Developmental Origins of Obesity: Early Feeding Environments, Infant Growth

AMERICAN JOURNAL OF HUMAN BIOLOGY 24:350–360 (2012)

Original Research Article

Developmental Origins of Obesity: Early Feeding Environments, Infant Growth, and the Intestinal Microbiome AMANDA L. THOMPSON1,2* 1 Department of Anthropology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 2 Carolina Population Center, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina

Objectives: Pediatric overweight and obesity are growing problems worldwide, with increasing prevalence among even infants and young children. The refractory nature of early overweight necessitates identifying the factors contributing to early excess weight gain for successful intervention. Early feeding practices may be particularly important in shaping long-term vulnerability to obesity. How and what infants are fed can influence weight gain, adiposity, and energy metabolism during infancy and across the life course through a number of interacting physiological and behavioral pathways. This article argues that these biological mechanisms interact with the social and behavioral context of infant feeding to create differential vulnerability to later obesity.

Methods: This article reviews recent research on the potential mechanisms linking infant feeding and risk of later obesity, focusing on the emerging role of microflora colonization.

Results: The nutritive and non-nutritive components of breastmilk, formula and solid foods and the practices surrounding feeding shape the infant metabolome, programming growth rates and body composition, altering metabolism and physiology, promoting differential microfloral colonization, and shaping behavioral responses to foods and eating.

Conclusion: The occurrence of chronic disease precursors at increasingly younger ages and the tendency of overweight young children to become overweight adolescents and adults underscore the importance of understanding this complex early exposure and intervening early to prevent the development of obesity in increasingly weight-promoting environments. Am. J. Hum. Biol. 24:350–360, 2012. ' 2012 Wiley Periodicals, Inc.

INTRODUCTION Childhood obesity has become a major concern in both the developing and developed world. In the United States, the prevalence of obesity among children and adolescents has been doubled over the past 20 years, and recent data indicate that more than one-third of children aged 2–19 are overweight (body mass index (BMI) > 85th percentile) and over 10% are obese (BMI > 95th percentile; Ogden et al., 2006). Along with these alarming increases in rates of pediatric overweight, the age at which children are becoming overweight appears to be declining as well.

According to the most recently released figures from the Pediatric Nutrition Surveillance Study, a study of lowincome US infants and children (Polhamus et al., 2009), the prevalence of obesity among children aged 2–5 years increased from 12.2% in 1998 to 14.9% in 2007, while 11.3% of children under 1 year and 17.1% of children aged 12–23 months had weight-for-length z-scores (WLZ) above the 95th percentile. What makes these figures so alarming is that childhood obesity has the potential to become a lifelong health problem; over 50% of obese children and 70– 80% of obese adolescents will become obese adults with increased risk of developing cardiovascular and metabolic disorders (Dietz, 1998). The occurrence of obesity-related health problems at increasingly younger ages (Daniels, 2006) and the seemingly refractory nature of childhood obesity (Dietz, 1998) highlight the need to identify factors contributing to early excess weight gain.

While the proximate causes of pediatric obesity, like adult obesity, can typically be attributed to an imbalance in energy intake and expenditure, obesity is also clearly a multifactorial condition with a number of underlying biological, social, genetic, and environmental determinants.

C 2012 V

Wiley Periodicals, Inc.

Recent calls have been made to increase attention to how these factors interact to contribute to the variation in individual risk of obesity seen even within highly obesogenic environments (Cole, 2007; Dietz and Robinson, 2008) and to the developmental processes shaping this variability (Gluckman and Hanson, 2008). The importance of early life exposures in shaping long-term risk of obesity and the development of concomitant cardiometabolic disease is widely recognized within human biology and public health (Benyshek, 2007; Kuzawa and Quinn, 2009). A vast amount of epidemiological and experimental literature has documented that factors operating pre- and perinatally can alter the occurrence of chronic disease throughout the life course (Barker, 2004; Gillman, 2005). Several recent systematic reviews also underscore the importance of postnatal growth (Baird et al., 2005; Parsons et al., 1999). Infants at the highest end of the distribution for weight or BMI and those gaining weight most rapidly have an increased risk of obesity in childhood and adolescence (Baird et al., 2005), higher abdominal and whole body fat mass in adolescence (Ekelund et al., 2007) and adulthood (Demerath et al., 2009), and elevated levels of metabolic risk factors, including blood pressure, insulin, cholesterol, and triglycerides, even when controlling for current adiposity, birthweight, childhood growth patterns, and maternal characteristics (Ekelund et al., 2007). *Correspondence to: Amanda L. Thompson, 123 W. Franklin St, CB#8120, Chapel Hill, NC 27516, USA. E-mail: althomps@email.unc.edu Received 1 October 2011; Revision received 6 January 2012; Accepted 9 January 2012 DOI 10.1002/ajhb.22254 Published online 29 February 2012 in Wiley Online Library (wileyonlinelibrary. com).

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Fig. 1.

Physiological and behavioral pathways linking infant feeding, growth, and the development of pediatric obesity.

Since nutrition is a key factor in infant growth, the early feeding environment has also received increasing attention as an important exposure shaping later vulnerability to obesity (Anzman et al., 2010). Animal models, beginning with those of McCance in the 1960s, show that overfeeding in the post-natal period is associated with larger adult body size with pronounced effects in animals subsequently introduced to a ‘‘cafeteria’’ or ‘‘junk food’’ diet after weaning (McCance, 1962; Ozanne and Hales, 2004). More recently, epigenetic processes continuing after birth in response to feeding transitions have been identified (Waterland et al., 2006). In humans, numerous studies indicate that breastfeeding protects against the development of later obesity (Dewey, 2003; Dietz, 2001; Gillman et al., 2001; Owen et al., 2005). Although the magnitude of this protective effect differs by age of followup, study size, and study location, the consensus from reviews and meta-analyses is that breastfeeding provides a weak to moderate protection against later overweight, with an overall reduction in odds between 20 and 30% (Arenz et al., 2004; Harder et al., 2005; Owen et al., 2005).

Longer durations and exclusivity of breastfeeding enhance this effect in a dose–response manner (Harder et al., 2005) with the lowest risk seen among those breastfed longest without formula supplementation (Arenz et al., 2004). Although the timing of solid food introduction has a less consistent relationship with overweight in infancy or childhood (Moorcroft et al., 2011), supplementation before 4 months has been associated

with sixfold higher risk of obesity at age 3 (Huh et al., 2011) and significantly higher BMI z-scores at age 7 (Wilson et al., 1998) among formula-fed, but not breast-fed infants.

These differential effects of solid feeding in breast and formula fed infants highlight the limitations inherent in isolating the impact of any one component of the early feeding environment on later obesity risk. Like obesity, infant feeding is a complex, multifactorial behavior influenced by biological, environmental, and social context. A wide range of research demonstrates that both what and how infants are fed affects short-term growth and longterm risk for overweight (Bartok and Ventura, 2009). The early feeding environment, therefore, can influence later vulnerability to obesity through a number of interacting physiological and behavioral pathways. As shown in Figure 1 and discussed in the following sections, the nutritive and non-nutritive components of breastmilk, formula and solid foods and the practices surrounding feeding can program growth rates and body composition, alter metabolism and physiology, promote differential microfloral colonization, and shape behavioral responses to foods and eating. This article reviews recent research on the potential mechanisms linking infant feeding and risk of later obesity, focusing on the emerging role of microflora colonization, and argues that these biological mechanisms interact with the social and behavioral context of infant feeding to create differential vulnerability to later obesity.

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A.L. THOMPSON TABLE 1. Infant feeding and macronutrient intakes

Growth differences in breast and formula fed infants An important proximate mechanism linking early feeding to later obesity risk is feeding-related differences in growth rate and body composition. In industrialized countries, where infection and poor nutrition have less influence on infant growth, breast-fed infants gain weight more slowly than formula-fed infants (Dewey, 2001), and this slower pattern of growth may contribute to the protective effect of breastfeeding against subsequent overweight (Singhal and Lanigan, 2007). The magnitude and duration of growth differences between breast-fed and formula-fed infants differ considerably between studies due to different definitions of breastfeeding, timing of follow-up, and ability to control for confounding factors; nonetheless, nearly all studies have documented weight differences based on feeding type (Dewey, 2009). Formula-fed infants weigh more within the first weeks of life, gaining weight as breast-fed infants typically lose weight (Dewey, 1998; Dewey, 2001).

Weight-for-age z-scores (WAZ) in breast-fed infants follow a downward trajectory beginning around 2–3 months in comparison to the CDC/NCHS growth reference of mainly formula-fed infants (Kramer et al., 2004), indicating a relative deceleration in weight velocity. By the end of the first year, formula-fed infants in affluent countries are 400 g heavier than infants breast-fed for 9 months and 600–650 g heavier than infants breast-fed for 12 months (Dewey, 2001).

Along with these divergent weight gain trajectories, the type of tissue being deposited, lean or fat mass, with weight gain differs by feeding type as well. Though study results vary by method and ages of follow-up, breast-fed infants tend to be leaner with lower WLZ and adiposity, particularly during the second half of infancy when weight gains are lower (Dewey, 2001). Exclusively, breast-fed infants participating in the third National Health and Nutrition Examination Study (NHANES III), for example, had lower WLZ and mid-upper arm circumference from 8 to 11 months when compared with CDC/ NCHS reference infants (Hediger et al., 2000). Conversely, formula-fed infants in the Davis Area Research on Lactation in Infant Nutrition and Growth (DARLING) Study, had greater subcutaneous skinfold thickness from 9 months through the second year of life (Dewey et al., 1993).

Few studies have directly measured body composition, however, so the nature of early weight gain and its longterm effects on obesity risk remain controversial. It has been proposed that rapid weight gain among Western infants is more likely represent fat mass gain (Wells et al., 2007) and, consequently, be a risk factor for the development of later obesity (Karaolis-Danckert et al., 2006). Yet, the question of how feeding differences shape differing growth rates and body compositions remains unanswered.

Recent studies show that breastfeeding mediates the effect of weight gain on overweight (van Rossem et al., 2011) and fat mass (Karaolis-Danckert et al., 2007) in childhood, suggesting that the impact of early feeding be subtler than just differences in absolute size. The remaining sections explore potential mechanisms linking infant feeding to metabolic and physiological differences that may operate independently of or in conjunction with infant growth to contribute to differential vulnerability to later obesity.

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Feeding type Breastfeeding 3 months 6 months (with solids) 12 months (with solids) Formula feeding 3 months 6 months (with solids) 12 months (with solids)

Energya (kcal/day)

Proteina (g/day)

Fatb (g/day)

535 612 825

6.8 8.1 22.5

37

614 755 970

11.3 14.1 24.6

31

a

Heinig et al. (1993).

Measured at 4 months of age with no solids; Noble and Emmett (2006).

b

Feeding, macronutrients, and obesity Substrate differences between human milk and infant formula likely underlie some of the observed growth differences between breast- and formula-fed infants.

Breastmilk is lower in energy and protein and higher in fat than commercial formulas (Table 1; Worthington-Roberts, 1993). Further, unlike formula, breastmilk composition varies between mothers, over the course of lactation, and during feeds (Dettwyler, 1992), providing a mechanism through which infant energetic needs and feeding behaviors, such as frequency and duration of feeds, can directly influence weight gain during on-demand breastfeeding.

Energy. Differences in the volume consumed and the slightly higher energy density of formula contribute to a 15–23% higher total energy intake in formula-fed infants from 3 to 18 months (Heinig et al., 1993). Along with these differences in absolute intake, patterns of intake differ as well. Six-week-old formula-fed infants consume 20–30% higher volumes per feed and, by 4 months, eat fewer, larger meals and feed less frequently through the night (Sievers et al., 2002). Differences in intake persist after complementary foods are added to the diet (Dewey, 2009), suggesting that breast-fed infants better match intake to energy needs. Heinig et al. (1993) found that breastmilk intake declined when solid foods were added to the diet of breast-fed infants, so that energy intake did not differ between supplemented and exclusively breast-fed groups.

A similar effect was not seen in the formula-fed infants resulting in higher overall energy intakes with supplementation. In our Infant Care and Risk of Obesity Study, a prospective cohort study of the development of obesity among low-income, African-American infants from central North Carolina, supplementation of formula-fed infants with solids and juices contributed 200 kcal above estimated needs to daily energy intakes beginning as early as 3 months of age (Wasser et al., 2011), indicating that infants were not compensating for supplementation with lower formula intake.

The long-term impact of such seemingly small differences in energy intake may be obesogenic. Each additional 100 kcal/day consumed at 4 months was associated with 46% higher odds of overweight at 3 years and 25% higher odds at 5 years among children in UK (Ong et al., 2006).

Animal models suggest that early energy intakes in excess of requirements for growth and maintenance, such as those seen with formula feeding and early supplementation in human infants, increase adipocyte number and fat content, with lasting effects on body composition (Harvey et al., 2007).

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Protein. The higher protein content of formula – as much as 50–80% higher than in breastmilk – is hypothesized to drive many of the growth differences between breast- and formula-fed infants (Koletzko et al., 2009a). According this ‘‘early protein hypothesis,’’ higher protein intakes during formula and complementary feeding, when intake is two to four times higher than requirements, program more rapid growth and later obesity by enhancing insulin and insulin-like growth factor I (IGF-1) secretion. These higher levels would, in turn, enhance growth (Hoppe et al., 2004) by up-regulating adipogenesis and adipocyte differentiation (Hauner et al., 1989).

Limited epidemiological evidence supports these growth-enhancing effects of higher protein intakes. A recent multicenter European randomized control trial, however, found higher weight, weight-for-length, and BMI in infants receiving formula with 3 g protein/100 kcal when compared with those receiving formula with lower protein content (1.8 g protein/100 kcal) or breastmilk, holding the volume-consumed constant. The impact of these different protein levels, which were within the range of commercially available formulas, were seen within the first 6 months and persisted to 24 months (Koletzko et al., 2009b). Other longitudinal studies suggest that the protein levels encountered during complimentary feeding rather than during early milk feeding, may be the more important for programming body composition and hormonal response (Gunther et al., 2010).

Protein intake at 12 months, but not at 6 months, was associated with higher child BMI and %body fat at age 7 in a longitudinal study of German infants and children (Gunther et al., 2010). Interestingly, the type of protein consumed was also important and higher dairy protein was independently associated with a higher %body fat at age 7 (Gunther et al., 2007). Cows’ milk formula and cows’ milk were similarly associated with higher weight, length, and weight-for-length beginning in the third month of life in the PROBIT study from Belarus (Kramer et al., 2004).

These studies, along with research in older children linking milk intake to adolescent height (Wiley, 2005), suggest that higher dairy protein intakes may stimulate linear growth and adiposity.

Fat. Unlike the lower energy and protein levels seen in human milk, fat content is higher in human milk than in commercially available formulas and contains a different concentration of long-chain polyunsaturated fatty acids (LCPUFAs; Shahkhalili et al., 2011). The proportion of energy received from fat also changes dramatically during complementary feeding. Intakes decline from around 50% of total energy in breastmilk to 30–35% of total energy because of the partial replacement of higher fat breastmilk and formula with more carbohydrate-rich weaning foods, such as fruits, vegetables, and cereals (Capdevila et al., 1998). To date, epidemiological studies have not found a significant association between fat intake in infancy and early childhood and weight gain or BMI (Agostoni et al., 2008); however, experimental studies document a plausible mechanistic link between fat intake and body composition. Weaning diets with a low ratio of fat to carbohydrates led to greater adult fat mass in rats, particularly when weaned animals were transitioned to a high-fat adult diet (Shahkhalili et al., 2011). Other research suggests that the omega 6/omega 3 ratio of infant

formula stimulates adipocyte growth and differentiation (Ailhaud et al., 2006). In humans, higher levels of breastmilk LCPUFAs are associated with lower glucose levels in the skeletal muscle of breast-fed infants and reduced plasma levels of pro-inflammatory cytokines (Das, 2002).

This link between fatty acid profile and inflammation may be particularly important given the well-established links between systemic inflammation and the development of obesity and cardiometabolic disease (Dandona et al., 2004; Yudkin, 2007).

Together these differences in energy, protein and fat content of breastmilk, and formula and differences in feeding patterns could program later vulnerability to obesity by promoting higher energy and protein intakes and altering energy balance among formula-fed infants.

Higher basal insulin levels and prolonged insulin response accompany formula-feeding as early as the first week of life (Lucas et al., 1981), and the presence of similar patterns in 4-month-old formula-fed infants suggest that formula feeding is associated with some degree of insulin resistance (Lonnerdal and Havel, 2000). The higher energy and protein intakes associated with formula-feeding, therefore, may promote hyperinsulinemia and more rapid growth characterized by increased fat tissue relative to lean body mass. The long-term effects of this differential growth would be obesogenic as insulin-mediated glucose utilization shifts from skeletal muscle to adipose tissue (Manco et al., 2011). Conversely, lower fat intake during complementary feeding may predispose infants to increased vulnerability to high fat diets later in life through possible effects on inflammation (Das, 2002; Shahkhalili et al., 2011). While many of these effects may be subtle in infancy, their long-term impact, particularly for children exposed to obesogenic environments, could be considerable in environments with abundant energydense foods (Symonds, 2007).

Feeding, hormones, and obesity Unlike infant formula, breastmilk also contains hundreds of non-nutritive, bioactive components, many of which can influence short and long-term patterns of growth through their regulation of nutrient use and metabolism (Hamosh, 2001). The recent identification of adipokines and hormones in breastmilk, including leptin, ghrelin, and adiponectin, has led some researchers to propose that these hormones are involved in both the shortterm regulation of infant weight gain and the long-term programming of the neuroendocrine pathways involved in appetite regulation with downstream effects on later obesity risk (Table 2; Agostini, 2005; Savino et al., 2009b).

Research to date has predominantly focused on confirming the presence of these growth-regulating factors in breastmilk, comparing serum-levels in formula- and breast-fed infants and relating serum levels to infant growth (Bartok and Ventura, 2009); consequently, less is known about how these hormones may regulate infant growth or the long-term impacts of these differences for later obesity risk. Theoretically, these breastmilk-derived hormones could influence weight gain and program appetite by providing hunger and satiety cues to infants along with consumed milk.

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A.L. THOMPSON TABLE 2. Infant feeding and hormonesa

Hormone Leptin Ghrelin Adiponectin

Sources

Function

Adipose tissue, mammary gland, other sites Stomach, intestine, other sites Adipose tissue

Satiety signal, reduces food intake Hunger signal, stimulates GH secretion Improves insulin sensitivity, increases fatty acid metabolism, anti-inflammatory

Present in breastmilk

Differences with infant feeding

Association with infant growth

Yes

Higher in breastfed infants Higher in formula fed infants Higher in breast-fed infants

Inversely associated with BMIb Positively associated with weight and length gainc Inversely associated with WAZ and WLZd

Yes Yes

a

Modified from Savino et al. (2009a,b).

Savino et al. (2005).

James et al. (2004). d Newburg et al. (2010), Woo et al. (2009). b c

Leptin. Leptin, a hormone produced by fat tissue that acts as a satiety factor, is negatively associated with weight gain across infancy and early childhood (Dundar et al., 2005). Breastmilk-derived leptin may promote slower weight gain during breastfeeding by providing infants with a satiety signal. Leptin receptors have been found in the gastrointestinal epithelium and experimental models document that physiological levels of leptin can be absorbed through the stomach, down-regulating endogenous leptin production and reducing food intake in neonatal rats (Sanchez et al., 2005). Whether human milkderived leptin can similarly avoid digestion and influence infant bioactivity is the source of considerable debate (Gillman and Mantzoros, 2007; Savino et al., 2009a); however, breastmilk levels are positively associated with circulating maternal levels and infant plasma levels (Savino et al., 2009b), leading to higher infant serum levels in some (Savino et al., 2009b), but not all (Lonnerdal and Havel, 2000), studies. Leptin concentrations also vary with milk composition, and levels are higher in whole than skimmed human milk (Wagner et al., 2008). This association of leptin with milk fat may couple the energydensity of breastmilk to fullness cues, since infants would receive the signal most strongly when emptying the breast and consuming the high-fat hindmilk (Daly et al., 1993).

While caution is needed in interpreting these findings, since milk fat artificially elevates radioimmunoassay leptin levels and levels in skimmed samples may be too low to be physiologically active (Lonnerdal and Havel, 2000), this coupling of satiety signal and energy density could provide a mechanism linking on-demand breastfeeding to the neural programming of appetite with consequences for later energy regulation.

Ghrelin. Less is known about the physiological function of ghrelin, a hormone produced by the stomach that functions as a hunger signal, in programming obesity risk.

Ghrelin may influence acute and chronic energy balance by stimulating food intake and growth hormone secretion, thereby increasing body weight and promoting adipogenesis (Castaneda et al., 2010). Ghrelin concentrations in the breast increase during lactation and breastmilk levels are significantly associated with infant serum levels (Agostini, 2005). Ghrelin is upregulated during periods of rapid growth and is positively associated with weight and length gain in the first months of life (James et al., 2004).

This upregulation may promote increased appetite and greater energy intake facilitating adipose tissue deposition during early infancy. Ghrelin levels are also higher in American Journal of Human Biology

formula-fed infants and a positive association between circulating ghrelin and between-meal fasting times develops within the first 6 months of life (Savino et al., 2009b), potentially linking patterns of formula feeding to increased appetite.

Adiponectin. The function of breastmilk-derived adiponectin in postnatal growth is unclear (Weyermann et al., 2007). In children and adults, adiponectin is produced by adipose tissue and is inversely associated with fat mass, insulin sensitivity, and fatty acid metabolism leading to a protective effect against obesity and cardiometabolic disease (Yamauchi et al., 2001). Questions remain about the bioavailability of breastmilk-derived adiponectin (Gillman and Mantzoros, 2007), but preliminary research reveals its presence in breastmilk at high levels in a glycosylated form that may avoid proteolysis in the stomach and promote biological activity in the infant (Newburg et al., 2010). In cohort studies in the United States and Mexico (Newburg et al., 2010; Woo et al., 2009), higher concentrations of breastmilk adiponectin were associated with lower infant WAZ and WLZ across the first 6 months.

The association was stronger during the first 3 months leading researchers to propose that protective effects of adiponectin depend on the current ingestion of milk (Woo et al., 2009).

Hormonally mediated hunger and satiety cues such as those provided by leptin, ghrelin, and adiponectin may be critical in programming of appetite regulation in response to infant diet and feeding patterns. Rapid infant growth and the macronutrients that promote, or at least support, it also appear to influence appetite regulation, since low birth weight and/or rapid infant growth both upregulate appetite (Cole, 2007; Drewett and Amatayakul, 1999).

Feeding differences and energy intake in particular may entrain the hypothalamic neural circuitry regulating appetite by inducing permanent changes in the complex pathway linking the hypothalamus, gastrointestinal tract, and adipose tissues (Agostini, 2005). The presence of hormonal differences between breast- and formula-fed infants provides evidence that feeding type has a metabolic effect in infants; however, it is still unknown whether these differences represent a cause or an effect of increased energy intake (Dewey, 2009). Growth differences and differential vulnerability to later obesity between breast- and formula-fed infants, therefore, might result from different endocrine responses to feeding or from exposure to the bioactive substances in breastmilk that

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subsequently influence energy intake and metabolism (Agostini, 2005).

Feeding, intestinal microflora, and obesity Along with its nutritive and hormonal content, the composition of the early diet also shapes differential bacterial colonization of the intestine during development. Established early in life and relatively stable once established, this complex microbiome, containing 1010 to 1011 bacterial cells of several hundreds of different species in combinations that are distinct even between monozygotic twins (Palmer et al., 2007; Turnbaugh et al., 2006), has received extensive attention over the past decade. Emerging evidence suggests that development of the intestinal microbiome is a critical pathway linking early environments and diet to later obesity risk and cardiometabolic disease (Edwards and Parrett, 2002). The gut microflora play an important role in host energy balance through a number of intertwined metabolic pathways (Backhed, 2010), including the processing of indigestible polysaccharides into simple sugars and short-chain fatty acids (Guarner and Malagelada, 2003). Since bacteria differ in their energy extracting capabilities (Blaut and Clavel, 2007; Cani and Delzenne, 2007), colonization patterns can influence infant growth and also long-term energy absorption and adipose development.

Human, and mammalian infants more generally, are born with sterile intestines, which undergo rapid colonization through exposure to the neonatal environment, including type of birth (vaginal or Caesarian), hygiene measures, and early feeding practices (Guarner and Malagelada, 2003). Exposure to maternal vaginal and fecal microbiota drives initial colonization (Edwards and Parrett, 2002), and changes in maternal bacteria with pregnancy weight gain can influence early infant colonization (Vael and Desager, 2009). In their prospective study, Collado et al. (2008) found that women who were overweight prior to pregnancy or who gained excess weight during pregnancy had higher levels of Bacteroides and Prevotella.

The prevalence of these bacteria types were higher in their children at 1 and 6 months of age (Collado et al., 2010), providing evidence for the inter-generational transmission of weight-promoting bacteria with colonization that persists at least through early infancy.

Microflora establishment is particularly responsive to the early feeding exposures, including the type of milk (breastmilk or formula) consumed and the introduction of solid foods (Edwards and Parrett, 2002; Guarner and Malagelada, 2003; Orrhage and Nord, 1999; Palmer et al., 2007). Breast-fed infants are traditionally characterized as having less diverse colonization and greater proportions of Bifidobacteria and Lactobacillus; formula-fed infants, on the other hand, have a more complex microbiota with greater proportions of Bacteroides, Clostridium, and Enterobacteria (Marques et al., 2010; Orrhage and Nord, 1999; Vael and Desager, 2009). These differences, shown in Table 3, have been attributed to the bioactive and dietary components of breastmilk, which acts as a source of bacteria (Marques et al., 2010) and promotes the growth of beneficial microbes (Chierici et al., 2003).

Breastmilk from healthy mothers provides a continuous source of bacteria and contains 109 microbes/l from different bacterial groups including Staphylococcus, Streptococcus, Bifidobacteria, and lactic acid bacteria (Marques

TABLE 3. Major bacteria types associated with infant feeding typesa Feeding type Breastfeeding (BF) Formula-feeding (FF) BF 1 solids FF 1 solids Weaned infants

Predominant colonies Bifidobacteria and Lactobacillusb >Staphylococcus and Lactobacillus rhamnosus Bifidobacteria and Lactobacillusc >Clostridium, Bacteroides, Enterobacteria, and Enterococcus 5Enterobacteria and Bifidobacteriad >Enterococcus and Bacteroides Fewer changese Adult-like > 400 species

a

Modified from (Orrhage and Nord, 1999).

Compared to FF. Compared to BF. d Compared to BF only. e Compared to FF only. b c

et al., 2010). Breastmilk oligosaccharides further promote the growth of beneficial microbiota, particularly Bifidobacteria. Studies since the 1980s have found fewer consistent differences between breast- and formula-fed infants in Bifidobacteria and Lactobacillus, and it is unknown whether this is due to different analytic techniques or to the recent inclusion of prebiotics in formula that more closely mimic human milk (Marques et al., 2010; Satokari et al., 2002). Nonetheless, Bifidobacteria – which are positively associated with improved glucose tolerance and inversely associated with weight gain and inflammation (Backhed, 2010) – are over-represented in breast-fed infants when compared with adults (Zivkovic et al., 2011).

Bacterial concentrations undergo additional change in both breast- and formula-fed infants as solids foods are introduced into the diet (Amarri et al., 2006; Nielsen et al., 2007). During weaning, infants are first exposed to many non-digestible plant carbohydrates, which then enter the colon and influence microfloral colonization by producing new substrates for the survival and dominance of species not supported by breastmilk and/or formula (Fallani et al., 2011; Parrett and Edwards, 1997). Mice show a dramatic shift in microbial ecology as a high-fat milk diet is replaced by a carbohydrate-rich weaning diet and this shift is accompanied by an increase in the metabolic capacity of the small intestine (Reinhardt et al., 2009). Although few studies have examined the dynamics of microflora colonization during early weaning in human infants or among infants who are fed with both breastmilk and formula, the establishment of a more adult-like microflora follows the transition to solid foods. A recent comparison of infants from five different European sites revealed that, while infant microfloral composition changed within 1 month of the introduction of solid foods, pre-weaning feeding type had a persistent effect on colonization (Fallani et al., 2011), indicating that this process may be more gradual than previously thought.

Few data exist on the association between early microbiome development and later risk of obesity; however, the composition of the intestinal microbiome, in particular, the relative proportion of Firmicutes to Bacteroides-type bacteria, is associated with obesity in both animal models and adult human studies. Obese mice have 50% lower levels of Bacteroides and correspondingly higher levels of Firmicutes than their lean counterparts (Ley et al., 2005).

Similarly, obese adults have more Firmicutes and fewer Bacteroides than lean controls and weight-disparate twin pairs have different phyla proportions (Turnbaugh and American Journal of Human Biology

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Gordon, 2009). The proportion of Bacteroides increases with weight loss, suggesting that bacterial type may be mechanistically related to body weight regulation. Causality between bacteria and weight changes is supported by germ-free rodent studies. Gut microbiota transfer from obese mice to germ-free mice resulted in higher weight gain when compared with genetically identical mice receiving gut microbiota from lean mice (Backhed et al., 2007). Weight gain in these animals resulted from increased energy extraction from plant-derived polysaccharides and the upregulation of carbohydrate and lipidutilizing genes in the microbiome, providing 10% additional energy to the host (Ley, 2010).

Preliminary evidence suggests that the composition of the microbiome may be similarly associated with weight gain and adipose deposition in infancy. A single prospective study of the association of infant colonization and later risk of obesity suggests that early microfloral differences precede the development of obesity. In their study of Belgian infants, Vael et al. (2011) found that BMI z-scores between 1 and 3 years old were positively associated with levels of Bacteroides at 3 and 52 weeks of age and negatively with Staphylococcus at 3 and 26 weeks of age, controlling for infant feeding and a number of other risk factors for higher BMI. Overweight incidence in 7-year-old children was related to differences in microbiota at 6 and 12 months of age in a recent study (Kalliomaki et al., 2008). The overweight children, however, already had greater BMI at 6 and 12 months, indicating a need for further analysis of the temporal relationship between intestinal bacteria development and body size in infancy. Preliminary data analysis from our longitudinal study of infant feeding, microflora development, and infant growth over the first 15 months of life in mainly breast-fed, US infants (Thompson et al., 2011) has identified phyla-level changes in bacterial colonization with feeding transitions. The proportion of Firmicutes-type bacteria increased with both the cessation of breastfeeding and the introduction of formula. Higher proportions of Firmicutes were associated with subsequently greater weight gain and higher adiposity, potentially linking changes in early feeding to later obesity risk.

While still a new and rapidly emerging field, studies of the developmental microbial ecology indicate that postnatal conditions, and the early feeding environment in particular, affect the dynamics of bacterial acquisition and microbiome maturation. Diet is a key determinant of microfloral colonization, providing nutrients for the maintenance and growth of commensal bacterial communities and acting as a selective factor for differential bacterial colonization (Blaut and Clavel, 2007). High fat or carbohydrate diets, for example, modulate dominant microflora populations in the gut, with downstream effects on inflammation and the development of insulin resistance and type 2-diabetes (Cani and Delzenne, 2007). Alterations in the gut flora associated with feeding patterns, therefore, may influence the absorption and storage of energy, linking the nutritive content and bioactive composition of early feeding to infant weight gain and long-term vulnerability to obesity.

Socioenviroments, feeding behavior, and obesity Interacting with these biological correlates of feeding type, milk composition and delivery mode, socioenvironmental factors shaping feeding practices, and the behavAmerican Journal of Human Biology

iors surrounding feeding further influence long-term vulnerability to obesity by shaping eating behaviors and responses to satiety cues. Although presented separately, infant feeding is inherently a biological and behavioral practice, and a large number of confounding factors, including maternal weight status, education, socioeconomic status, maternal smoking, sleep duration, physical activity and television viewing, can influence child growth and weight status independently of or interactively with infant feeding (Bartok and Ventura, 2009).

Disentangling the physiological effects of breast, formula, or complementary feeding is difficult and requires control of confounding variables that are not always present or complete (Butte, 2009). Retrospective studies often rely on maternal recall of infant feeding practices and have limited ability to control for factors associated with both feeding and the development of overweight (Adair, 2008). In industrialized countries, for example, mothers who breastfeed tend to be more educated, wealthier, older, and have more social support (Hendricks et al., 2006), characteristics that are also associated with healthier lifestyles, higher levels of physical activity, and better diets (Dietz, 2001). Further, these mothers may be more aware of the risks of obesity and may try to limit the amount of formula and types of foods given to their infants (Kramer et al., 2002). Conversely, overweight mothers are substantially more likely to have children who are overweight (Dietz, 2001) and are also less likely to breastfed (Li et al., 2005) partly due to physiological challenges in initiating breastfeeding. Higher maternal pre-pregnancy BMI is associated with delayed onset of milk production and failure to establish lactation before hospital discharge, a risk factor for shorter breastfeeding duration (Rasmussen et al., 2001). Such differences in maternal and environmental characteristics, therefore, could mask or enhance a biological association between feeding and the development of obesity.

The decision to breastfeed and the continuation of breastfeeding are inherently markers of multivalent cultural, lifestyle, and environmental characteristics, all of which can vary by location, cultural context, and individual mother–infant dyads. Yet, caregiver decisions shape the early feeding environment beyond just the decision to breast or formula feed. Caregivers regulate the frequency of feeding and the types and amounts of food offered to infants and young children (Adair, 2008; Birch and Davison, 2001) and model patterns of eating (Savage et al., 2007). Children’s preferences and dietary intake largely reflect the foods that become familiar to them (Savage et al., 2007). Consequently, the transition to solid feeding represents a salient period for shaping later eating behaviors. Breastfeeding shapes this later food acceptance by exposing infants to the flavors of mothers’ diets and serving as a ‘‘flavor bridge’’ between a milk-based diet and a more adult-like diet (Mennella and Beauchamp, 1996; Taveras et al., 2004). Food acceptance is higher in breast-fed infants, particularly for foods like vegetables that are not normally accepted flavors (Sullivan and Birch, 1994). Food neophobia, preference for a single preparation type and food rejection are lower among pre-school children who were exclusively breast-fed, while earlier complimentary feeding before 6 months was associated 2.5 higher risk of neophobia (Shim et al., 2011).

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Maternal diet quality also shapes food acceptance and child diet patterns both positively and negatively. Fruit and vegetable intakes are higher among infants and young children whose mothers eat more fruits and vegetables (Hart et al., 2010) while infants whose mothers have ‘‘poor’’ diet quality (do not eat breakfast and have fewer than one serving of fruits, vegetables, or dairy per day) are more likely to be given solid foods early and to be fed inappropriate quantities of foods (Lee et al., 2005). Since the presence and accessibility of fruits and vegetables or snack foods (Hart et al., 2010) appear to influence intake, differences in early food environments and feeding may both promote adiposity during infancy and also shape long-term preferences for energy-dense foods, a risk factor for the development of obesity in a nutrient-rich environment (Drewnowski, 2004).

The interaction between physiological and behavioral characteristics of the early feeding environment can be seen in the development of self-regulation and responsivity to satiety cues. Both breast- and formula-fed infants appear to be able to alter their daily intake in response to fat content and energy density of milk (Dewey, 2009); however, parental feeding practices can override these internal cues. Formula-fed infants, for example, consume more in response to bottle size and mothers’ bottle-feeding behaviors. The use of larger bottles at 3 months has been associated with greater infant energy intake and higher weight gain from 3 to 5 months of age, and the practice of emptying the bottle has been associated with larger subcutaneous skinfolds at 5 months of age (Dewey, 2009).

Controlling feeding styles, such as pressuring infants to finish a bottle or restricting children’s access to preferred foods, promote over-eating and poor self-regulation (Fisher and Birch, 1999). Maternal control of feeding at 6 months influenced rates of weight gain between 6 and 12 months in British infants (Farrow and Blissett, 2006) while parental encouragement to eat was associated with higher WAZ in 12–30 month old children (Klesges et al., 1983).

Breastfeeding promotes a more responsive maternal feeding style and allows infants more control over feeding volume and cessation (Fisher et al., 2000). Exclusive breastfeeding for 6 months is associated with lower levels of restriction in later infancy (Taveras et al., 2004) and breastfeeding for 12 months with lower levels of control at 18 months (Fisher et al., 2000). Lower levels of maternal control allow infants to self-regulate their intake in response to hunger and satiety. Birch and Fisher (1998) found that children who were breast-fed as infants were better able to adjust their intake at meals in response to a high-calorie preload, suggesting that breast-fed infants were better able to judge satiety signals. This learned selfregulation – along with exposure to energy-regulating hormones within breastmilk and the establishment of a healthy gut microbiome – might have long-term effects on eating behavior, linking breastfeeding to reduced rates of obesity in childhood and later adolescence (Agras et al., 1990; Fisher et al., 2000).

CONCLUSION AND FUTURE DIRECTIONS As summarized in Figure 1, the early feeding environment may influence the long-term development of obesity and cardiometabolic disease through a number of interrelated pathways. The epidemiological and experimental

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research outlined above suggests that differences in food composition and feeding behavior interact with physiological, neurohormonal, and microbiological factors to shape infant growth, body composition, appetite, and energy metabolism (Haemer et al., 2009). The lower levels of energy and protein and higher levels of fat in human milk may directly influence obesity risk by slowing weight gain and reducing adiposity. Conversely, the higher energy and protein intakes of formula- and complementary-fed infants may drive more rapid weight gain, greater fat deposition, and reduced insulin sensitivity through the upregulation of insulin and IGF-1 (Koletzko et al., 2009a). Hormonal mediators, provided by breastmilk or endogenously produced in response to the differing energy, protein and fat intakes of breastmilk, formula, and complementary foods, may shape long-term obesity risk by entraining the infant metabolome, linking food intake, adipose tissue deposition, and the developing hypothalamus to program appetite and energy utilization (Agostini, 2005). The intestinal microbiome established in response to early feeding may alter energy metabolism and body composition by determining the amount of energy that can be extracted from the diet. Formula and early complementary feeding may influence the development of obesity by promoting the establishment of microflora better able to extract more utilizable energy from carbohydrate- and fat-rich diets.

These nutritive and non-nutritive components of early diets further interact with the socioenvironmental conditions influencing infant feeding decisions and the attitudes and practices surrounding feeding. The foods available in the early feeding environment may shape long-term eating patterns while parental feeding styles may enhance or suppress infants’ ability to self-regulate intake in response to energetic needs for growth and activity. Together these nutritive, hormonal, microbiological, social, and behavioral exposures interact to shape longterm vulnerability to obesity through their overt effects on infant growth rates and their more subtle, and potentially more long-lasting, impacts on appetite, energy utilization, and eating behaviors.

Given this complexity, it is not surprising that studies examining one aspect of feeding, such as breastfeeding duration, have not found strong associations with later obesity risk. Nonetheless, substantial evidence points to the importance of the early feeding environment in shaping the physiological, metabolic, and behavioral pathways leading to the development of child and adolescent obesity.

Developmental cues received through even subtle behavioral and physiological feeding experiences may create sensitivity to later conditions, influencing appetite, food intake, and metabolic partitioning (Gluckman and Hanson, 2008) and creating vulnerability to obesity as children grow up in increasingly weight-promoting environments (Adair, 2008). Further research is needed to more fully understand the maternal-infant, household, and community factors shaping the development of an obesityvulnerable physiology. In particular, greater attention has to be paid to the impacts of mixed feeding and early complementary feeding, two common and understudied feeding practices, on infant macronutrient intakes and hormonal development. Longitudinal examination of early feeding behaviors and their physiological sequelae will permit researchers to better assess the causal relationship between feeding and obesity, controlling for the bi-directionality inherent in maternal-infant feeding practices American Journal of Human Biology

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and the important mediating effects of sociocultural and behavioral factors. This clearer understanding of the impact of early feeding on the physiological and behavioral regulation of eating behaviors and energy metabolism is critical for intervening early to prevent the development of obesity and concomitant cardiometabolic disease.

LITERATURE CITED Adair LS. 2008. Child and adolescent obesity: epidemiology and developmental perspectives. Physiol Behav 94:8–16.

Agostini C. 2005. Ghrelin, leptin and the neurometabolic axis of breastfed and formula-fed infants. Acta Paediatr Suppl 94:523–525.

Agostoni C, Decsi T, Fewtrell M, Goulet O, Kolacek S, Koletzko B, Michaelsen KF, Moreno L, Puntis J, Rigo J, Shamir R, Szajewska H, Turck D, van Goudoever J. 2008. Complementary feeding: a commentary by the ESPGHAN committee on nutrition. J Pediatr Gastroenterol Nutr 46:99– 110.

Agras WS, Kraemer HC, Berkowitz RI, Hammer LD. 1990. Influence of early feeding style on adiposity at 6 years of age. J Pediatr 116:805–809.

Ailhaud G, Massiera F, Weill P, Legrand P, Alessandri JM, Guesnet P. 2006. Temporal changes in dietary fats: role of n-6 polyunsaturated fatty acids in excessive adipose tissue development and relationship to obesity. Prog Lipid Res 45:203–236.

Amarri S, Benatti F, Callegari ML, Shahkhalili Y, Chauffard F, Rochat F, Acheson KJ, Hager C, Benyacoub J, Galli E, Rebecchi A, Morelli L. 2006. Changes of gut microbiota and immune markers during the complementary feeding period in healthy breast-fed infants. J Pediatr Gastroenterol Nutr 42:488–495.

Anzman SL, Rollins BY, Birch LL. 2010. Parental influence on children’s early eating environments and obesity risk: implications for prevention.

Int J Obes (Lond) 34:1116–1124.

Arenz S, Ruckerl R, Koletzko B, von Kries R. 2004. Breast-feeding and childhood obesity – a systematic review. Int J Obes Relat Metab Disord 28:1247–1256.

Backhed F. 2010. 99th Dahlem conference on infection, inflammation and chronic inflammatory disorders: the normal gut microbiota in health and disease. Clin Exp Immunol 160:80–84.

Backhed F, Manchester JK, Semenkovich CF, Gordon JI. 2007. Mechanisms underlying the resistance to diet-induced obesity in germ-free mice. Proc Natl Acad Sci U S A 104:979–984.

Baird J, Fisher D, Lucas P, Kleijnen J, Roberts H, Law C. 2005. Being big or growing fast: systematic review of size and growth in infancy and later obesity. BMJ 331:929.

Barker DJ. 2004. Developmental origins of adult health and disease. J Epidemiol Community Health 58:114–115.

Bartok CJ, Ventura AK. 2009. Mechanisms underlying the association between breastfeeding and obesity. Int J Pediatr Obes 4:196–204.

Benyshek DC. 2007. The developmental origins of obesity and related health disorders – prenatal and perinatal factors. Coll Antropol 31:11–17.

Birch LL, Davison KK. 2001. Family environmental factors influencing the developing behavioral controls of food intake and childhood overweight.

Pediatr Clin North Am 48:893–907.

Birch LL, Fisher JO. 1998. Development of eating behaviors among children and adolescents. Pediatrics 101(3 Pt 2):539–549.

Blaut M, Clavel T. 2007. Metabolic diversity of the intestinal microbiota: implications for health and disease. J Nutr 137(3 Suppl 2):751S–755S. Butte NF. 2009. Impact of infant feeding practices on childhood obesity.

J Nutr 139:412S–416S. Cani PD, Delzenne NM. 2007. Gut microflora as a target for energy and metabolic homeostasis. Curr Opin Clin Nutr Metab Care 10:729–734.

Capdevila F, Vizmanos B, Marti-Henneberg C. 1998. Implications of the weaning pattern on macronutrient intake, food volume and energy density in non-breastfed infants during the first year of life. J Am Coll Nutr 17:256–262.

Castaneda TR, Tong J, Datta R, Culer M, Tschop MH. 2010. Ghrelin the regulation of body weight and metabolism. Front Neuroendocrinol 31:44–60.

Chierici R, Fanaro S, Saccomandi D, Vigi V. 2003. Advances in the modulation of the microbial ecology of the gut in early infancy. Acta Paediatr Suppl 91:56–63.

Cole TJ. 2007. Early causes of child obesity and implications for prevention. Acta Paediatr Suppl 96:2–4.

Collado MC, Isolauri E, Laitinen K, Salminen S. 2008. Distinct composition of gut microbiota during pregnancy in overweight and normalweight women. Am J Clin Nutr 88:894–899.

Collado MC, Isolauri E, Laitinen K, Salminen S. 2010. Effect of mother’s weight on infant’s microbiota acquisition, composition, and activity dur-

American Journal of Human Biology

ing early infancy: a prospective follow-up study initiated in early pregnancy. Am J Clin Nutr 92:1023–1030.

Daly SE, Di Rosso A, Owens RA, Hartmann PE. 1993. Degree of breast emptying explains changes in the fat content, but not fatty acid composition, of human milk. Exp Physiol 78:741–755.

Dandona P, Aljada A, Bandyopadhyay A. 2004. Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 25:4–7.

Daniels SR. 2006. The consequences of childhood overweight and obesity.

Future Child 16:47–67.

Das UN. 2002. The lipids that matter from infant nutrition to insulin resistance. Prostaglandins Leukot Essent Fatty Acids 67:1–12.

Demerath EW, Reed D, Choh AC, Soloway L, Lee M, Czerwinski SA, Chumlea WC, Siervogel RM, Towne B. 2009. Rapid postnatal weight gain and visceral adiposity in adulthood: the Fels Longitudinal Study.

Obesity (Silver Spring) 17:2060–2066.

Dettwyler KA. 1992. Infant feeding practices and growth. Annu Rev Anthropol 21:171–204.

Dewey KG. 1998. Growth characteristics of breast-fed compared to formula-fed infants. Biol Neonate 74:94–105.

Dewey KG. 2001. Nutrition, growth and compelmentary feeding of the breastfed infant. Pediatr Clin North Am 48:87–104.

Dewey KG. 2003. Is breastfeeding protective against child obesity? J Hum Lact 19:9–18.

Dewey KG. 2009. Infant feeding and growth In: Goldberg GR, Prentice AM, Prentice A, Filteau S, Simondon K, editors. Breast-feeding: early influences on later health (Advances in experimental medicine and biology). New York: Springer.

Dewey KG, Heinig MJ, Nommsen LA, Peerson JM, Lonnerdal B. 1993.

Breast-fed infants are leaner than formula-fed infants at 1 y of age: the DARLING study. Am J Clin Nutr 57:140–145.

Dietz WH. 1998. Childhood weight affects adult morbidity and mortality.

J Nutr 128(2 Suppl):411S–414S. Dietz WH. 2001. Breastfeeding may help prevent childhood overweight.

JAMA 285:2506–2507.

Dietz WH, Robinson TN. 2008. What can we do to control childhood obesity? Ann Am Acad Pol Soc Sci 615:222.

Drewett RF, Amatayakul K. 1999. Energy intake, appetite and body mass in infancy. Early Hum Dev 56:75–82.

Drewnowski A. 2004. Obesity and the food environment: dietary energy density and diet costs. Am J Prev Med 27:154–162.

Dundar NO, Anal O, Dundar B, Ozkan H, Caliskan S, Buyukgebiz A. 2005. Longitudinal investigation of the relationship between breast milk leptin levels and growth in breast-fed infants. J Pediatr Endocrinol Metab 18:181–187.

Edwards CA, Parrett AM. 2002. Intestinal flora during the first months of life: new perspectives. Br J Nutr 88(Suppl 1):S11–S18.

Ekelund U, Ong KK, Linne Y, Neovius M, Brage S, Dunger DB, Wareham NJ, Rossner S. 2007. Association of weight gain in infancy and early childhood with metabolic risk in young adults. J Clin Endocrinol Metab 92:98–103.

Fallani M, Amarri S, Uusijarvi A, Adam R, Khanna S, Aguilera M, Gil A, Vieites JM, Norin E, Young D, et al. 2011. Determinants of the human infant intestinal microbiota after the introduction of first complementary foods in infant samples from five European centres. Microbiology 157(Part 5):1385–1392.

Farrow C, Blissett J. 2006. Does maternal control during feeding moderate early infant weight gain? Pediatrics 118:e293–e298.

Fisher JO, Birch LL. 1999. Restricting access to foods and children’s eating. Appetite 32:405–419.

Fisher JO, Birch LL, Smiciklas-Wright H, Picciano MF. 2000. Breast-feeding through the first year predicts maternal control in feeding and subsequent toddler energy intakes. J Am Diet Assoc 100:641–646.

Gillman MW. 2005. Developmental origins of health and disease. N Engl J Med 353:1848–1850.

Gillman MW, Mantzoros CS. 2007. Breast-feeding, adipokines, and childhood obesity. Epidemiology 18:730–732.

Gillman MW, Rifas-Shiman SL, Camargo CA Jr, Berkey CS, Frazier AL, Rockett HR, Field AE, Colditz GA. 2001. Risk of overweight among adolescents who were breastfed as infants. JAMA 285:2461–2467.

Gluckman PD, Hanson MA. 2008. Developmental and epigenetic pathways to obesity: an evolutionary-developmental perspective. Int J Obes (Lond) 32(Suppl 7):S62–S71.

Guarner F, Malagelada JR. 2003. Gut flora in health and disease. Lancet 361:512–519.

Gunther AL, Karaolis-Danckert N, Kroke A, Remer T, Buyken AE. 2010.

Dietary protein intake throughout childhood is associated with the timing of puberty. J Nutr 140:565–571.

Gunther AL, Remer T, Kroke A, Buyken AE. 2007. Early protein intake and later obesity risk: which protein sources at which time points throughout infancy and childhood are important for body mass index and body fat percentage at 7 y of age? Am J Clin Nutr 86:1765–1772.

INFANT FEEDING AND THE DEVELOPMENT OF OBESITY Haemer M, Huang T, Daniels SR. 2009. The effect of neurohormonal factors, epigenetic factors, and gut microbiota on the risk of obesity. Prev Chronic Dis 6:1–8.

Hamosh M. 2001. Bioactive factors in human milk. Pediatr Clin North Am 48:69–86.

Harder T, Bergmann R, Kallischnigg G, Plagemann A. 2005. Duration of breastfeeding and risk of overweight: a meta-analysis. Am J Epidemiol 162:397–403.

Hart CN, Raynor HA, Jelalian E, Drotar D. 2010. The association of maternal food intake and infants’ and toddlers’ food intake. Child Care Health Dev 36:396–403.

Harvey NC, Poole JR, Javaid MK, Dennison EM, Robinson S, Inskip HM, Godfrey KM, Cooper C, Sayer AA. 2007. Parental determinants of neonatal body composition. J Clin Endocrinol Metab 92:523–526.

Hauner H, Wabitsch M, Zwiauer K, Widhalm K, Pfeiffer EF. 1989. Adipogenic activity in sera from obese children before and after weight reduction. Am J Clin Nutr 50:63–67.

Hediger ML, Overpeck MD, Ruan WJ, Troendle JF. 2000. Early infant feeding and growth status of US-born infants and children aged 4-71 mo: analyses from the third National Health and Nutrition Examination Survey, 1988-1994. Am J Clin Nutr 72:159–167.

Heinig MJ, Nommsen LA, Peerson JM, Lonnerdal B, Dewey KG. 1993.

Intake and growth of breast-fed and formula-fed infants in relation to the timing of introduction of complementary foods: the DARLING study.

Davis Area Research on Lactation, Infant Nutrition and Growth. Acta Paediatr Suppl 82:999–1006.

Hendricks K, Briefel R, Novak T, Ziegler P. 2006. Maternal and child characteristics associated with infant and toddler feeding practices. J Am Diet Assoc 106(1 Suppl 1):S135–S148.

Hoppe C, Udam TR, Lauritzen L, Molgaard C, Juul A, Michaelsen KF. 2004.

Animal protein intake, serum insulin-like growth factor I, and growth in healthy 2.5-y-old Danish children. Am J Clin Nutr 80:447–452.

Huh SY, Rifas-Shiman SL, Taveras EM, Oken E, Gillman MW. 2011. Timing of solid food introduction and risk of obesity in preschool-aged children. Pediatrics 127:e544–e551.

James RJ, Drewett RF, Cheetham TD. 2004. Low cord ghrelin levels in term infants are associated with slow weight gain over the first 3 months of life. J Clin Endocrinol Metab 89:3847–3850.

Kalliomaki M, Collado MC, Salminen S, Isolauri E. 2008. Early differences in fecal microbiota composition in children may predict overweight. Am J Clin Nutr 87:534–538.

Karaolis-Danckert N, Buyken AE, Bolzenius K, Perim de Faria C, Lentze MJ, Kroke A. 2006. Rapid growth among term children whose birth weight was appropriate for gestational age has a longer lasting effect on body fat percentage than on body mass index. Am J Clin Nutr 84:1449.

Karaolis-Danckert N, Gunther AL, Kroke A, Hornberg C, Buyken AE. 2007. How early dietary factors modify the effect of rapid weight gain in infancy on subsequent body-composition development in term children whose birth weight was appropriate for gestational age. Am J Clin Nutr 86:1700–1708.

Klesges RC, Coates TJ, Brown G, Sturgeon-Tillisch J, MoldenhauerKlesges LM, Holzer B, Woolfrey J, Vollmer J. 1983. Parental influences on children’s eating behavior and relative weight. J Appl Behav Anal 16:371–378.

Koletzko B, von Kries R, Closa R, Escribano J, Scaglioni S, Giovannini M, Beyer J, Demmelmair H, Gruszfeld D, Dobrzanska A, Sengier A, Langhendries JP, Rolland Cachera MF, Grote V. 2009a. Can infant feeding choices modulate later obesity risk? Am J Clin Nutr 89: 1502S–1508S. Koletzko B, von Kries R, Closa R, Escribano J, Scaglioni S, Giovannini M, Beyer J, Demmelmair H, Gruszfeld D, Dobrzanska A, Sengier A, Langhendries JP, Cachera MF, Grote V. 2009b. Lower protein in infant formula is associated with lower weight up to age 2 y: a randomized clinical trial. Am J Clin Nutr 89:1836–1845.

Kramer MS, Guo T, Platt RW, Shapiro S, Collet JP, Chalmers B, Hodnett E, Sevkovskaya Z, Dzikovich I, Vanilovich I. 2002. Breastfeeding and infant growth: biology or bias? Pediatrics 110(2 Pt 1):343–347.

Kramer MS, Guo T, Platt RW, Vanilovich I, Sevkovskaya Z, Dzikovich I, Michaelsen KF, Dewey K. 2004. Feeding effects on growth during infancy. J Pediatr 145:600–605.

Kuzawa CW, Quinn EA. 2009. Developmental origins of adult function and health: evolutionary hypotheses. Annu Rev Anthropol 38:131–147.

Lee SY, Hoerr SL, Schiffman RF. 2005. Screening for infants’ and toddlers’ dietary quality through maternal diet. MCN Am J Matern Child Nurs 30:60–66.

Ley RE. 2010. Obesity and the human microbiome. Curr Opin Gastroenterol 26:5–11.

Ley RE, Backhed F, Turnbaugh P, Lozupone CA, Knight RD, Gordon JI. 2005. Obesity alters gut microbial ecology. Proc Natl Acad Sci U S A 102:11070–11075.

359

Li C, Kaur H, Choi WS, Huang TT, Lee RE, Ahluwalia JS. 2005. Additive interactions of maternal prepregnancy BMI and breast-feeding on childhood overweight. Obes Res 13:362–371.

Lonnerdal B, Havel PJ. 2000. Serum leptin concentrations in infants: effects of diet, sex, and adiposity. Am J Clin Nutr 72:484–489.

Lucas A, Boyes S, Bloom SR, Aynsley-Green A. 1981. Metabolic and endocrine responses to a milk feed in six-day-old term infants: differences between breast and cow’s milk formula feeding. Acta Paediatr Scand 70:195–200.

Manco M, Alterio A, Bugianesi E, Ciampalini P, Mariani P, Finocchi M, Agostoni C, Nobili V. 2011. Insulin dynamics of breast- or formula-fed overweight and obese children. J Am Coll Nutr 30:29–38.

Marques TM, Wall R, Ross RP, Fitzgerald GF, Ryan CA, Stanton C. 2010.

Programming infant gut microbiota: influence of dietary and environmental factors. Curr Opin Biotechnol 21:149–156.

McCance RA. 1962. Food, growth, and time. Lancet 2:671–676.

Mennella JA, Beauchamp GK. 1996. The early development of human flavor preferences. In: Capaldi ED, editor. Why we eat what we eat: the psychology of eating. Washington, DC: American Psychological Association. p.83–112.

Moorcroft KE, Marshall JL, McCormick FM. 2011. Association between timing of introducing solid foods and obesity in infancy and childhood: a systematic review. Matern Child Nutr 7:3–26.

Newburg DS, Woo JG, Morrow AL. 2010. Characteristics and potential functions of human milk adiponectin. J Pediatr 156(2 Suppl):S41–S46.

Nielsen S, Nielsen DS, Lauritzen L, Jakobsen M, Michaelsen KF. 2007.

Impact of diet on the intestinal microbiota in 10-month-old infants.

J Pediatr Gastroenterol Nutr 44:613–618.

Noble S, Emmett PM. 2006. Differences in weaning practice, food and nutrient intake between breast- and formula-fed 4-month-old infants in England. J Hum Nutr Diet 19:303–313.

Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. 2006. Prevalence of overweight and obesity in the United States, 1999– 2004. JAMA 295:1549–1555.

Ong KK, Emmett PM, Noble S, Ness A, Dunger DB. 2006. Dietary energy intake at the age of 4 months predicts postnatal weight gain and childhood body mass index. Pediatrics 117:e503–508.

Orrhage K, Nord CE. 1999. Factors controlling the bacterial colonization of the intestine in breastfed infants. Acta Paediatr Suppl 88:47–57.

Owen CG, Martin RM, Whincup PH, Smith GD, Cook DG. 2005. Effect of infant feeding on the risk of obesity across the life course: a quantitative review of published evidence. Pediatrics 115:1367–1377.

Ozanne SE, Hales CN. 2004. Lifespan: catch-up growth and obesity in male mice. Nature 427:411–412.

Palmer C, Bik EM, DiGiulio DB, Relman DA, Brown PO. 2007. Development of the human infant intestinal microbiota. PLoS Biol 5:e177.

Parrett AM, Edwards CA. 1997. In vitro fermentation of carbohydrate by breast fed and formula fed infants. Arch Dis Child 76:249–253.

Parsons TJ, Power C, Logan S, Summerbell CD. 1999. Childhood predictors of adult obesity: a systematic review. Int J Obes Relat Metab Disord 23(Suppl 8):S1–S107.

Polhamus B, Dalenius K, Borland E, Mackintosh H, Smith B, GrummerStrawn L. 2009. Pediatric Nutrition Surveillance 2007 report, U.S. Department of Health and Human Services, Centers for Disease Control and Prevention, Atlanta.

Reinhardt C, Reigstad CS, Backhed F. 2009. Intestinal microbiota during infancy and its implications for obesity. J Pediatr Gastroenterol Nutr 48:249–256.

Rasmussen KM, Hilson JA, Kjolhede CL. 2001. Obesity may impair lactogenesis II. J Nutr 131:3009S–3011S. Sanchez J, Oliver P, Miralles O, Ceresi E, Pico C, Palou A. 2005. Leptin orally supplied to neonate rats is directly uptaken by the immature stomach and may regulate short-term feeding. Endocrinology 146:2575–2582.

Satokari RM, Vaughan EE, Favier CF, DorÈ J, Edwards C, Vos WM. 2002.

Diversity of Bifidobacterium and Lactobacillus spp. in breast-fed and formula-fed infants as assessed by 16S rDNA sequence differences.

Microb Ecol Health Dis 14:97–105.

Savage JS, Fisher JO, Birch LL. 2007. Parental influence on eating behavior: conception to adolescence. J Law Med Ethics 35:22–34.

Savino F, Fissore MF, Grassino EC, Nanni GE, Oggero R, Silvestro L. 2005. Ghrelin, leptin and IGF-I in breast-fed and formula-fed infants in the first years of life. Acta Paediatr Suppl 94:531–537.

Savino F, Fissore MF, Liguori SA, Oggero R. 2009a. Can hormones contained in mothers’ milk account for the beneficial effect of breast-feeding on obesity in children? Clin Endocrinol (Oxf) 71:757–765.

Savino F, Liguori SA, Fissore MF, Oggero R. 2009b. Breast milk hormones and their protective effect on obesity. Int J Pediatr Endocrinol 2009:327505.

Shahkhalili Y, Mace K, Moulin J, Zbinden I, Acheson KJ. 2011. The fat:carbohydrate energy ratio of the weaning diet programs later susceptibility to obesity in male sprague dawley rats. J Nutr 141:81–86.

American Journal of Human Biology

360

A.L. THOMPSON

Shim JE, Kim J, Mathai RA. 2011. Associations of infant feeding practices and picky eating behaviors of preschool children. J Am Diet Assoc 111:1363–1368.

Sievers E, Oldigs HD, Santer R, Schaub J. 2002. Feeding patterns in breast-fed and formula-fed infants. Ann Nutr Metab 46:243–248.

Singhal A, Lanigan J. 2007. Breastfeeding, early growth and later obesity.

Obes Rev 8(Suppl 1):51–54.

Sullivan SA, Birch LL. 1994. Infant dietary experience and acceptance of solid foods. Pediatrics 93(2):271–277.

Symonds ME. 2007. Integration of physiological and molecular mechanisms of the developmental origins of adult disease: new concepts and insights. Proc Nutr Soc 66:442–450.

Taveras EM, Scanlon KS, Birch L, Rifas-Shiman SL, Rich-Edwards JW, Gillman MW. 2004. Association of breastfeeding with maternal control of infant feeding at age 1 year. Pediatrics 114:e577–e583.

Thompson AL, Lampl M, Azcarate-Peril MA. 2011. Developmental microbial ecology: the effects of age and diet on the establishment of intestinal microflora in infants. Am J Hum Biol 23:280.

Turnbaugh PJ, Gordon JI. 2009. The core gut microbiome, energy balance and obesity. J Physiol 587(Part 17):4153–4158.

Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. 2006. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 444:1027–1031.

Vael C, Desager K. 2009. The importance of the development of the intestinal microbiota in infancy. Curr Opin Pediatr 21:794–800.

Vael C, Verhulst SL, Nelen V, Goossens H, Desager KN. 2011. Intestinal microflora and body mass index during the first three years of life: an observational study. Gut Pathog 3:8. van Rossem L, Taveras EM, Gillman MW, Kleinman KP, Rifas-Shiman SL, Raat H, Oken E. 2011. Is the association of breastfeeding with child obesity explained by infant weight change? Int J Pediatr Obes 6:e415–e422.

Wagner CL, Taylor SN, Johnson D. 2008. Host factors in amniotic fluid and breast milk that contribute to gut maturation. Clin Rev Allergy Immunol 34:191–204.

American Journal of Human Biology

Wasser H, Bentley M, Borja J, Davis Goldman B, Thompson A, Slining M, Adair L. 2011. Infants perceived as ‘‘fussy’’ are more likely to receive complementary foods before 4 months. Pediatrics 127:229–237.

Waterland RA, Lin JR, Smith CA, Jirtle RL. 2006. Post-weaning diet affects genomic imprinting at the insulin-like growth factor 2 (Igf2) locus. Hum Mol Genet 15:705–716.

Wells JC, Chomtho S, Fewtrell MS. 2007. Programming of body composition by early growth and nutrition. Proc Nutr Soc 66:423– 434.

Weyermann M, Brenner H, Rothenbacher D. 2007. Adipokines in human milk and risk of overweight in early childhood: a prospective cohort study. Epidemiology 18:722–729.

Wiley AS. 2005. Does milk make children grow? Relationships between milk consumption and height in NHANES 1999-2002. Am J Hum Biol 17:425–441.

Wilson AC, Forsyth JS, Greene SA, Irvine L, Hau C, Howie PW. 1998.

Relation of infant diet to childhood health: seven year follow up of cohort of children in Dundee infant feeding study. BMJ 316:21–25.

Woo JG, Guerrero ML, Altaye M, Ruiz-Palacios GM, Martin LJ, DubertFerrandon A, Newburg DS, Morrow AL. 2009. Human milk adiponectin is associated with infant growth in two independent cohorts. Breastfeed Med 4:101–109.

Worthington-Roberts B. 1993. Human milk composition and infant growth and development. In: Worthington-Roberts B, Williams S, editors.

Nutrition in pregnancy and lactation. St. Louis: Mosby. p 347–401.

Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N. 2001. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 7:941–946.

Yudkin J. 2007. Inflammation, obesity, and the metabolic syndrome. Horm Metab Res 39:707–709.

Zivkovic AM, German JB, Lebrilla CB, Mills DA. 2011. Human milk glycobiome and its impact on the infant gastrointestinal microbiota. Proc Natl Acad Sci U S A 108(Suppl 1):4653–4658.