuitry that regu- and a very low birth weight increasing the risk of obesity lates energy balance and behavior in offspring, having a in adulthood [16, 17] . The relationship between maternal sustained inf luence on their physiology and behavior. obesity and the development of offspring obesity appears Metabolic imprinting refers to the programming of an to be independent of gestational diabetes as women who offspring’s future metabolic responses by a stimulus oc- are obese, but able to maintain normal glycemia, also curring during a critical developmental period. As the have heavier offspring with increased adiposity [18] . type and amount of available nutrition are crucial deter- Although epidemiological studies implicate the intra- minants of survival and reproductive success, the evolu- uterine environment, including maternal diet and energy tionary purpose of metabolic imprinting is to enhance status, in programming offspring obesity, in these studies offspring survival by programming energy balance regu- it is not possible to directly link maternal diet and energy lation so that available metabolic fuels are most efficient- status with the offspring’s metabolic profile, as several ly utilized. Mammals are exposed to two environments other factors could contribute to the association between during development, the intrauterine and early postnatal maternal and offspring obesity, including genetics and environments, both of which are heavily impacted by ma- shared environment factors such as access to energy- ternal diet and adiposity. Perinatal nutrition has endur- dense foods and a sedentary lifestyle. Also, there is rela- ing effects on many aspects of physiology and behavior tively limited information on normal brain development including the regulation of energy balance, susceptibili- in humans, making it challenging to examine the impact ty to metabolic disorders [5, 6] , programming of body of maternal diet on offspring’s brain development. Fur- weight set point [7, 8] , stress response [9, 10] and mental thermore, it is difficult to accurately monitor and poten- health-related behaviors [11, 12] . In addition to perinatal tially unethical to manipulate the diet of pregnant wom- nutrition, a number of factors associated with maternal en. Thus, it is critical to use animal models to directly consumption of a high-fat diet (HFD), including mater- examine the effects of maternal overnutrition on subse- nal adiposity, hyperlipidemia, lipotoxicity, glucose levels quent generations and to develop effective therapeutic in- and insulin resistance, also have a long-term impact on tervention strategies. the developing offspring and are associated with in- creased risk of obesity, metabolic disorders, and mental health disorders [5, 11, 12] . As maternal obesity is associ- Animal Models of Maternal HFD Consumption/ ated with consumption of a HFD in humans and a HFD Overnutrition is used to promote maternal obesity in most animal mod- els, a major challenge faced by the field is the ability to Providing animals with a HFD during pregnancy and disassociate the effects of the HFD from the maternal lactation is a common method of inducing maternal obe- metabolic phenotype. sity. However, the duration of exposure to the diet (acute vs. chronic), the percent of calories from fat, and diet composition are variable across studies, hindering com- Maternal Obesity Is Associated with Increased Risk parisons. The diets commonly used to promote maternal of Offspring Obesity obesity are either a purified HFD with fat in place of car- bohydrates as an energ y source or a cafeteria diet in which The most common perturbation of maternal nutrition animals are provided with a selection of palatable food is nutritional excess and maternal obesity. In 2008, over items that have a high fat content along with their regular 64% of women of child-bearing age in the USA were over- diet. The cafeteria diet is most effective in promoting weight or obese [13] and the majority consume an excess obesity; however, as several food items are provided, it is amount of calories and fat [14] . Epidemiological studies difficult to calculate the amount and composition of the clearly indicate that maternal obesity is associated with diet consumed by each animal and the diet consumed by Neuroendocrinology 2011;93:1–8 2 Sullivan/Smith/Grove animals in the same group is variable. Several studies late feeding [17, 38] . Early postnatal overfeeding increases have used purified diets with different sources of fat to the orexigenic peptides neuropeptide Y and agouti-relat- compare the impact of maternal consumption of satu- ed peptide (AGRP) in the arcuate nucleus of the hypo- rated fat [19–22] , polyunsaturated fat [20, 23]  –3 [ 9, 21, thalamus (ARH) of juvenile rats [38] . Offspring of rat 22] or  –6 fatty acids [9, 22] on offspring physiology and dams fed a HFD during the perinatal period also display brain development. It is clear from these studies that the a long-term upregulation in the expression of orexigenic source of fat in the HFD matters. For example, a study in peptides including galanin, enkephalin, and dynorphin rodents determined that while a maternal diet high in in the paraventricular nucleus of the hypothalamus saturated fat programs hyperphagia in offspring, expo- (PVH), and orexin and melanin-concentrating hormone sure to a diet of equivalent percent of calories from fat as in the perifornical lateral hypothalamus [32] . Exposure to fish oil does not [21] . Thus, it is essential that future stud- HFD during gestation stimulates the proliferation of neu- ies determine which sources of fat in a mother’s diet are ronal and neuroepithelial cells of the embryonic third beneficial and which are detrimental to the developing ventricle of the hypothalamus and increases their migra- offspring in order for physicians and nutritionists to tion to hypothalamic regions resulting in an increase in make appropriate recommendations to expecting moth- the proportion of neurons expressing orexigenic peptides ers. [3 2] . Also, offspring from HFD mothers have reduced Most rodent studies report that offspring exposed to a sensitivity to the anorectic effects of leptin [33] . Thus, in HFD during gestation and lactation have increased body rodents it is postulated that perinatal exposure to overnu- weight and adiposity at weaning [24, 25] . However, sev- trition or maternal HFD consumption results in disrup- eral studies report that maternal HFD consumption re- tion of the homeostatic feedback regulation and nutrient sults in lighter offspring [26–28] which they speculate is sensing capabilities of the hypothalamic feeding circuits due to HFD/obesity-induced impairments in the initia- leading to hyperphagia. Though rodent models have sig- tion and production of milk by obese mothers [26, 29] . nificant advantages, such as a relatively short period of The differences in offspring’s body weight phenotypes gestation and the ability to manipulate genetics, the crit- across studies are likely due to differences in the duration ical periods for the development of energy balance regu- of HFD consumption and fatty acid composition of the latory systems differ between rodents and humans. In ro- diets. Using nonhuman primates, our group is examin- dents, the neural pathways regulating energy balance are ing the impact of chronic maternal HFD consumption on immature at birth and are not completely developed until offspring body weight regulation. Brief ly, infant offspring the third postnatal week (mice) [39] . In contrast, in hu- from HFD mothers are underweight at birth and display mans, nonhuman primates, pigs, and sheep, the hypo- rapid catch-up growth, so that by 6 months of age they thalamic circuitry that regulates feeding develops pri- are heavier and have increased adiposity [30] . This off- marily prenatally [38] . Thus, models of maternal over- spring phenotype appears to be independent of whether nutrition in which the development of energy balance the HFD-consuming mother is obese with insulin resis- regulation occurs prenatally are particularly relevant. In tance or lean with normal sensitivity to insulin. These the nonhuman primate model of maternal HFD-induced studies indicate that in primates, as in rodents, maternal obesity, our group has determined that fetal offspring HFD consumption, independent of maternal weight and also display alterations in the development of the hypo- metabolic status, predisposes offspring to increased risk thalamic melanocortin system that may contribute to of developing obesity and metabolic disorders early in disrupted homeostatic signaling [40] . life. In addition to hyperphagia, there is evidence that feed- ing behavior and food choice are also programmed by perinatal nutrition. Overweight children are reported to Programming of Food Intake and Feeding Behavior have increased preference for high-fat foods which is associated with increased parental adiposity [41] . Also, Rodents that experience an early environment in children with one or two overweight parents consume a which they are exposed to maternal HFD consumption larger percentage of energy from fat than children who [31 –33] or overnutrition [34–37] are consistently reported have two normal-weight parents [42] . In these studies it to be hyperphagic as adults. A number of studies have is unclear if the children’s increased fat preference is due found that maternal HFD consumption plays a critical to programming as a result of perinatal HFD exposure, role in programming hypothalamic pathways that regu- genetics or increased availability of high-fat food during Neuroendocrinology 2011;93:1–8 Maternal HFD Has a Long-Term Impact 3 on Offspring Physiology and Behavior childhood. Animal models in which offspring are ex- metabolic rate has not been examined. Thus, a major gap posed to a HFD during the perinatal period provide fur- in the knowledge of the field of metabolic programming ther evidence for an inf luence of perinatal HFD exposure is the impact of perinatal HFD exposure on the regula- on food choice. For example, adult rat offspring exposed tion of energy expenditure. Future studies are needed to junk food during either gestation or lactation displayed which examine not only the effects of perinatal exposure increased preference for fatty, sugary and salty foods [21, to HFD on average basal energy expenditure, but its im- 33, 43] . The source of fat in the perinatal diet inf luences pact on compensatory changes in energy expenditure in the programming of food preference, as rat pups from response to metabolic challenges, such as fasting, dieting mothers that consumed a HFD with lard as the main and chronic consumption of a HFD. source of fat displayed increased preference for the HFD, whereas offspring exposed to maternal consumption of HFD with fish oil as the fat source do not [21] . In rodents, HFD Programming of Mental Health Disorders there is evidence that maternal HFD consumption causes perturbation in the dopamine system of adult animals in In addition to being associated with metabolic disor- areas associated with the rewarding value of food such as ders, epidemiological data indicate that obesity is associ- the nucleus accumbens and ventral tegmental area [44] . ated with increased risk of behavioral/mental health dis- Preliminary findings from our studies examining the orders, such as depression [47] , anxiety [47] , and attention impact of exposure to maternal HFD consumption on the deficit hyperactivity disorder [48] . Moreover, anxiety and food preference of nonhuman primate offspring also in- depression influence the feeding behavior, food prefer- dicate that offspring display increased preference for di- ence and physical activity level. Depression and anxiety ets with a high sugar and fat content [Sullivan and Grove, are associated with increased craving for palatable food unpubl. observation]. Together, these studies provide items [49] and decreased physical activity level [50] . Vari- compelling evidence that perinatal nutrition has a long- ations in mood also alter food choice, with increased pref- term inf luence on dietary preference and feeding behav- erence for high-fat/high-sugar foods being reported dur- ior and may be an important contributing factor to the ing negative emotions [51] . Maternal nutrition has long- development of obesity. As differences in food preference term implications for the offspring’s risk of developing and diet consumption will have a long-term impact on mental health disorders. Perinatal exposure to a HFD may stress response and depressive behaviors of adult off- contribute to this association by altering the development spring [45] , future studies examining the impact of peri- of key pathways implicated in regulating mood and be- natal HFD exposure on food preference should include havior such as the serotonin system [52] . Recently, mater- the examination of stress response and behavioral disor- nal HFD consumption has been associated with increased ders. anxiety in rodent [12] and nonhuman primate offspring Although many studies have examined the impact of [1 1] . In a rat model, male adult offspring from mothers perinatal nutrition on food intake and food intake regu- exposed to either a diet high in saturated or trans fat dur- lation, the number of studies examining the other com- ing gestation and lactation displayed increased anxiety ponent of energy balance, energy expenditure, are limit- and deficits in spatial learning [12] . Using a nonhuman ed. Offspring from mothers undernourished during ges- primate model, our group recently demonstrated that tation are reported to be less active than offspring from perinatal exposure to a HFD causes a decrease in seroto- dams fed ad libitum [46] . Offspring exposed to maternal nergic tone perturbations in the serotonin system, which overnutrition have also been reported to be hypoactive predisposes female offspring to increased anxiety [11] . [31] or to have no difference in physical activity as com- The finding that female nonhuman primate offspring ex- pared to offspring exposed to a control diet [44]. T he ef- posed to maternal HFD consumption are more sensitive fect of maternal diet on physical activity level depends on to developing anxiety than male offspring is consistent the type of fat in the diet. Rat pups from dams fed a diet with evidence in humans which suggests that females are rich in polyunsaturated fat displayed increased locomo- more prone to anxiety than males and that the association tor activity when compared to offspring from dams fed a between obesity and anxiety is stronger in women than saturated fat or standard laboratory diet [20] . This study men [53] . Thus, nonhuman primates appear to be an ide- also reported increased locomotor response to stimulants al model in which to examine the impact of maternal HFD in offspring from dams that consumed a saturated fat diet consumption on the development of mental health disor- [20] . Currently, the impact of early exposure to HFD on ders such as anxiety and depression. Neuroendocrinology 2011;93:1–8 4 Sullivan/Smith/Grove Lipotoxicity Fig. 1. Maternal obesity and HFD con- sumption have an enduring impact on the developing fetal brain and the juvenile off- spring. A fetus from a HFD-consuming mother experiences a fetal environment in which levels of glucose, insulin, fatty acids, triglycerides and inf lammatory cytokines are elevated, leading to changes in the crit- ical neural circuitry for the regulation of physiology and behavior. Mechanism by Which Maternal HFD Programs tors such as hormones (leptin, insulin), nutrients (fatty Physiology and Behavior acids, triglycerides and glucose) and inf lammatory cyto- kines play important roles ( fig. 1 ). Maternal obesity and A lthough there is clear evidence from studies in both diabetes result in maternal hyperglycemia [54] , and as rodents and nonhuman primates that maternal HFD glucose can readily pass through the blood-placenta bar- consumption leads to increased risk of obesity and meta- rier, it is transferred to the fetus. However, the elevated bolic diseases, the mechanisms responsible are largely insulin levels associated with maternal obesity do not unknown. We have very limited information on the im- cross the placenta [15] ; thus, the fetal pancreas must se- pact of maternal HFD consumption on the brain and the crete increased levels of insulin to respond to the mater- complex neural circuitry that regulates physiology and nal hyperglycemia. This fetal hyperinsulinemia is postu- behavior. Recent evidence indicates that circulating fac- lated to be involved in the programming of obesity and Neuroendocrinology 2011;93:1–8 Maternal HFD Has a Long-Term Impact 5 on Offspring Physiology and Behavior diabetes in the developing offspring [55] . Administering the developing fetus to increased circulating cytokines insulin to rats during the last term of gestation produces has been proposed as a potential mechanism by which obesity in the offspring [6, 56] and administering insulin maternal HFD consumption impacts brain development. to the hypothalamus of rat pups during the time that The development of many neural systems that are critical projects from the ARH to the PVH results in elevations in regulating energy balance, such as the melanocorti- in body weight, insulin level, impaired glucose tolerance, nergic system, the serotonergic system, and the dopami- and increased vulnerability to diabetes [57] . Insulin is an nergic system, is sensitive to circulating cytokine levels important growth factor in the central nervous system [64] . Also, rodent studies report that AGRP [66] and pro- [55]; t hus, it is postulated that early exposure to hyperin- opiomelanocortin [67] neurons in the ARH are directly sulinemia alters the development of the brain circuitry impacted by cy tokines. A recent study by Bilbo and Tsang regulating energy balance and behavior. [1 2] reported that offspring from mothers consuming a The hyperleptinemia that offspring from obese moth- saturated fat diet had increased microglial activation in ers experience during development is also implicated in the hippocampus at birth that persisted into adulthood. metabolic imprinting. There is substantial evidence in We have recently observed that fetuses from nonhuman rodents that postnatal leptin is a critical factor in the de- primates consuming a HFD have increased circulating velopment of neural pathways in the hypothalamus [39, and hypothalamic cytokines [40] . We postulate that ex- 58] . Human studies report that leptin is elevated in obese posure to increased inf lammatory cytokines leads to the and diabetic mothers [59, 60] and lower in infants that perturbations in the melanocortin [40] and serotonin experienced intrauterine growth restriction at term [61] . system observed in fetal offspring [11] . Given the large However, in human and nonhuman primate gestation, number of neurotransmitter systems that are inf luenced circulating leptin levels do not rise until after hypotha- by inflammation, future research is needed to examine lamic development is mostly complete [61, 62] . Though the impact of maternal HFD-induced inf lammation on critical for brain development in rodents, there is limited each critical regulator of physiology and behavior. evidence for leptin’s role in the development of primate In summary, many common brain regions and neu- brains [63] . rotransmitters regulate energy balance, stress response Obesity has recently been described as a state of chron- and mental health disorders including the melanocorti- ic inflammation. Increased adiposity is associated with nergic system, serotoninergic system and dopaminergic elevations in peripheral markers of inflammation, such system ( fig. 1 ). Thus, it is not surprising that maternal as C-reactive protein, interleukin-6, interleukin-1 , and HFD consumption has a long-term impact on metabolic tumor necrosis factor-  [64] . These inf lammatory mark- and behavioral regulation. As maternal HFD consump- ers are associated with increased risk of cardiovascular tion and obesity are commonplace and rapidly increas- disease, heart disease, insulin resistance, type 2 diabetes ing, we speculate that future generations will be at in- mellitus and hypertension [64] . The association between creased risk for both metabolic and mental health disor- obesity and increased inf lammatory cytokines has been ders. Given the prevalence of maternal obesity, future confirmed in pregnant women such that obese pregnant studies need to identify therapeutic strategies that are ef- women have increased levels of inf lammatory cytokines fective at preventing maternal HFD-induced malpro- which lead to endothelial dysfunction [65] . Exposure of gramming. 1 Flegal KM, Carroll MD, Ogden CL, Curtin 5 Vickers MH, Breier BH, Cutfield WS, Hof- References LR: Prevalence and trends in obesity among man PL, Gluckman PD: Fetal origins of hy- US adults, 1999–2008. 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Neuroendocrinology 2011;93:1–8 8 Sullivan/Smith/Grove

Journal

NeuroendocrinologyPubmed Central

Published: Nov 13, 2010

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