early life influences on obesity risk: maternal overnutrition and programming of obesity

625

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The obesity epidemicThroughout much of our evolutionary history, the primary challenge to the metabolic health of humans has been food shortages. A major concern at the beginning of this century, how-ever, is the economic, psychological and medical consequences of readily available and inexpensive food. Obesity is one of the world’s greatest public-health challenges; there are now more than one billion adults overweight and a third of these are clinically obese [201]. Predictions of the WHO suggest that by 2015, 75% of the adult popu-lation will be overweight, and 41% obese [201]. Obesity is the second biggest cause of mortality after smoking [1,2] and obesity-associated com-plications account for 10% of healthcare costs in most countries [3]. As with many chronic diseases, human obesity is multifactorial, with key genetic and environmental drivers. Rare loss-of-function mutations in a number of genes can lead to obe-sity. One of the first discovered, but less com-monly encountered, are defects in production of the circulating hormone product of obese gene, leptin, and its receptor (LEPR) [4–6]. Defects in the melanocortin 4 receptor (MC4R), normally activated by melanocortins, such as a-melano-cyte-stimulating hormone, to inhibit feeding,

are thought to account for approximately 6% of early-onset obesity [4,6]. A large genome-wide association study showed that common variants near MC4R influence fat mass, weight and obe-sity risk [7]. Another gene discovered using this technique, the fat mass and obesity-associated gene, confers a 1.6-fold increased risk for obesity in homozygotes, possibly related to food intake or changes in lipolytic activity [8]. The obesity gene map describes 244 genes that affect body-weight and adiposity when mutated or expressed as transgenes in the mouse [9]. While a suscep-tibility gene may have only a slight effect on bodyweight, the cumulative contribution of these genes may become important when they interact with the environment (Figure 1). Indeed, genetic factors play an important role in deter-mining the response of body mass to chronic alterations in energy balance [10].

Although obesity is a multifactorial condi-tion, the marked rise in obesity within only a few decades is more likely to be due to increased consumption of high-fat and high-energy foods, coupled with reduced physical activity, rather than a rapid change in the global gene pool (Figure 1) [1,11–13] . Increasing evidence suggests that the macronutrient composition of the diet

Margaret J MorrisDepartment of Pharmacology, School of Medical Sciences, University of New South Wales, NSW 2052, Australia Tel.: +61 293 851 560 Fax: +61 293 851 059 [email protected]

While adult lifestyle factors undoubtedly contribute to the incidence of obesity and its attendant disorders, mounting evidence suggests that programming of obesity may occur following over-nutrition during development. As hypothalamic control of appetite and energy expenditure is set early in life and can be perturbed by certain exposures, such as undernutrition and altered metabolic and hormonal signals, in utero exposure to maternal obesity-related changes may contribute to programming of obesity in offspring. Data from animal studies indicate both intrauterine and postnatal environments are critical determinants of the development of pathways regulating energy homeostasis. This review summarizes recent evidence of the impact of maternal obesity on subsequent obesity risk, paying particular attention to the hypothalamic regulation of appetite and markers of metabolic control. The extraordinary rise in the rates of maternal obesity underlines an urgent need to investigate the mechanisms contributing to its transgenerational effects.

Keywords: appetite • fetal • gestation • hypothalamus • intrauterine • obesity • programming • rat

Early life influences on obesity risk: maternal overnutrition and programming of obesityExpert Rev. Endocrinol. Metab. 4(6), 625–637 (2009)

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Expert Rev. Endocrinol. Metab. 4(6), (2009)626

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‘Programming’

Individual factorse.g., maternal obesity,in utero environment

Neuroendocrine adaptation

Obesity

Apetite circuitsadapted to maximize intake

+

+

+

Reward pathways

Positive energybalance Physical activity

Palatability

Foodavailabilityand choice

+ +Obesogenicenvironment

Geneticbackground

Gene–environmentinteraction

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may also be an important factor in the development of obe-sity [14], more so than total energy intake [15]. Rodents fed a high-fat Western diet, but pair-fed to equivalent energy intake as those consuming low-fat chow, lay down more fat and showed increased circulating insulin, leptin and triglycerides [16]. As diet is a modifiable factor in the etiology of obesity, understanding the influence of high-fat diets (HFDs) on the neuroendocrine systems involved in energy homeostasis is essential for the treatment and prevention of obesity.

Childhood obesityThe obesity epidemic is no longer restricted to adults. Obesity in children is rising worldwide, with 22 million children under 5 years of age estimated as being overweight [202]. In the USA, the number of overweight children has doubled and the number of overweight adolescents has tripled since 1980, while in Australia 19–23% of children and adolescents were overweight or obese in 1995–1997 [17]. Similar data are emerging from studies of urban children in China [18].

Another recent important, and possibly related, demographic change has been the increasing rate of obesity in women, including women of childbearing age [2]. Presently, 61.8% of adult women in the USA, 62.1% in the UK, 40% in Australia, and 38.6% in Canada are overweight or obese [201]. Increasing numbers of women are overweight or obese on entering pregnancy [19,20]. Obesity brings a number of obstetric complications, including gestational diabetes, hypertension, preeclampsia, neonatal death and complications during labor [21,22]. Infants born to obese women also have a higher prevalence of congenital anomalies than do the offspring of normal-weight women [19,20,23]. The rising rate of maternal obesity represents a new metabolic challenge for many offspring. The high prevalence of metabolic complications among obese pregnant women suggests that obesity exacerbates the usual metabolic adjustments that occur in pregnancy [20]. Obesity in pregnancy has also been associated with impaired endothelial function, higher blood pressure and upregulation of inflammatory mediators [24]. In humans, maternal obesity

and hyperglycemia during pregnancy can lead to high birth weight, increased circulating insulin, glucose, triglycerides and lead to glucose intolerance, as well as obesity in offspring [25,26]. High birth weight also leads to increased rate of body mass index (BMI) gain [25] and an increased risk of developing metabolic syndrome [27]. Children with a higher BMI are more likely to become obese adults [28]. Studies addressing size at birth and the relation-ship with later obesity can be limited by reliance on birth weight alone; weight and length provides a better index of adipos-ity [26]. Recent data from a prospective study showed that a more rapid increase in weight for length in the first 6 months of life was associated with increased risk

of adiposity and obesity at 3 years of age, independent of socio-economic status, maternal smoking, gestational weight gain and prepregnancy BMI [26]. Therefore maternal obesity may be an important factor not only in programming obesity in offspring but also in the amplification and intergenerational transmission of the obesity epidemic.

Developmental programming of obesityEffects of undernutritionChanges in maternal nutrition during gestation and lactation can exert profound and long-term effects on offspring. One of the earliest observations of prenatal programming of offspring obesity was made through studies of the effects of the Dutch famine, whereby maternal undernutrition during early preg-nancy but not late gestation, caused offspring obesity [29–31]. The concept of programming emerged from epidemiologi-cal studies that linked size at birth and disease rates later in life [32]. Barker proposed the ‘fetal origins’ hypothesis, which posits that poor fetal nutrition causes adaptations that program future propensity to obesity, diabetes and cardiovascular dis-ease. These observations were also interpreted as the ‘thrifty phenotype hypothesis’ [33], where a fetus responds to under-nutrition, in the short term, by selectively distributing nutrients to preserve the growth of the brain and certain key organs at the expense of others. However, the consequences of such mater-nal nutritional perturbations suggest that the adaptations that occur in fetal tissues as a result of early exposure to nutritional insults result in an increased susceptibility to the development of metabolic disease in later life. Alterations in the functional capacity of key tissues and organs increase the prevalence of Type 2 diabetes and coronary heart disease [33]. Candidate mechanisms underlying the association between intrauterine growth restriction and the development of the metabolic syn-drome include variations in organ structure, cell number and clonal selection of specific populations of cells, in addition to epigenetic modification of intrinsic cell functional capacity and behavior (see [34] for review). Targeting and resetting of the

Figure 1. Proposed mechanisms contributing to the global increase in obesity. The current ‘obesogenic’ environment, coupled with our genetic background and the rewarding nature of food, promote obesity. Other individual factors early in life can contribute to the programming of obesity in offspring (e.g., maternal obesity and in utero environment). This is exacerbated by implementation of a high-fat diet after weaning.

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ReviewEarly life influences on obesity risk: maternal overnutrition & programming of obesity

hypothalamo–pituitary–adrenal axis has also been proposed to participate in the pathophysiology of obesity and the metabolic syndrome associated with intrauterine growth restriction.

Relationship between parental obesity & offspring obesityMuch of the initial work examining early-life programming influ-ences on obesity dealt with the impact of undernutrition during gestation, utilizing restricted feeding or protein deprivation of the mother, but the relatively recent increase in obesity among pregnant women brings an urgent need to examine the impact of maternal obesity on offspring. The degree to which prepreg-nancy parental obesity/overweight affects bodyweight in the next generation is not entirely clear. Several studies across different countries demonstrate a link between parental and childhood obesity, particularly that of the mother [35–40]. It should be noted that adjustment for all of the possible confounding variables may be difficult in observational studies. Most work investigating intergenerational links to obesity has been based on the current BMI of parents.

In their investigation of a large (17,000) 1958 British birth cohort, Li et al. report that parental BMI during their own child-hood had a long-term impact on their offspring [41]. Parents born in 1958 were weighed at ages 7, 11, 16, 23 and 33 years, and their offspring from 4–18 years (average 8.7 years) [41]. The associations for parental BMI as children were independent of current parental adult BMI, and importantly the effect of parental BMI in both childhood and adulthood were associated with offspring BMI to a similar degree [41]. While an impact of parental BMI in adult-hood may be linked to shared environment, including lifestyle factors, this study showed that offspring BMI was influenced by the parent’s BMI when they were children themselves, supporting the notion that obesity is in part programmed early in life [41]. A substantial increase in obesity/overweight was seen across the two generations.

Modulation of pathways involved in energy balanceOne mechanism whereby maternal obesity may impact obesity risk in offspring is the regulation of appetite pathways within the CNS. Appetite is regulated by a homeostatic network com-prising central and peripheral components that maintain the balance between energy intake and expenditure [42,43]. The brain plays a critical role in the regulation of energy homeo-stasis. Circuits in the CNS assess and integrate peripheral metabolic, endocrine and neuronal signals that reflect current energy status, influencing orexigenic and anorexigenic sig-nals to allow adequate energy balance. Despite considerable daily variation in both energy intake and expenditure, most animals, including humans, maintain a steady bodyweight for long periods. The hypothalamus is the main integrator and processor of peripheral metabolic information and this region contains many neurotransmitters that stimulate or inhibit appe-tite (Box 1). Orexigenic peptides, such as neuropeptide Y (NPY) and agouti-related peptide (AGRP), are produced in the arcuate nucleus (ARC) and released in several hypothalamic regions,

including the paraventricular nucleus where they have potent stimulatory effects on appetite [42]. Parallel pathways release the anorexigenic mediators proopiomelanocortin (POMC)-derived melanocyte-stimulating hormone and cocaine–amphetamine regulated transcript (Box 1 & Figure 2).

Studies in rodents demonstrate that adult-onset obesity can modulate the expression of the hypothalamic transmitters impli-cated in the regulation of appetite, as well as responses to their administration [44,45], but the impact of maternal obesity on the developing hypothalamus is unclear. Until very recently, the effects of early-life overfeeding (e.g., during gestation, lactation, or both) on the neurochemistry of the hypothalamic regions subserving appetite control received little attention [34,46]. Insulin has critical CNS actions and regulates feeding and glucose dis-posal through central actions. Insulin is known to be pivotal to neuronal differentiation and synapse formation in the hypothala-mus [47], so that alterations in prevailing insulin abundance dur-ing development of these circuits could have long-lasting repercus-sions. High levels of insulin during critical periods of development may contribute to malprogramming of neuroendocrine systems regulating bodyweight [48]. Recent PET data in patients with systemic insulin resistance illustrated lower central responses to insulin, supporting the notion of brain insulin resistance in this cohort [49]. The possible CNS impact of early and sustained expo-sure to hyperinsulinemia induced through maternal obesity and related metabolic and hormonal changes are not known.

Another critical player is leptin, the adipose-derived hormone that inhibits food intake by activating the long isoform of its receptor, ObRb, in the hypothalamus. In rodents, leptin level is low at birth, increases in the early postnatal period and then declines prior to weaning. Exposure to increased leptin during a critical window early in development is vital for the maturation of projections from the ARC of the hypothalamus to other key regions, including the ventromedial and lateral hypothalamus in rodents. Defective neurite outgrowth linked to the absence

Box 1. CNS transmitters implicated in appetite control.

Orexigenic

• Neuropeptide Y

• Melanin concentrating hormone

• Orexins/hypocretins

• Agouti-related peptide

• Galanin

• Galanin-like peptideAnorexigenic

• Cocaine and amphetamine regulated transcript

• Melanocortins

• Glucagon-like peptide

• Corticotropin releasing factor

• Serotonin

• Histamine

The activity of these CNS pathways is regulated by peripherally derived anorexigenic (leptin, insulin, cholecsystokinin, GLP-1, Peptide YY) signals, as well as the stomach-derived orexigenic hormone ghrelin.


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NPY/AGRP POMC/CART Lateral hypothalamusArcuate nucleus

3v

CRFR2 PVN

CRH -

-

Y1Y5 MC4R

Ghrelin Leptin Glucocorticoids Insulin

MCH

Orexin

+

+

Specific modulation

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of leptin in ob/ob mice can be ameliorated by leptin treatment, but only when applied in the early postnatal period [50]. The more recently described stomach-derived hormone, ghrelin, has also been implicated in the development of hypothalamic feeding circuits in critical windows of development [51]. As hypothalamic control of appetite appears to be established early in life, and modulated by nutrient-related factors, effects of abnormal nutrient availability in the fetal/early postnatal period may contribute to programming of adult obesity.

Epigenetic mechanisms implicated in the programming of obesityEpigenetic modification of genes relevant to metabolic control may contribute to the development of obesity following intra-uterine overnutrition. Epigenetics refers to covalent modifications of DNA that regulate gene activity without altering the DNA sequence. Processes such as DNA methylation and histone modi-fication, chromatin and noncoding regulatory RNAs are probably important mediators of early-life programming. Methylation of cytosine residues is an important gene-silencing mechanism. As discussed recently the epigenetic state of DNA and associated phenotype can be inherited if epigenetic modifications are not completely erased during gametogenesis and early embryogen-esis [52,53]. Numerous studies have provided evidence that altered gene methylation can occur in response to altered nutrition during pregnancy; for example, protein restriction led to altered methyla-tion of the hepatic glucocorticoid receptor gene [54]. Recent human data linked maternal pregestational BMI with methylation of the PPARGC1A promoter in newborns [55]. More work is required to elucidate the extent of epigenetic changes in mediating the effects of maternal obesity. Animal models suggest this may be an important mediator by which environmental influences operating early in life modulate disease susceptibility [56].

Studying the impact of windows of overnutrition: relevance of rodent modelsWe have seen that epidemiological data points to positive relationships between maternal obesity and increasing risk of early-onset obesity in offspring. Managing childhood obesity and its consequences requires an understanding of the under-lying pathophysiological changes that occur as a consequence of early-onset over-nutrition, whether these occur during ges-tation, lactation or in the later postnatal period. Determining the relative impacts of overnutrition during different criti-cal developmental periods is challenging in humans, and prospective studies are difficult and demanding to implement. Moreover, the important genetic and envi-ronmental contributions to the develop-ment of obesity further complicate such studies given the difficulties of controlling

or accounting for these in humans. As the appetite regulatory pathways are highly conserved across mammalian species, infor-mation gained in the rodent should have relevance to humans. A major benefit of using nonhuman species is the capacity to rigorously control diet and other relevant environmental fac-tors that impact on obesity. In rats, the short gestational period (21 days) means that transgenerational studies in offspring can readily be carried out under controlled conditions. In altricial species, such as the rat, the lactation period correlates with the third trimester of human gestation.

In rodents, both maternal and early postnatal overnutrition leads to early-onset obesity and alter glucose metabolism and insu-lin sensitivity. One of the advantages of experimental paradigms in such species is the ability to dissect the impact of timing of overnutrition in early life, and to study any interactions of pre- and post-natal overfeeding. While this review will focus on work in the rodent, programming of obesity in other species has been reviewed previously [34].

Over nutrition in the early postnatal periodImpact up to weaningOne of the first interventions adopted to study the impact of overnutrition independent of uterine influences was litter size adjustment in rodents [57]. In rodents, reducing litter size to three–four animals soon after birth increases milk availabil-ity, rapidly increasing bodyweight, which persisted into adult life [58]. In other studies, reduced litter size in the rat increased circulating leptin and insulin, and impaired glucose tolerance in rat offspring [59,60]. At weaning (24 days of age), rats that were overfed during lactation owing to litter size reduction weighed 10% more than control rats, with significantly increased adipos-ity, even when corrected for bodyweight [60,61]. Other studies have shown that rats raised in reduced litters showed remodeling

Figure 2. Simplified schematic of hypothalamic regulation of food intake. NPY, MCH, orexin and AGRP stimulate feeding (+), while aMSH derived from POMC, CART and CRH inhibit food intake (-). NPY activates Y1/Y5 receptors; aMSH stimulates, while AGRP antagonises, MC4R. Hormones, including insulin, glucocorticoids, leptin and ghrelin modulate these circuits, thereby regulating food intake. For more detail see [13,42,43].aMSH: a-melanocyte-stimulating hormone; AGRP: Agouti-related peptide; CART: Cocaine-amphetamine regulated transcript; CRH: Corticotropin-releasing hormone; MCH: Melanin concentrating hormone; NPY: Neuropeptide Y; POMC: Proopiomelanocortin; PVN: Paraventricular nucleus.



of the hypothalamic pathways involved in appetite, with changes in the orexigenic neuropeptide NPY (Box 1) observed at weaning in offspring [62].

Overnourished rats raised in small litters continue to overeat relative to controls after weaning, suggesting that the level of nutrition in early postnatal life may affect long-term appetite regulation. Another approach has been to provide a maternal HFD in the perinatal period [63]. Feeding mothers a HFD for the last week of gestation and during lactation increased pup weight by postnatal day 12, and doubled plasma leptin [63]. This expo-sure also altered hypothalamo–pituitary–adrenal responsiveness,

known to affect appetite and its regulation, suggesting that pro-gramming of multiple pathways in early life has effects on energy intake of offspring [64].

It is noteworthy that several key systems involved in the regula-tion of feeding are immature at birth, and continue to develop during the postnatal period in the rodent [65]. Arcuate nucleus expression of ObRb and orexigenic and anorexigenic neuro-peptides increase dramatically in the early postnatal period, and leptin stimulates suppressor of cytokine signaling-3 expression in the third ventricle at postnatal day 4, but not day 14 [66]. A poten-tial mechanism driving the altered appetite in early overnourished

Table 1. Effects of maternal obesity on offspring: rodent studies.

Study (year) Strain Maternal diet Weight change* (%)

Alterations observed in offspring Ref.

As adult

Taylor et al. (2005)

SDawley Chow + 20% lard 10 days before mating

↑ adiposity, BW, leptin, insulin in offspring of dams fed HFD at 6 months; reduced glucose stimulated insulin secretion at 9 months

[93]

Srivinasan et al. (2006)

SDawley 60% fat from weaning +19 ↑ BW, insulin, glucose, FFA, TG, and glucose intolerance in offspring

[90]

Bayol et al. (2007)

Wistar Palatable café-chow, supplemented with Western foods

+13 ↑ BW in offspring of junk fed dams, and greater preference for junk food

[89]

Parente et al. (2008)

Wistar Chow or HF chow postnatally and during gestation

↑ adiposity, BW, leptin and insulin in offspring of dams fed HFD, amplified by postnatal HFD

[98]

Shankar et al. (2008)

SDawley Enteral, 15% excess energy; pups cross-fostered to lean

+31 ↑ adiposity and insulin resistance in offspring of overfed dams; effects of obesity reinforced by postweaning HFD

[80]

Howie et al. (2009)

Wistar 45% fat +11 ↑ adiposity in offspring of dams fed HFD prior to/during P or just during P

[82]

White et al. (2009)

Long Evans

60% fat, 20% carbohydrate 4 weeks before mating

Modest ↑ adiposity, BW and leptin in 18-week offspring of dams fed HFD

[86]

Tamashiro et al. (2009)

SDawley 60% fat from day 2 of P +20 ↑ adiposity, BW and leptin and insulin in offspring of dams fed HFD; ↓ insulin to glucose load

[83]

Nivoit et al. (2009)

Wistar 11%fat, 43% sugar 8 weeks before mating

+17 ↑ BW, adiposity at 12 months; no difference in leptin, insulin; males were insulin-resistant

[94]

Chen et al. (2009)

SDawley 33% fat 5 weeks before mating

+31 Offspring of obese dams gained more weight independent of postweaning diet; differential effects of litter size/maternal diet on appetite regulators; glucose intolerance

[99]

Kirk et al. (2009)

SDawley 16% fat, 31% sugar 6 weeks before mating

+20 ↑ BW, adiposity, leptin resistance, reduced pSTAT3 in Arc; reduced AgRP-ir in PVN at 90 days

[68]

Samuelsson et al. (2008)

C57Bl6 mouse

16% fat, 33% sugar 6 weeks before mating

+20 ↑ BW and adiposity, hyperphagia. Endothelial dysfunction; increased night-time BP; altered adipocyte b-adrenoceptor 2 and 11-bHSD-1 and PPAR-g

[92]

Selected summary of rat and mouse studies exploring the effects of existing maternal obesity or maternal HFD around the time of conception on offspring. Studies where an increase in maternal body weight was observed are included. Note differences in experimental protocols and diet composition led to markedly differing degrees of maternal overweight/obesity; the reader is referred to the original article for full details of diet composition.Alterations column is based on changes in offspring versus control group fed low-fat diet. *Weight change refers to effect of diet on the mother.11-bHSD: 11-b hydroxysteroid dehydrogenase; AgRP: Agouti related protein; Arc: Arcuate nucleus; BP: Blood pressure; BW: Bodyweight; Café: Cafeteria; FFA: Free fatty acid; HFD: High-fat diet; IRS2: Insulin receptor substrate-2; L: Lactation; N: Normal diet; NPY: Neuropeptide Y; ObRb: Long form of leptin receptor; P: Pregnancy; POMC: Proopiomelanocortin; SDawley: Sprague–Dawley; SL: Small litter size; STAT3: Signal transducer and activator of transcription-3; TG: Triglyceride.


Review Morris

animals is the effects of leptin and insulin on hypothalamic areas important in feeding. Changes in maternal nutrition may affect the leptin surge that occurs postnatally. For instance, maternal perinatal undernutrition in the rat was reported to reduce the postnatal leptin surge and affect development of the ARC [67]. Conversely, offspring of dams rendered obese by consumption of a diet high in fat and simple sugars had an exaggerated increase in plasma leptin relative to controls from days 9 to 18 after birth, coinciding with greater adipose leptin mRNA expression [68]. Nursing of control pups by dams rendered diabetic with strep-tozotocin altered the development of hypothalamic appetite cir-cuits, with increases in NPY and AGRP and reduced POMC and cocaine amphetamine regulated transcript [69]. Excess weight gain during the early postnatal period was also associated with permanent reprogramming of brown adipose tissue adaptive ther-mogenesis [70]. Therefore, early-life programming and resetting of hypo thalamic function may target energy expenditure as well as intake, but do such effects persist?

Long-term impact of postnatal overnutritionVarious experimental paradigms have been used to examine the long-term impact of altered postnatal nutrition. Certainly the changes in adiposity and bodyweight induced by overfeeding rodents by reducing litter size during the suckling period per-sisted for several months [60,71], suggesting a long-lasting impact of this intervention. We also found that overfeeding during lactation increased adipose expression of 11-b hydroxysteroid

dehydrogenase in adult offspring, independent of their post-weaning diet [60], which may influence fat accumulation through increased exposure of the adipocyte to corticosterone. When rodents from normal mothers were nursed by obese mothers, they developed late-onset obesity, insulin resistance [72] and cardiovas-cular dysfunction [73]. The impact of increased perinatal maternal fat intake, which increased offspring bodyweight and adiposity, also persisted after puberty in rats consuming a low-fat diet [63].

Thus, a number of different experimental paradigms of peri-natal overnutrition in rodents demonstrate long-lasting changes in adiposity and bodyweight of offspring. This implies that independent of intrauterine influences, the early postnatal environment is crucial in the developmental programming of obesity and obesity-related diseases, at least in rodents. One factor responsible for increased body size in adulthood sub-sequent to overfeeding in early life appears to be the greater voluntary food intake after weaning, although this was not universally observed, possibly related to the variations in the ages examined and the power of the studies. However it is clear that the amount of food consumed during suckling in the rat plays an important role in determining subsequent food intake in later life.

The quality of nutrition in early postnatal life, in addition to the quantity, is also critical. Increased carbohydrate intake by rats in the immediate postnatal period resulted in adult-onset obesity and hyperinsulinemia, with altered pancreatic islet gene expression [74]. This exposure also increased expression of the

Table 1. Effects of maternal obesity on offspring: rodent studies.

Study (year) Strain Maternal diet Weight change* (%)

Alterations observed in offspring Ref.

At weaning

Srivinasan et al. (2006)

SDawley 60% fat from weaning +19 ↑ insulin, greater insulin to glucose load in offspring [90]

Chen et al. (2008)

SDawley 33% fat 5 weeks before mating

+23 ↑ adiposity and TG in offspring of dams fed HFD or SL, amplified by combination; ↓ Arc NPY, ↑ POMC; glucose intolerance

[84]

Howie et al. (2009)

Wistar 45% fat from weaning +11 ↑ adiposity in offspring [82]

White et al. (2009)

Long Evans

60% fat, 20% carbohydrate 4 weeks before mating; modest increase in BW

Modest ↑ adiposity, BW and leptin in offspring of dams fed HFD; ↓ insulin tolerance

[86]

Tamashiro et al. (2009)

SDawley 60% fat from day 2 of P +20 ↑ adiposity and BW only if weaned onto HFD [83]

Kirk et al. (2009)

SDawley 16% fat, 31% sugar 6 weeks before mating

↑ adiposity and leptin resistance at day 30 [68]

Selected summary of rat and mouse studies exploring the effects of existing maternal obesity or maternal HFD around the time of conception on offspring. Studies where an increase in maternal body weight was observed are included. Note differences in experimental protocols and diet composition led to markedly differing degrees of maternal overweight/obesity; the reader is referred to the original article for full details of diet composition.Alterations column is based on changes in offspring versus control group fed low-fat diet. *Weight change refers to effect of diet on the mother.11-bHSD: 11-b hydroxysteroid dehydrogenase; AgRP: Agouti related protein; Arc: Arcuate nucleus; BP: Blood pressure; BW: Bodyweight; Café: Cafeteria; FFA: Free fatty acid; HFD: High-fat diet; IRS2: Insulin receptor substrate-2; L: Lactation; N: Normal diet; NPY: Neuropeptide Y; ObRb: Long form of leptin receptor; P: Pregnancy; POMC: Proopiomelanocortin; SDawley: Sprague–Dawley; SL: Small litter size; STAT3: Signal transducer and activator of transcription-3; TG: Triglyceride.



orexigenic mediators NPY, AGRP and galanin in the hypothala-mus [75]. Moreover, a transgenerational effect was observed, as females that were overfed in this fashion as neonates gave rise to offspring that went on to develop adult-onset obesity [74]. Human data also suggest that intake during lactation may impact an infant’s bodyweight trajectory. For instance, intensive breastfeed-ing, with over 80% of milk feeds being breast milk in the first 6 months of life, is associated with lower risk of excess weight in late infancy [76]. Moreover an infant’s propensity to empty bottles early in infancy, particularly if initiated by the infant, was associ-ated with excess weight [76]. Importantly, cross-sectional data in 3075 women showed that overweight and obesity was associated with a shorter duration of breastfeeding and cessation both in the immediate postpartum period and in the first 6 months [77].

Maternal consumption of HFD or maternal obesity Initial studies in rodents examining the effect of increased mater-nal bodyweight focused on feeding mothers a HFD after con-ception [78]. More recently, attention has turned to the effects of pre-existing maternal obesity, that is, obesity that is established prior to conception, which more accurately reflects the shifting demographic in humans.

Impact on birthweightReports of effects of postconception maternal consumption of HFD on the birthweight of offspring are conflicting. Several groups reported no effect on birthweight [72,73,79,80], with some reports of lower [81,82] and higher [83] birthweights.

More recently the impact of maternal obesity predating con-ception on growth and metabolic parameters in offspring has been investigated. In several studies pre-existing maternal obe-sity induced by maternal consumption of a cafeteria HFD prior to conception did not significantly influence birthweight [84–87], while others observed lower birthweight [82]. These different observations may relate to strain differences (e.g., Wistar versus Sprague–Dawley) or variation in the macronutrient composi-tions in the diets. A maternal HFD implemented before concep-tion and throughout gestation, increased whole hypothalamic mRNA expression of the ObRb and insulin receptor at term, while that of their downstream signals, signal transducer and activator of transcription-3 and insulin receptor substrate-2 were decreased in offspring [87]. Marked modulation of hypothalamic NPY and POMC mRNA expression was already apparent at day 1 of life in both male and female offspring of obese dams and, in our hands, ObRb and signal transducer and activator of transcription-3 mRNA expression were reduced [85]. We and others have reported that offspring of obese mothers showed reductions in plasma leptin early in life (day 1 [85], day 2 [82]), which, as stated above, may impact on the development of hypo-thalamic appetite pathways. Others have reported increased leptin in term fetuses of obese dams [87]. Overall, recent reports point to significant changes in the hypothalamic regulators of appetite evident as early as birth in the offspring of obese moth-ers. More work is required to determine the regional specificity of some of these changes.

Impact at weaning of maternal obesityMaternal obesity leads to greater bodyweight and fat mass in offspring at weaning. The extent of the increase ranges across studies. At 3 weeks of age, increased bodyweights were observed in male and female offspring of dams consuming a high-fat/high-simple sugar diet [68]. Howie et al. observed 12 and 14% increases in bodyweight in female and male offspring of dams who themselves consumed HFD postweaning, respec-tively [82]. Larger increases were observed by White [86] and, in our hands, male pups born of dams rendered obese by cafeteria HFD were 42% heavier than controls, with marked increases in fat mass in all pads sampled [84]. Maternal obesity also led to reduced insulin tolerance [86]. Impaired glucose tolerance was also observed at weaning in offspring of rats consuming a HFD [83,84]. Data from studies investigating the offspring of obese rat dams at weaning are summarized in TaBle 1. Only those studies where the dietary intervention induced weight gain in the dam are considered.

Differences between studies may relate to differing levels of maternal obesity and the type of diet used. Our rat dams were consuming more than double the energy intake of controls, with a doubling of leptin and insulin and quadrupling of triglycerides prior to mating [84]. One recent study explored the impact of HFD feeding in a pair-fed paradigm where dams consumed the same energy as controls prior to conception and during gesta-tion and lactation. At weaning the offspring of pair-fed dams weighed the same as those from control dams, with no difference in leptin, but an increased percentage of body fat [86]. Thus, it appears maternal obesity per se, or at least caloric excess, is criti-cal to the programming effect. The importance of energy intake of the mother during lactation is demonstrated by the finding that increased energy intake via litter reduction exacerbated the effects of maternal obesity on bodyweight, adiposity and glucose intolerance [84].

Other work in nonhuman primates demonstrated that even if mothers did not develop obesity, the developing fetus is highly vulnerable to excess lipids, and exposure led to increased liver tri-glycerides, the expression of markers of oxidative stress and prema-ture gluconeogenic gene expression, promoting non alcoholic fatty liver disease [88]. These authors postulated that adverse effects of excess fuels on fetal development may, in part, be related to a lack of white adipose tissue in most species until relatively late in pregnancy.

Long-term impact of maternal obesityMost rodent studies indicate that maternal obesity predating conception is associated with increased bodyweight and adipos-ity in offspring as they age [80,82,84,86,89–92], with alterations in adipose gene expression, including 11-b hydroxysteroid dehy-drogenase, PPARg and a-adrenoceptor. Interestingly, when the impact of maternal obesity was isolated from the influence of nutrition during lactation using cross fostering, obesity during gestation alone conferred significant increases in bodyweight (7%) and adiposity (30%) in offspring at adulthood with no significant change in leptin or insulin [80]. When the long-term


Review Morris

(5 months) effects of modest maternal obesity (11% increase in bodyweight) predating conception, and maternal HFD con-sumption only during gestation and lactation were compared, similar effects were observed on offspring [82], confirming a crit-ical role for postconception diet on outcome. Long-term deficits in insulin sensitivity and secretory capacity were observed in 12 and 9-month-old offspring of dams who consumed a fat-rich diet in pregnancy [93]. Data from these studies are summarized in TaBle 1.

Maternal obesity has been shown to predispose individu-als to overeating, increased adiposity and glucose intolerance [63,79,84,89,94]. However, the underlying neural mechanisms are still unclear. Previously, we found reduced hypothalamic NPY and increased POMC mRNA levels in offspring from obese dams at postnatal day 20 in the free-feeding state [84], which is similar to the changes in adult-onset dietary obesity [44]. An elegant study from the Liebowitz group demonstrated increased proliferation of hypothalamic peptide-producing neurons in offspring [95]. A recent study examined the impact of low brain MCR activity induced by chronically infusing the MCR antagonist SHU9119 during gesta-tion in rat dams. Greater weight gain was observed, particularly in male offspring, with greater deposition of visceral fat [96].

A number of groups have reported changes in macronutrient preference in offspring of mothers who were consuming a HFD perinatally, or in mothers who were obese. Maternal HFD dur-ing the perinatal period was associated with increased preference for fat, particularly during the transition to adolescence [63]. A maternal ‘junk food’ diet during pregnancy and lactation in rats was shown to promote an exacerbated taste for ‘junk food’ in off-spring, who were also at greater risk of obesity [89]. A recent report in mice suggests that the window for developmental programming of effects of diet may extend beyond lactation, as mice exposed to high sucrose immediately postweaning showed greater subse-quent weight gain when offered high-fat and high-sugar foods [97]. Supporting a critical effect of the immediate postweaning period, in rats postweaning dietary history affected food- motivated behav-ior, as junk food-fed rats earned less food pellets on fixed ratio and progressive ratio cost schedules than chow-fed controls [91].

There is mounting evidence of an additive detrimental impact of HFD consumption after weaning in animals born of obese mothers. Deleterious effects of a HFD during pregnancy on metabolic profile, adiposity and cardiac hypertrophy were enhanced by postnatal consumption of HFD [84,86,98]. The impact, in terms of adiposity, of being born of an obese mother was approximately equivalent to that of HFD consumption later in life [86]. The combination of maternal obesity and HFD con-sumption after weaning led to additive effects on bodyweight in adulthood; offspring of obese mothers remained heavier than those of lean mothers with increases in adiposity independent of their postweaning diet [99].

Role of leptinIn addition to its appetite-regulating effects, leptin promotes growth and survival of neurons [100,101]. Leptin is produced by the placenta and can be transferred to the fetus, with evidence

that this transfer is increased late in pregnancy, at least in the rodent [102]. Leptin is also found in breast milk in levels that reflect maternal adiposity [86,103] and may influence levels in infants. Through its actions on hypothalamic appetite pathways during development, leptin appears to provide an important link between maternal nutrition and adiposity and the development of offspring [47]. Maternal obesity has been shown to promote hypo-thalamic leptin resistance in offspring before they were exposed to HFD, and this was associated with increased weight gain [104].

As mentioned previously, some rat studies have shown reduced leptin levels in the perinatal period in offspring of obese moth-ers [82,85], although this is not a universal finding [87]. By day 7 leptin concentrations were increased in offspring of obese dams [68,86]. A negative association between breast milk leptin concentration and bodyweight gain was observed in human infants [105]. The postnatal surge of plasma leptin was reduced by maternal under-nutrition, and this was linked to altered hypothalamic wiring as well as expression of the anorexigen POMC in male rat pups [67]. As reviewed by McMillen and colleagues, a number of studies have shown protective effects of leptin supplementation early in life [106]. Oral dosing of rats with leptin during the suckling period was protective against age-related increases in bodyweight, and treated rats were resistant to HFD-induced obesity [107]. Stocker et al. demonstrated that treatment of obese dams with leptin reduced the exaggerated weight gain of their pups [108]. A recent study comparing leptin treatment in offspring of normally fed or underfed dams reported differential effects of leptin; beneficial effects were seen in rats from undernourished mothers, but only if they ate chow, while offspring of normally nourished mothers showed increased weight gain [109]. Notwithstanding these dif-ferences, it appears that leptin levels early in life are critical in regulating energy homeostasis, prompting some to promote the benefits of leptin supplementation [110].

Behavioral effects of maternal obesity?Leptin appears to exert other effects on the developing brain. While many studies have focused on the programmed changes in appetite and metabolic regulation induced by altered nutri-tion early in life, the potential impact on offspring behavior has been relatively neglected. Exposure to a HFD during the neonatal period has been suggested to benefit the developing hippocampus by promoting neurogenesis and reducing apoptosis [63]. The early postnatal overnutrition induced by litter size reduction in rats reduced offspring anxiety-like behavior, assessed on the elevated plus maze, in a gender-specific manner [111], with greater effects in females. Interestingly, antidepressant effects of leptin have been reported [112]. A recent study using leptin injection over the first 10 days of life reported increased anxiety and novelty-seeking behavior at adulthood [113].

The impact of maternal obesity on other aspects of behav-ior has received little attention, and studying this in humans is challenging on a number of levels. A recent prospective study across cohorts in Sweden, Denmark and Finland totaling 12,556 school-aged children reported that prepregnancy maternal over-weightness, or obesity, is associated with increased odds ratio for



attention-deficit/hyperactivity disorder symptoms, after correc-tion for weight gain during pregnancy, gestational age, birth weight, maternal age and education [114]. The authors point out that dissecting the possible contributing mechanisms underlying such effects will be challenging – common genetic pathways may underlie obesity and poor mental health. Moreover, other fac-tors, such as maternal stress, which may impact caloric intake, as well as food selection, may influence subsequent offspring brain development [115]. Recent data from experiments in rats show that maternal stress during pregnancy increased the susceptibil-ity of offspring to diet-induced obesity [83]. This is a fertile area for further investigation, particularly given the possibility of environmental differences in maternal diet and behavior exerting effects on the epigenetic programming of behavior [116].

ConclusionThe developing fetus is influenced by the level of nutrition pro-vided in utero, during lactation and in the early post-weaning period. The obesity epidemic represents not only an immediate public-health threat, but it threatens future generations. A range of animal and human data demonstrate that maternal obesity increases the risk of offspring obesity. Differential effects of over-nutrition during gestation or lactation has led to the notion of critical windows during development, whereby programming of appetite circuits, adiposity and metabolic functions contribute to subsequent risk. Dissecting the relative contributions of neuro-endocrine adaptations during these windows, and the underlying mechanisms, is a priority.

Expert commentary Higher prepregnancy BMI is an emerging clinical issue. The developing fetus is influenced by the level of nutrition pro-vided in utero, during lactation and in the early postweaning period. Adequate leptin action appears necessary for optimal

development of appetite circuits, and leptin has other effects on neuro development. Determining the optimal postnatal leptin trajectory in human infants requires further research.

Approaches to minimize or reverse the consequences of early-life exposure to increased nutrition are of great therapeutic impor-tance. While we know that the early experience shapes later food-seeking behavior, one unanswered question is what is the critical window? Finally, it is important to keep in mind that current diet and lifestyle are critical determinants of overall risk, regardless of early-life events.

Five-year view While maternal obesity exerts a long-lasting impact on off-spring’s metabolic risk, the extent and mechanisms of its impact on appetite pathways remain to be elucidated. A critical remain-ing question is to identify the developmental windows during which suboptimal nutrition or psychosocial aspects exert their effects, in the hope of implementing advantageous environmen-tal conditions to minimize their consequences. Another major challenge will be to understand the epigenetic regulation of genes relevant to obesity.

AcknowledgementsThe author acknowledges the research contributions of staff and students in her laboratory: H Chen, MJ Hansen, J Maniam, SF Ng, JM Pavia, L Prior, S Rajia and E Velkoska.

Financial and competing interestsThis work was supported by a Project Grant of the National Health and Medical Research Council of Australia to MJ Morris (299875). The author has no other relevant affiliations or financial involvement with any organiza-tion or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Key issues

• The increasing prevalence of obesity suggests an inadequacy of mechanisms that regulate bodyweight to cope with environments that promote overconsumption of energy and discourage physical activity. The rapidity of the change also implicates factors other than genetic influences as being responsible.

• Maternal obesity and hyperglycemia during pregnancy can affect birth weight, insulin, leptin, glucose and lipids in the newborn. Both maternal obesity and a high birth weight predict an increased body mass index or obesity in offspring in later life. This association may in part reflect genetic but also environmental influences with persistent effects on offspring, termed programming.

• Modification of the epigenetic state and expression of key molecular determinants of hypothalamic function and various targets occurs following some exposures in early life and this mechanism may help mediate programming by maternal obesity.

• Much early experimental work focused on the impact of maternal undernutrition followed by catch-up growth induced by overfeeding. Recent work in rodents has examined the impact of dietary obesity and postnatal overfeeding on the metabolic profile of subsequent generations.

• Significant changes in the hypothalamic regulators of appetite are evident as early as birth in offspring of obese mothers.

• In rodents, both maternal obesity predating conception and early postnatal overnutrition lead to early-onset obesity and altered glucose metabolism and insulin sensitivity. This implies that independent of intrauterine influences, the early postnatal environment is crucial in the developmental programming of obesity.

• Mounting experimental evidence points to an additive detrimental impact of high-fat diet consumption after weaning in animals born of obese mothers. Deleterious effects of a high-fat diet during pregnancy on metabolic profile, adiposity and cardiac hypertrophy were enhanced by postnatal over consumption. Studies are needed to determine to what extent the effect of maternal and early nutritional changes persist.


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Websites

201 World Health Organization. Global database on body mass index (2007) www.who.int/bmi/index.jsp

202 World Health Organization. Childhood overweight and obesity www.who.int/dietphysicalactivity/childhood/en

Affiliation• Margaret J Morris

Department of Pharmacology, School of Medical Sciences, University of New South Wales, NSW 2052, Australia Tel.: +61 293 851 560 Fax: +61 293 851 059 [email protected]

early life influences on obesity risk: maternal overnutrition and programming of obesity

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