can hormones contained in mothers’ milk account for the beneficial effect of breast-feeding on...

R E V I E W A R T I C L E

Can hormones contained in mothers’ milk account for the beneficialeffect of breast-feeding on obesity in children?

Francesco Savino, Maria F. Fissore, Stefania A. Liguori and Roberto Oggero

Department of Pediatrics, Regina Margherita Children’s Hospital, University of Turin, Turin, Italy

Summary

Nutrition and growth during infancy are an emerging issue

because of their potential link to metabolic health disorders in

later life. Moreover, prolonged breast-feeding appears to be

associated with a lower risk of obesity than formula feeding.

Human milk is a source of various hormones and growth fac-

tors, namely adipokines (leptin and adiponectin), ghrelin, resi-

stin and obestatin, which are involved in food intake regulation

and energy balance. These compounds are either not found in

commercial milk formulas or their presence is still controversial.

Diet-related differences during infancy in serum levels of factors

involved in energy metabolism might explain anthropometric

differences and also differences in dietary habits between breast-

fed (BF) and formula-fed (FF) infants later in life, and may thus

have long-term health consequences. In this context, the recent

finding of higher leptin levels and lower ghrelin levels in BF

than in FF infants suggests that differences in hormonal values

together with different protein intake could account for the dif-

ferences in growth between BF and FF infants both during

infancy and later in life. In this review, we examine the data

related to hormones contained in mothers’ milk and their

potential protective effect on subsequent obesity and metabolic-

related disorders.

(Received 4 December 2008; returned for revision 1 February 2009;

finally revised 4 February 2009; accepted 12 February 2009)

Introduction

Nutrition and growth during infancy are now under close scru-

tiny because of their possible link to obesity and metabolic disor-

ders in later life. However, the mechanisms that link early growth

and nutrition with long-term obesity risk are not well defined.

Obesity is a chronic condition, frequent in both developed and

developing countries, that affects both adults and children.1

Overweight and obesity in childhood result primarily from an

energy imbalance whereby dietary energy intake exceeds energy

expenditure,2 but the dynamics of this imbalance are complex

and not fully understood. One of the driving forces behind obes-

ity is increased appetite, which is controlled in the arcuate

nucleus of the hypothalamus via a complex process involving

hormones, such as leptin and ghrelin that act as mediators

between the adipose tissue, the gastrointestinal tract and the

brain.3

Interestingly, the pathways involved in appetite regulation

mature early in postnatal life. Indeed, patterns of foetal and

neonatal growth influence appetite regulation as shown by the

finding that a low birth weight and rapid postnatal weight gain

up-regulate appetite.4 While up-regulation of appetite may be

advantageous in the short term, it could promote obesity in the

long term. This could to a certain extent explain the link between

early growth and the risk of metabolism-related diseases later in

life.

It is well known that growth pattern and body composition in

the first period of life differ between breast-fed (BF) and formula-

fed (FF) infants. Formula feeding is associated with a greater weight

and length gain after 3 months of age. Moreover, a dose–response

relationship has been observed between formula intake and both

length and weight gain with the greatest effects occurring between

3 and 6 months of age.5 Butte et al. reported that BF infants have a

higher fat mass than FF babies in the first months of life.6 It has

been suggested that differences in growth pattern and body compo-

sition between BF and FF infants might be because of a different

endocrine response to feeding or to bioactive substances present in

breast milk that could influence infants’ response to energy intake

and metabolism.7

Leptin, ghrelin, adiponectin,8 resistin,9 and obestatin10 have

recently been identified in breast milk. These hormones, which are

involved in energy balance regulation, may play a role in the regula-

tion of growth and development in the neonatal period and

infancy, and could influence the programming of energy balance

regulation in childhood and adulthood.

In this review, we examine the data related to hormones

contained in mothers’ milk and their potential protective effect on

subsequent obesity and metabolic-related disorders.

Correspondence: Francesco Savino, Dipartimento di Scienze Pediatriche e

dell’Adolescenza, Ospedale Infantile Regina Margherita, Piazza Polonia 94,

10126 Turin, Italy. Tel.: +390113135257; Fax: +39011677082;

E-mail: [email protected]

Clinical Endocrinology (2009) 71, 757–765 doi: 10.1111/j.1365-2265.2009.03585.x

� 2009 Blackwell Publishing Ltd 757

Nutritional programming

The concept that nutrition in infancy could influence later health

first emerged in the 1960s with the pioneering study of McCance,

who observed that, in rats, nutrition acts during a critical, early

postnatal window to program later body size.11 In 1974, Dorner

proposed that hormones, metabolites and neurotransmitters dur-

ing a critical window in early development may program brain

development and body functions as well as risk for diseases in

human adulthood.12 Forty years of animal experiments and epide-

miological studies in humans have shown that early nutrition is a

key factor for health later in life, thereby supporting the concept of

‘nutritional programming’.13

Low birth weight and rapid catch-up growth during the early

postnatal period have been associated with a subsequent higher

ratio of fat mass to lean mass, a greater central fat deposition and

insulin resistance and consequently an increased risk of adverse

outcomes, namely obesity, cardiovascular diseases and type 2 dia-

betes.14 The link between growth acceleration and later obesity was

confirmed by two systematic reviews: one of 15 studies that dem-

onstrated an association between rapid growth during the first

years of life and the prevalence of obesity in during life,15 and the

other of 24 studies (22 cohort and two case–control studies) show-

ing that infants at the highest end of the distribution for weight or

body mass index (BMI) or who grow rapidly during infancy are at

increased risk of subsequent obesity.16 In a cohort study, rapid

weight gain during infancy and early childhood predicted larger

BMIs and waist circumferences in young adulthood and taller adult

height.17 Moreover, weight gain between 0 and 6 months was

inversely related to rapid weight gain between 3 and 6 years, indi-

cating that weight gain in early childhood tended to slow down in

individuals who rapidly gained weight in infancy.

Considering that much of the evidence on nutritional program-

ming in humans comes from animal models, there is a need for

observational studies and clinical intervention trials to determine

whether there is a causal association between early nutrition and

later health.18

Breast-feeding and childhood obesity

The view that early nutrition could affect long-term health, and the

observation of different growth patterns and body composition

between BF and FF infants prompted nutrition researchers to

address the question: does breast-feeding protect against the devel-

opment of obesity? However, while breast milk is undoubtedly the

best source of nutrients for the newborn and protects against infec-

tious diseases during the breast-feeding period,19 whether it has

long-term health benefits has not been unequivocally demon-

strated. A case–control study by Kramer was one of the first studies

to suggest that breast-feeding protected against later obesity.20

Armstrong et al., in a large cohort study of Scottish children sug-

gested that breast-feeding was associated with a reduction in child-

hood obesity risk.21 Subsequently, epidemiological surveys showed

a protective effect of breast-feeding, when compared with formula

feeding, on the long-term overweight risk in children.22 Moreover,

a meta-analysis of 17 studies (16 cohort studies and one case–

control study) revealed that the longer the duration of breast-feed-

ing, the lower the risk of overweight in later life.23

Various hypotheses have been proposed to explain how breast-

feeding protects against faster weight gain and consequently against

later obesity.24 BF babies can self-control the amount of milk they

consume, and so they may learn to self-regulate their energy intake

better than FF infants.25 Furthermore, a higher protein intake in FF

infants could determine a higher risk of later obesity by causing an

earlier adiposity rebound.26 A higher protein intake from skimmed

cow’s milk by stimulating serum insulin-like growth-factor I (IGF-

I) levels in infancy could promote later obesity.27 Similarly, associa-

tions between an earlier age at weaning and a greater risk of later

obesity28 may reflect the influence of a greater nutrient and particu-

larly protein intake with weaning on growth rate in infancy.

Another study showed that a mother’s prepregnant BMI, duration

of breast-feeding and timing of complementary food introduction

are associated with infant weight gain from birth to 1 year of life.29

Breast milk contains many bioactive factors (lactoferrin, oligo-

saccharides, long-chain polyunsaturated fatty acids, glycoproteins

and secretory IgA antibodies) that do not function primarily as

nutrients, but that may control nutrient use, protect infants from

pathogens and play a role in regulating metabolic pathways.30

Moreover, breast milk contains other biologically active factors,

namely hormones, growth factors and cytokines, which are

involved in energy balance regulation and seem to play a role in

infant nutrition and growth. Epidermal growth factor and IGF-I

are two major milk-derived peptide growth factors, which are rela-

tively resistant to proteolysis and stable in the gastrointestinal tract.

Furthermore, specific receptors have been identified in gastrointes-

tinal mucosa, suggesting a role of these hormones in stimulating

growth and development of the gastrointestinal tract.31 It remains

unclear whether hormones, more recently identified in breast milk

and which we will deal with in the present review, are resistant to

proteolysis in the gastrointestinal tract and absorbed across the

intestinal mucosa.

Hormones in mother’s milk implicated in nutritionalprogramming

The hormones identified thus far in breast milk are listed in Table 1.

Leptin

Structure. Leptin, the product of the obesity (ob) gene on chromo-

some 7q31.3, is a 167-amino acid peptide discovered in 1994 and

mainly synthesized by the white adipose tissue proportionally to

the amount of body fat mass.32 Leptin is also produced by

mammary gland and is secreted by epithelial cells in milk fat

globules.33

Role in appetite, energy homeostasis and body composition. Leptin

functions directly in the regulation of food energy intake and

expenditure. At the level of the central nervous system, leptin exerts

an anorexigenic effect by signalling satiety and decreasing the

sensation of hunger.34 Leptin exerts an anorexigenic effect by

activating anorexigenic pro-opiomelanocortin (POMC)/cocaine

758 F. Savino et al.

� 2009 Blackwell Publishing Ltd, Clinical Endocrinology, 71, 757–765

amphetamine-regulated transcript neurons in the hypothalamic

arcuate nucleus, and inhibiting orexigenic NPY/AgRP neurons.

The physiological role of leptin was first investigated in the ob/ob

mouse model that has a single-base mutation leading to a nonfunc-

tional leptin protein. ob/ob mice had low leptin concentrations and

became obese when they ate ad libitum. Humans with leptin defi-

ciency caused by genetic mutations are affected by congenital obes-

ity and endocrine abnormalities, similar to the ob/ob mouse.35 The

administration of exogenous leptin to leptin-deficient children

resulted in a decrease in their energy intake and a dramatic loss of

fat mass, whereas lean body mass was unaffected.36 However,

administration of exogenous leptin failed to reduce adiposity sig-

nificantly in most cases of human obesity characterized by

increased adipocyte leptin content and high circulating leptin levels

– a condition known as ‘leptin resistance’.37

A large body of experimental data suggests that control of energy

homeostasis, food intake and body composition by leptin begins in

early life, when the hormone also controls foetal growth and devel-

opment. Growth during foetal life is linked with specific changes in

leptin levels: small-for-gestational age (SGA) neonates have lower

leptin levels at birth than appropriate-for-gestational age (AGA)

ones, and large-for-gestational age (LGA) neonates have higher

leptin levels than the other infants.38 The observation of a surge in

leptin soon after birth in mice suggests that leptin is essential for

the development of the hypothalamic pathways involved in the regu-

lation of energy balance and appetite, and that this activity could be

restricted to a critical neonatal window.39

Interestingly, there is evidence that serum leptin concentration

reflects body fat mass in adults, in children, during foetal life40 and

also in infants.41

Leptin in breast milk. It is now well established that leptin is a

component of mothers’ milk. Casabiell et al. identified leptin in

human milk, and reported that, in nursing rats, leptin is trans-

ferred via milk to the stomach and then to the infant rat circula-

tion.42 Smith-Kirwin et al. showed that the leptin gene is

expressed in the mammary gland of lactating women and that

leptin is produced by mammary epithelial cells.33 Bonnet et al.

showed through immunohistochemistry that the cellular location

of the leptin protein differed between gestation and lactation

stages: leptin protein was detected in mammary adipocytes dur-

ing early stages of pregnancy, and in epithelial cells (mainly on

their apical membrane) just before parturition, and in myoepi-

thelial cells during lactation; moreover, secretory epithelial cells

may transfer leptin from the blood to milk.43 Thus, leptin can be

secreted into milk by the mammary gland and it can be trans-

ferred from the blood. Leptin receptors have been identified in

gastric epithelial cells and in the absorptive cells of mouse and

human small intestine,44 which suggests that leptin could pass

from milk to infant blood.

Leptin concentration, assayed by radioimmunoassay, was found

to be higher in whole than in skimmed samples of human milk,45

probably because a portion of leptin could be associated with the

milk fat droplet or fat-associated proteins. Milk leptin concentra-

tion was shown to be higher in colostrum than in transitional milk

(4–5 days postpartum milk).46 Leptin is present also in preterm

human breast milk at levels similar to those in term breast

milk, although levels can be lower after preterm than after term

delivery.47

Houseknecht et al. were the first to report that leptin in breast

milk correlated with maternal plasma leptin concentration,

although breast milk leptin concentration was lower than maternal

plasma leptin levels. They also observed a positive correlation

between breast milk leptin concentration and maternal BMI, sug-

gesting that BF infants nursed by overweight/obese mothers might

be exposed to higher amounts of leptin than infants nursed by lean

mothers.45 More recently, leptin concentrations in breast milk were

found to correlate positively with maternal circulating leptin levels,

maternal BMI and the mothers’ adiposity.48 A positive correlation

has also been reported between breast milk leptin levels and infant

plasma leptin.49 We have observed higher serum leptin concentra-

tions in BF infants than in FF babies in the first months of life50,51

and also a positive correlation between serum leptin concentration

in BF infants and maternal BMI.52

Table 1. Breast milk hormones

Hormone

Amino

acids Gene

Year of

discovery Sources Receptor Main functions

Year of

discovery in

breast milk

Leptin 167 7q31.3

(gene Ob)

1994 White adipose tissue,

placenta, mammary

gland, other sites

Ob-receptor Anorexigenic effect 1997

Adiponectin 244 3q27

(gene apM1)

1995 Adipose tissue Adipo-R1

Adipo-R2

Improvement of insulin sensitivity,

increase in fatty acid metabolism,

anti-inflammatory and

anti-atherogenic properties

2006

Ghrelin 28 3p25-26 1999 Stomach, intestine,

pancreas, other sites

Growth hormone

secretagogue-receptor-1a

Orexigenic action; stimulation

of GH secretion; stimulation of

acid gastric secretion and motility

2006

Resistin 114 2q21 2001 Adipose tissue Unknown Regulation of insulin sensitivity 2008

Obestatin 23 3p25-26 2005 Stomach, small

intestine, salivary gland

Unknown Anorexigenic effect? 2008

Hormones in mother’s milk and obesity 759


Is milk-borne leptin a link between maternal body composition

and neonatal growth and development? Dundar et al. were the first

to show that leptin is involved in the growth of BF infants. They

suggested that the production of leptin in breast tissue might be

regulated physiologically depending on need and the state of the

infant.53 They found that SGA infants grew more rapidly during

the first postnatal 15 days than AGA and LGA infants, and that

human milk leptin levels were significantly lower in the SGA

group.

Milk-borne leptin has been implicated not only in growth, but

also in short-term appetite regulation in infancy, especially during

early lactation. Oral administration of leptin at doses close to the

physiological concentration in milk reduced food intake in new-

born rats, and was absorbed by the rat’s stomach during neonatal

development thereby triggering down-regulation of endogenous

leptin production. Consequently, oral intake of leptin supplied by

maternal milk could play a role in the short-term control of food

intake in neonates by acting as a satiety signal.54

Breast milk leptin could exert a long-term effect on energy bal-

ance and body weight regulation. Indeed, by acting on the brain

during a critical neonatal period that coincides with the naturally

occurring leptin surge, the hormone promotes the formation of

neural circuits that control food intake and adiposity later in life.55

The presence of leptin in the breast milk of nonobese mothers at

1 month of lactation was found to be negatively correlated with

BMI at 18 and 24 months of age, suggesting that milk leptin may

regulate body weight gain during the first months of life.56 In a

study of rat pups monitored into adulthood, animals given physio-

logical doses of oral leptin during lactation had lower body weight

and fat content than untreated animals, which suggests that leptin

could have long-term effects on body weight regulation.57 More

recently, leptin-treated animals were found to have lower body

weight in adulthood, to eat fewer calories, to have higher insulin

sensitivity and to show a lower preference for fat-rich food than

their controls.58 Breast milk leptin, in addition to its effect on sati-

ety, may prime or set the endocrine system at a different homeo-

static regulation balance.59

One would expect to find leptin in milk formula because whey

proteins added to the formula are isolated from skimmed bovine

milk and leptin associated with milk fat globules would be removed

during the skimming process.48 Lage et al. using radioimmunoas-

say reported significant and variable leptin concentrations in edible

commercial bovine milk, and noted that concentrations were

higher in infant formulas.60 However, radioimmunoassay is not

appropriate for the detection of leptin in infant formulas because

supplemented iron, emulsifiers and other additives contained in

formulas could confound the assay.61 Therefore, further research is

required to determine whether leptin is present in milk formula.

Ghrelin

Structure and functions. Ghrelin, a 28-amino acid peptide pro-

duced primarily in the stomach, is involved both in the short-term

regulation of feeding and in the long-term regulation of weight and

energy metabolism. The human ghrelin gene is localized on chro-

mosome 3p25-26. It is mainly produced in the oxyntic mucosa of

the stomach by enteroendocrine X/A-like cells.62 A portion of ghre-

lin possesses a fatty acid modification, an n-octanoylation, at Ser 3;

the remainder is unacylated (desacyl ghrelin). The acylated form,

also known as active ghrelin, is thought to be essential for binding

to the growth hormone secretagogue receptor 1a (GHSR-1a), and

stimulates GH secretion in humans.63

Role in appetite, energy homeostasis and body composition. Ghrelin

has many endocrine and nonendocrine functions; it is involved in

energy balance regulation, and it stimulates food intake in rats and

humans.64 The orexigenic action is mediated by three distinct path-

ways: (i) circulating ghrelin reaches and activates the orexigenic

NPY/AgRP neurons in the arcuate nucleus of the hypothalamus

that are implicated in the central control of meal initiation, and

inhibits neurons expressing POMC that suppresses appetite; (ii)

circulating ghrelin or ghrelin produced locally in the stomach acts

via afferent vagal fibres that innervate the nucleus tractus solitarius,

which then relays ghrelin to the hypothalamus; and (iii) ghrelin is

produced locally in the hypothalamus by ghrelin neural cells.65

Unlike leptin, ghrelin increases food intake and decreases energy

expenditure. Leptin exerts a tonic dual restraint both on gastric

ghrelin secretion peripherally and on activation by ghrelin of the

orexigenic neurons centrally.66

Ghrelin is released in a pulsatile fashion, with a nocturnal peak.

Although several dietary and hormonal factors influence ghrelin

concentration, in adults, ghrelin has a meal response: it increases

1–2 h before a meal67 and returns to trough levels 1–2 h after a

meal.68 Ghrelin secretion increases under negative energy-balance

conditions, such as acute energy restriction and anorexia nervosa,

and decreases under positive energy-balance conditions, such as

food intake and obesity.64 In newborns, levels of ghrelin were

higher in SGA babies than in AGA babies.69 Reduced ghrelin sup-

pression and higher postprandial ghrelin levels in SGA infants

could result in a sustained orexigenic drive and could contribute to

postprandial catch-up growth in these infants.

Ghrelin also exerts adipogenic activity, and is involved in the

long-term regulation of body weight.70 Administration of ghrelin

induced body weight gain and adiposity in rodents by stimulating

food intake and reducing fat utilization and energy expenditure.71

Kitamura et al. reported high ghrelin levels during the early neonatal

period.72 In term infants, plasma ghrelin was inversely associated to

birth weight and body length.73 This contrasts with a more recent

study in which ghrelin levels did not correlate significantly with

anthropometric parameters in newborns.74 In another study, ghre-

lin significantly increased during the first 2 years of life, after which

it decreased until the end of puberty, at which point it reached adult

levels.75 We found a direct correlation between the circulating level

of ghrelin and age, weight and length in both BF and FF infants, and

a negative correlation between circulating ghrelin levels and weight

gain in BF infants.76 We observed higher values in FF infants in the

first months of life,77 and more recently a positive correlation

between circulating ghrelin levels and fasting time in the first

6 months of life in infants fed exclusively with formula.78

Ghrelin in breast milk. Ghrelin is a component of breast milk. The

levels of ghrelin were found to be lower in colostrum, and in



transitional and mature milk than those typically found in plasma,

which suggests that ghrelin comes from the plasma.79 There is

compelling evidence that ghrelin in breast milk is synthesized and

secreted by the breast. In fact, ghrelin occurs in both term and

preterm human breast milk; its levels are higher in whole milk than

in skim milk, and higher in breast milk than in plasma.80 Acylated

ghrelin has also been reported in breast milk; its concentrations

increase during lactation and are significantly related with serum

ghrelin concentrations in BF infants.81

Dass et al. recently demonstrated growth hormone secreta-

gogue-receptor (GHSR) immunoreactivity within the enteric ner-

vous systems of rat and human stomach and colon. These GHSRs

may be activated by ghrelin released into the blood from the large

deposit within the stomach. In addition, the presence of both ghre-

lin and the receptor within neuronal and non-neuronal structures

of the gut suggests that local supplies of ghrelin can act at least in a

paracrine manner within both the stomach and the large intestine.

Ghrelin may have the potential to operate within the gut both via

the enteric nervous system and via vagus nerve-dependent mecha-

nisms.82

Considering that ghrelin is involved both in short-term regula-

tion of food intake, by stimulating appetite, and in long-term

body-weight regulation, by inducing adiposity, ghrelin in breast

milk could be one of the factors through which breast-feeding may

influence infant feeding behaviour and body composition.

Adiponectin

Structure and functions. Adiponectin, discovered in 1995, is the

most abundant adipose-specific protein and its multiple functions

have started to emerge in recent years.83 This protein circulates in

very high concentrations in human serum. A reduction in adipo-

nectin expression has been associated with insulin resistance,

whereas administration of adiponectin is accompanied by an

increase in insulin sensitivity. In humans, adiponectin levels are

inversely related to the degree of adiposity and positively associated

with insulin sensitivity as Rasmussen-Torvik et al. showed recently

in adolescents.84

Circulating adiponectin levels correlate negatively with the

degree of adiposity also in children aged between 5 and 10 years.85

In contrast, in full-term neonates, during the first few days of life,

serum and plasma adiponectin levels correlate positively with birth

weight and length, neonatal adiposity and circulating levels of lep-

tin.86 Furthermore, adiponectin concentrations in cord blood are

higher than those reported in adolescents and in adults.87 In pre-

term infants, serum adiponectin levels are lower than those in full-

term infants and correlate positively with body weight.88 Blood

adiponectin levels increase with postnatal age in premature infants,

suggesting a rapid, as yet unexplained, metabolic adaptation to pre-

mature extrauterine life.89

Adiponectin in breast milk. Martin et al. recently reported that

immunoreactive adiponectin levels in human milk were signifi-

cantly higher than leptin levels, and that they decreased with the

duration of lactation.90 Bronsky et al. looked for adipose tissue-

generated proteins that are related to lipid metabolism in breast

milk and found adiponectin, adipocyte fatty acid binding protein

and epidermal fatty acid binding protein.91 Interestingly, adiponec-

tin was found to be more abundant in cord blood than in either

breast milk or maternal serum.92 Given the biological properties of

adiponectin, its presence in breast milk and the expression of

adiponectin receptor 1 in the small intestine of neonatal mice,93

not only adipose tissue-produced adiponectin but also milk adipo-

nectin may affect infant growth and development.

Recently discovered hormones in breast milk

Resistin

Resistin is a cytokine identified in 2001 that is secreted by adipo-

cytes.94 Resistin mRNA encodes a 114-amino acid polypeptide with

a 20-amino acid signal sequence. Resistin has been implicated in

the development of insulin resistance in mice; the effects of resistin

on insulin sensitivity in humans are less well known.95 In the peri-

natal period, resistin does not seem to be directly involved in the

regulation of insulin sensitivity and adipogenesis.96 Mouse serum

levels of resistin decreased with fasting and increased after re-feed-

ing. Circulating resistin levels were found to be elevated in both

genetic (ob/ob and db/bd) and diet-induced mouse obesity and

insulin-resistance models.95

Resistin is expressed in the human placenta and it may play a role

in the regulation of energy metabolism during pregnancy. Umbili-

cal serum resistin levels are positively correlated with maternal

serum resistin levels and negatively with neonatal birth weight,

while Cortellazzi et al. observed decreasing resistin levels with

advancing gestation in women with normal BMI.97 In a cohort

study that included overweight and obese women, Jansson et al.

found an increase in maternal serum resistin level between the first

and third trimesters, and a positive correlation between first-

trimester resistin level and birth weight, independently of BMI and

dietary variables.98

Resistin was recently identified in human milk, and its concen-

tration decreases during lactation.9 Both milk and serum resistin

concentrations in breast-feeding mothers correlated positively with

oestradiol, progesterone, prolactin, thyroxine, triiodothyronine,

cortisol, leptin and C-reactive protein concentrations. Moreover,

serum resistin concentrations in BF infants were higher than in the

breast milk, and serum of their mothers. It is conceivable that resi-

stin is another breast milk hormone involved in the metabolic

development of infants.

Obestatin

Obestatin is a 23-amino acid peptide derived from the ghrelin pep-

tide precursor preproghrelin and produced by the cells lining the

human stomach and small intestine.99 This hormone was initially

found to reduce food intake, body weight gain and gastric empty-

ing and to suppress intestinal motility thereby exerting effects

opposite to those of ghrelin. However, these findings have been

questioned by other studies; it has been observed that obestatin is

involved in inhibiting thirst and anxiety, improving memory, regu-

lating sleep, inducing cell proliferation and increasing exocrine



pancreatic secretion.100 Increased plasma obestatin levels have been

observed in subjects with anorexia nervosa, in whom obestatin

seemed to be a marker of acute and chronic changes in nutritional

state.101 Obestatin was recently identified in breast milk,10 and

there are no data concerning its relationship with infant metabolic

development.

Conclusions

Early nutrition could exert both short- and long-term effects on the

programming of metabolic development and growth. Epidemio-

logical surveys indicate that breast-feeding protects against obesity

in later life, although the precise magnitude of this association

remains unknown. Breast milk contains the hormones leptin, ghre-

lin, adiponectin, resistin and obestatin, which play a role in energy

balance regulation. These hormones may be involved in the regula-

tion of growth and development in the neonatal age and infancy

and could influence the programming of energy balance regulation

in childhood and adulthood. Thus, as shown in Fig. 1, these hor-

mones may represent the link between breast-feeding and protec-

tion against obesity in later life.

Competing interests/financial disclosure

Nothing to declare.

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Leptin

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Ghrelin

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Fig. 1 Breast-milk hormones: possible link between

breast-feeding and central energy balance regula-

tion in infants.



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