A Review of the Relationship Between the Appetite-Regulating Hormone Leptin Present in Human Milk and Infant Growth

Abstract

Objective:

The relationship between leptin in human milk (HM) and infant growth is quite controversial. The aim of the present study was to review the epidemiological literature currently available on the relation between the appetite-regulating hormone leptin in HM with growth and infant weight gain. Also, to know if it influences on the center of satiety of the infant, and if this hormone has an effect in the self-regulation of food intake.

Methods:

A review of review and original research articles published from January 1, 2015 up to December 31, 2019 measuring leptin in HM and infant weight gain was performed in the PubMed and Embase databases. The literature showed a total of 237 articles, where the title and abstract were evaluated to eliminate duplicate citations and later exclusion criteria were established to discard articles. Eighteen articles met the inclusion criteria.

Results:

Six articles showed a relationship between leptin present in HM and infant weight. Five articles reported on leptin in HM and the effect on satiety and self-regulation of infant intake. Studies of leptin in infant serum blood were quite controversial. There is an inverse relationship between the leptin in HM and infant weight gain. Also, breastfed infants better self-regulate their intake and have a better relationship with food. The duration of breastfeeding directly influences on the growth of the infant due to the hormones present in the milk. However, these mechanisms are unclear, and the results are controversial.

Conclusion:

The evidence from the studies allowed us to establish that there is an association between leptin in HM and infant weight gain. However, there is still a lack of longitudinal studies, with a larger number of participants and well-established inclusion criteria about the relationship between leptin in HM exposure and the development of infant weight gain.

Introduction

The health impact of events in very early life has been a topic of research that has attracted great interest in recent years.¹ Nutrition in the very early stages of life plays a vital role in the correct growth and development of an infant.¹ Breastfeeding (BF) covers the nutritional needs of the infant, providing them with personalized and adequate amounts of macro and micronutrients for correct growth and development. Human milk (HM), due to some of its bioactive components and hormones, can regulate the infant's weight, affect body composition and growth pattern, exert an effect on satiety and promote the ability to self-regulate food intake.^2–4 Likewise, studies have shown that certain components of HM may have long-term effects on metabolic programming.^3,4

Among the components of HM, appetite-regulating hormones (ARHs) play a role in the regulation of infant food intake by indicating satiety and in body composition and energy reserves through hypothalamic receptors. These signals emitted by ARH are protective factors against the development of obesity.⁵ Some studies show that, compared with formula-fed (FF) infants, infants fed with HM better self-regulate nutrient intake and develop excellent appetite control when fed solid foods.⁶

One of the most ARHs studied is leptin, an anorectic hormone of a protein nature made up of 167 amino acids. It is encoded by the leptin gene (lep) and is synthesized mainly by white adipose tissue, which acts through the arcuate nucleus of the hypothalamus.⁴ The main function of leptin is the neuroendocrine regulation of the appetite, exercising anorexigenic effects on the central nervous system. Leptin decreases food intake, promotes satiety, decreases the desire to eat, and increases metabolic rate.⁵ While several studies have shown that it could play a crucial role in fetal and neonatal growth³ with findings showing significant associations between the concentration of leptin and childhood growth⁷ and also identifying an inverse association between leptin levels in HM and infant weight gain,^2,4 its influence on childhood growth is not yet well established.²

Previous studies have shown an association between ARHs and other bioactive compounds presents in HM and obesity prevention,⁸ but in the case of leptin in HM, a direct relationship with infant body weight has not yet been clearly established.⁴

The purpose of this literature review was to establish whether there is a direct relationship between the ARH leptin present in HM with infant growth and weight gain and if the leptin transferred to the infant through HM influences satiety and basal metabolism. In addition, the existing evidence on the mechanism by which leptin influences the capacity of the infant to self-regulate intake has been reviewed.

Materials and Methods

A preliminary search performed to assess the prevalence of other reviews covering the possible association between leptin in HM and infant weight gain was performed. The databases on which the query was performed to identify the publications eligible for inclusion in the review were EMBASE and MEDLINE (accessed from PubMed). The literature search was conducted using the following search terms in both databases: ([“leptin” AND “breast milk/human milk”] AND “infant growth/weight gain”).

Moreover, the authors have used the following search filters: articles published from January 1, 2015 up to December 31, 2019, the exclusion of animal studies and publication in English, French, or Spanish. Figure 1 shows the search strategy followed for this review. A total of 237 articles were identified. An initial screening performed by two of the authors identified 134 candidate studies. The initial screening of the studies was performed using the information available in both the titles and the abstracts. These potentially relevant studies were retrieved in full text and assessed for eligibility according to the following criteria:

FIG. 1.

Article identification and selection.

the inclusion of human infant as study subjects.

the conduction of an exposure assessment to leptin during BF or early childhood.

Any perceived conflict regarding eligibility for inclusion was taken to a third author for resolution. The studies not included were excluded due to the following: (1) information in the abstract and/or title (n = 31), (2) not a peer-reviewed publication (congress presentation) (n = 8), (3) not a peer-reviewed publication (letter to the editor) (n = 4), (4) full text was not available (n = 16), (5) used animal models (n = 35), (6) written in a language other than English, French, or Spanish (n = 1), and (7) which did not address the subject of interest (n = 21).

The publications were included in the analysis only if they met all the eligibility criteria. After a full assessment of the potentially relevant studies, 18 were proposed to be included in the present review.

While this work is not intended to be a systematic review or meta-analysis, when writing this article, the authors considered the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) recommendations’^9–11 methodological norms as a guide for this work and applied them when possible.

The literature search initially yielded a total of 237 articles for consideration. Duplicates (n = 134) were eliminated, and the title and abstract were evaluated taking into account the established inclusion criteria (original research and review article, human subjects, full-text availability, language, and relevant content). After assessment, 18 articles were eligible to be included in this review. The selection procedure used to identify the articles is shown in Figure 1.

During the analysis of the results from the different studies, the authors noticed how these had been expressed either in a nonhomogeneous or in a nonstandardized manner. Therefore, the authors have attempted to present the results of each study as similarly as possible for better comparison.

Results

The characteristics of each study included in the review are summarized in Tables 1 and 2. Table 1 summarizes the research design of each study, the age and sex of the subjects, the sample size, division by groups if applicable, and if effects can be observed in the prevention of obesity in infants. The methodological characteristics and results are summarized in Table 2, where the methodology used by each study included in this review is shown, as well as the results obtained and the existence of potential biases and limitations for each study.

Table 1.

Characteristics of the Studies Included in the Literature Review on Leptin and Its Association with Childhood Growth

Author (year of publication)	Design of the investigation	Age and sex of the subjects	Sample size (n)	Groups	Effects on the prevention of obesity in infants
Verzura et al. (2019)⁴	Nonexperimental, field, longitudinal prospective study.	Women (age does not apply). Healthy term infants.	Nursing mothers (n = 20) and their babies (n = 20).	Mothers according to their BMI: 2 groups, 50% normal weight and 50% overweight.	Correlation tests do not allow conclusions on the effect of leptin and anthropometric growth of the infant, probably due to the sample size and the need to investigate other bioactive molecules.
Rolland-Cachera et al. (2015)¹	Longitudinal study.	Healthy term infants. Subsequent follow-up until adulthood.	126 children at 6 years old.	Not applicable.	These studies demonstrate the importance of feeding young children in their future health. Significant relationships between nutrient intake at the beginning of life and the development of FM were highlighted. However, more studies (particularly intervention) are needed to confirm the role of early nutrition in the genesis of obesity.
Nuss et al. (2019)²	Prospective cohort study.	Women of 30 years. Infants 5.5 weeks of age.	Pregnant women (n = 33) and their healthy term infants (n = 33).	Mothers according to their BMI: group I normal weight (n = 18) and group II overweight (n = 15).	More studies are needed to assess the long-term effects of this intervention.
Breij et al. (2017)¹⁸	Birth Cohort Study (Sophia Pluto Study).	Healthy term infants.	Healthy term infants (n = 197)	Classification of infants by sex: girls (n = 93) and boys (n = 104)	The hormone leptin was associated with body composition in babies at 3–6 months of age. Other studies will be helpful in further elucidating whether ARHs contribute to metabolic health programming in adulthood.
Larrosa-Haro et al. (2019)⁵	Nonrandomized cohort study.	Women of 23.6 years.	Nursing mothers (n = 131) and their babies (n = 131).	2 groups: exclusive BF (56.5%) and partial BF (43.5%)	There were significant differences with leptin that could have different interpretations. The leptin concentration in maternal serum is highly correlated with the concentration in HM.
Kaya et al. (2016)²⁰	Prospective cohort study.	Infants between 14 and 28 days of age.	Infants (n = 62)	2 groups: exclusive BF (n = 52) and partial BF (n = 10).	There were no differences in terms of diet and sex in leptin levels in the neonatal period. Furthermore, no correlation was found between weight, length, or BMI and serum leptin levels.
Cannon et al. (2017)⁶	Prospective cohort study.	Nursing mothers, 32 years old. Infants, 10 weeks old.	Nursing mothers (n = 20) and their exclusively breastfed babies (n = 20).	Not applicable.	There was no association, possibly due to sample size, between bioactive composition of the HM and the adiposity of the infant.
Vásquez-Garibay et al. (2019)¹⁹	Cross-sectional analysis.	Nursing mothers between 22 and 24 years old. Infants, 16 weeks old.	Nursing mothers (n = 167) and their babies (n = 167).	3 groups: exclusive BF (n = 74), partial BF (n = 56), and substitutes of HM (n = 37).	Mother–infant couples with exclusive BF had more significant direct correlations of ARHs than those who received substitutes of HM, suggesting that exclusive BF (due to its bioactive components and regulatory mechanisms), protects against subsequent risk of obesity.
Brunner et al. (2015)¹²	Randomized clinical trial (data from the INFAT study).	Pregnant women from 18 to 43 years old. Healthy term infants.	Pregnant women (n = 208). Nursing mothers at 6 weeks (n = 152) and at 4 months (n = 120). 118 children were examined at 2 years.	2 groups: intervention group (supplemented with 1200 mg of PUFAs n-3) and control group (nutritional counselling).	An inverse relationship of leptin with infant weight, BMI, and lean HM was found at 4 months of age in infants. No subsequent significant relationships were found.
Patel et al. (2018)¹⁵	Multicenter, randomized, controlled trial.	Women of 30 to 32 years old.	Nursing mothers (n = 353) and their babies (n = 353).	Classification of mothers according to the type of babies feeding: exclusive BF (n = 165), FF (n = 161) and mixed BF (n = 27).	Measures of appetite in general were associated with measures of adiposity, weight, and recovery growth. These findings strongly support the provision of BF support of obese women. More research and replication with other birth cohorts is required regarding the effects of ARH.
Hellmuth et al. (2018)²¹	Secondary analysis of PreventCD (prospective, double-blind, placebo-controlled, randomized study).	Women of 33.6 years old. Infants, 0–3 months of age.	Nursing mothers (n = 196) and their babies (n = 196).	Not applicable.	The determined HM hormones showed a weak association with the infant serum metabolites.
Gila-Diaz et al. (2019)³	Bibliographic review.	Preterm infants (<37 weeks of gestation).	14 studies on leptin between the period of 1997 to 2019 were examined.	Not applicable.	The results present some controversy. Topics, such as maternal eating habits and metabolic status, deserve further investigation.
Eriksen et al. (2018)⁷	Bibliographic review.	Infants from 1 to 6 months of age.	6 studies on the hormones present in milk between the period of 2015 to 2017 were examined.	Not applicable.	The available evidence is limited in how the composition of the BF influences the growth of the baby and its composition. More longitudinal studies are necessary to assess these long-term effects.
Lemas et al. (2016)¹³	Bibliographic review.	Not applicable.	20 studies on the composition of BF and its hormones content between the period of 1997 to 2015 were examined.	Not applicable.	No association was found with the risk of obesity. Further research should consider the role of hormones in HM in the development of the gut microbiome to attenuate the risk of pediatric obesity.
Marseglia et al. (2015)¹⁴	Bibliographic review.	Healthy term infants.	10 studies on the leptin present in HM and the obesity prevention mechanism between the period from 1998 to 2015 were examined.	Not applicable.	BF seems to represent a protective factor for obesity in childhood. Certain maternal factors influence this relationship. More research is needed to improve knowledge about overweight/obesity and BF, especially regarding its composition.
Briffa et al. (2015)¹⁶	Bibliographic review.	Not applicable.	Studies on the leptin present in the HM between periods from 1997 to 2015 were examined.	Not applicable.	There is an increase in leptin concentrations in the HM that can affect postnatal growth and development. Overall, there appears to be an emerging link between leptin dysregulation in pregnancy and development and altered organ function that can lead to disease in adulthood.
Socha et al. (2016)¹⁷	Bibliographic review.	Healthy term infants.	8 studies on the composition of BF and the effects on the prevention of childhood obesity between the period of 2013 to 2016 were examined.	Not applicable.	The evidence from the different clinical trials shows a strong relationship between the feeding of infants and the risk of childhood obesity. These effects are related to the concentration of bioactive compounds present in the HM. More research on these issues is necessary to provide new lines of prevention.
Nouri and Tarighat-Esfanjani (2016)⁸	Systematic review.	Nursing mothers and their babies (in addition to other studies).	27 studies on the mechanisms of BF in the prevention of obesity between the period of 2005 to 2015 were examined.	Not applicable.	Recent evidence suggests that BF can prevent obesity risk not only in childhood but also in other periods of life, through various mechanisms, including hormones and bioactive compounds present in HM. Future studies on the mechanisms of BF will be of special interest, especially controlling for cofounding factors, such as maternal BMI.

ARH, appetite-regulating hormone; BMI, body mass index; FF, formula fed; FM, fat mass; HM, human milk; PUFAs, polyunsaturated fatty acids.

Table 2.

Methodology and Results of Included Studies

Author (year of publication)	Methodology	Results	Potential biases and limitations of the studies
Verzura et al. (2019)⁴	In this nonexperimental study, the leptin concentrations in mature milk and blood serum of 20 exclusively BF mothers were investigated using the ELISA method, and were related to the anthropometric measurements of their infants during the first 6 months of life. In mothers, BMI was determined and leptin values were investigated in 20 samples of mature milk and blood serum in months 1, 3, and 6 postpartum, and in infants, anthropometric development at birth was evaluated and on reaching 1, 3, and 6 months of life.	The results showed that the correlation between leptin in mature milk and the weight of infants was negative at 1 month of birth and positive at 3 and 6 months of life, whereas with height it was negative at months 1 and 6 and positive in month 3. These variations in the weight and height correlation records were not statistically significant.	No conclusions could be drawn about the effect of leptin on the anthropometric growth of the infant, due to the sample size and the need to investigate, in addition to leptin, other bioactive molecules involved in the regulation of energy balance, in maternal blood serum and milk.
Rolland-Cachera et al. (2015)¹	This is a longitudinal study that reports the findings of the ELANCE study; a contrast to the results of this study with more recent studies on early infant feeding and the risk of obesity in adulthood. Epidemiological data are presented.	Low lipid intake early in life was shown to be associated with an increase in FM and leptin concentration at age 20, suggesting that leptin resistance was programmed by early lipid restrictions.	The data presented in this work have suggested other avenues of research, but more studies, particularly intervention, are needed to confirm the role of early nutrition in preventing obesity.
Nuss et al. (2019)²	In this prospective cohort study, blood leptin and exclusive BF were compared between the prepregnancy BMI groups: group I (normal weight) and group II (overweight/obesity), with weight, length, head circumference, and % of FM of the infant.	The total leptin values present in the BF in the group of women with normal weight were negatively correlated with measures of infant growth in their infants. No relationship was observed in overweight/obese women.	There is no known information describing a possible mechanism for the relationship of BF leptin to maternal BMI and measures of child growth in human subjects, linking it to adverse health outcomes later in life. The resulting resistance to leptin would probably result in unfavorable energy consumption and expenditure and would favor the development of obesity.
Breij et al. (2017)¹⁸	In this cohort study, in 197 healthy term infants, serum leptin levels (among other parameters) were measured fasting at 3 months and in 41 infants also at 6 months and their association with type of feeding was reported. and the percentage of longitudinal fat mass (% of FM by plethysmography) at 1, 3, and 6 months and visceral and subcutaneous abdominal fat (ultrasound) at 3 and 6 months.	Serum leptin levels in infants were significantly higher in the FF group compared with the HM-fed group at 3 months of age. Interestingly, all ARHs were different between formula-fed infants compared with breastfed infants.	Further studies are needed to identify the underlying mechanisms and possible implications for the possible programming effects of serum ARHs on posterior body composition. No differences in ARH between boys and girls could be identified. Hormone levels in the HM were also not investigated, only in blood samples.
Larrosa-Haro et al. (2019)⁵	This cohort study was performed on 131 mother–infant dyads who were admitted to a physiological postpartum ward. Independent variables: type of diet, complete BF (56.5%) and partial BF (43.5%). Dependent variables: serum leptin concentration (ng/mL), pretested and post-tested HM at eight and 16 weeks. Subjects were evaluated at 2 and 4 months.	The leptin concentration in HM was higher in the group of exclusive BF at eight and 16 weeks. Leptin concentration was higher in serum than in HM in both groups. These values showed a direct and significant linear correlation. In some cases, it was not possible to obtain enough HM to analyze the ARH, particularly in the postprandial sample.	It is probable that the characteristics of the mother were confounding factors (especially regarding her body composition and adiposity) and had a greater influence on the concentration of hormones in HM.
Kaya et al. (2016)²⁰	This prospective study was conducted in sixty-two 14–28-day old infants, 26 females and 36 males. The age, height, and body weight of the patients were recorded. Feeding status was also recorded. Infants were divided into two groups: those who received exclusive BF and those who received BF and FF. Plasma leptin levels were measured using an enzyme-amplified sensitivity immunoassay (EASIA).	No significant difference was found between leptin (p = 0.228) in terms of feeding status. There was also no significant difference between sex in terms of leptin levels (p = 0.775).	The limitations of this study were the small sample size and the general neonatal period was not included.
Cannon et al. (2017)⁶	In this cohort study, infant gastric volumes were calculated from ultrasound imaging of the infants' stomachs (n = 20) taken before and after BF, and then every 12.5 min (median; range: 3–45 min) until the next feeding. Skim leptin and macronutrient concentrations were measured and doses calculated.	No relationship was found between leptin concentration and dose and time between meals or residual stomach volumes before subsequent feeding). Post-feeding stomach volumes (GE rate) were not associated with leptin concentration or dose.	We were unable to show any relationship between the concentration of leptin in skim milk and the dose of leptin administered during BF and the rate of gastric emptying or the time between meals of infants.
Vásquez-Garibay et al. (2019)¹⁹	In a cross-sectional analysis, 167 mother–infant dyads were enrolled at the Hospital Civil de Guadalajara: 74 complete BF, 56 partial BF, and 37 receiving HM substitutes. Serum leptin levels (ng/mL) (among other parameters) were measured. We performed a one-way analysis of variance, the unpaired Student's t-test, Tukey's post hoc test, and Pearson's correlation.	The total sample at 16 weeks postpartum included 167 dyads. The mean age was 16 ± 1 weeks. In their results, there were no significant differences in serum leptin concentration in 4-month-old infants between the 3 groups, but mother–infant dyads fed with exclusive BF did have more significant direct correlations of ARHs than those who received HMS.	The main limitation of the study was that the number of babies fed with HMS was less than those who received exclusive BF and partial BF.
Brunner et al. (2015)¹²	In this controlled trial, 353 pairs of mothers and infants attended a 6-month postpartum follow-up visit, during which they completed the Baby Feeding Behavior Questionnaire. Infant body composition measures were also taken. Using regression analysis, we examined the relationships between diet and composition and body growth (among other aspects).	Infants fed with formula milk from obese women compared with exclusively breastfed infants showed higher z-scores for weight (mean difference 0.26; 95% confidence interval 0.01–0.52), higher rate of weight gain (0.04; 0.00–0.07), and higher catch-up growth (2.48; 1.31–4.71).	No previous studies reporting results in infants at 6 months of age limited to a study of obese women is unknown. This research did not specifically study whether its results were caused by the content of the ARH present in the BF or if it was due to the macronutrient composition of both forms of diet.
Patel et al. (2018)¹⁵	In this randomized clinical trial, samples of HM were collected from mothers who exclusively or partially breastfed at 6 weeks (n = 152) and 4 months (n = 120) after delivery. Leptin was determined in skim HM and evaluated for infant growth and FM by measures of skin fold thickness. A total of 118 children were examined at 2 years.	Leptin concentration in milk at 4 months was inversely associated with infant weight and body mass significantly. Milk leptin levels were slightly lower at 4 months compared with 6 weeks postpartum. Leptin from the HM was largely unrelated to infant anthropometric measurements at later times.	The biases and limitations of the study were the considerable loss of follow-up up to 2 years of life and treatment with n-3 LCPUFA in a part of the study population, which could be masking or affecting the relationship between leptin in the HM and the child outcomes. It should also be considered that both milk samples within the study reflected mature milk.
Hellmuth et al. (2018)²¹	In this secondary analysis, 196 pairs of mothers and babies from a European research project (PreventCD) were analyzed. The samples of HM collected at month 1 and 4 after birth were analyzed to determine the content of classes of macronutrients, hormones, and FA. Associations between milk components and infant metabolites were analyzed.	The fat content in milk in the first month was weakly related to ARH and only weak associations were shown with infant serum metabolites.	No information was available on the amount of milk intake in infants, which might have been more important in determining the amount of macronutrient intake rather than their concentrations in milk. It was assumed that a lower amount of fat and protein would result in a lower caloric content in the BF.
Gila-Diaz et al. (2019)³	This literature review summarizes several studies that discuss the role of some bioactive factors present in BF, with specific attention to the differences between HM from preterm and term babies. Their role in development and possible beneficial actions on neonatal and long-term health of premature babies are also summarized.	Various studies report that the bioactive factors present in milk, such as ARH (among other components) are of special interest and it has been shown that the highest levels are found in colostrum. It is also interesting to note that these bioactive factors are higher in premature infants compared with the milk of full-term babies, however the literature review evidences some controversy.	There is insufficient clinical evidence to show that raw HM is better than donated milk for infant growth.
Eriksen et al. (2018)⁷	This literature review highlights relevant studies published between 2015 and 2017 on the composition of HM and the association with infant growth.	Recent observational studies show that macronutrient concentrations in HM probably have a major influence on infant growth and body composition. Studies examining hormone concentrations in HM suggested a functional relevance for the growth of infants. However, it was reported that the association with HM in relation to infant growth is still speculative and more research is needed.	There is limited evidence available on how the composition of HM influences infant growth and body composition. The few observational studies available suggest functional implications of the composition of the HM and a significant importance for childhood growth.
Lemas et al. (2016)¹³	The objective of this review is to describe maternal factors such as feeding practices and the use of antibiotics that can influence the infant gut microbiome and the risk of obesity. The complex components in HM have many nutritional benefits for the baby; we discuss maternal antibiotics and the effects on BF as critical exposures that alter the baby's gut microbiome and influence the risk of pediatric obesity.	ARHs are present in HM and have been associated with the development of pediatric obesity. Several studies have reported that leptin concentrations in BF at the age of 1 month were associated with lower body weight and adiposity in exclusively breastfed infants. Leptin was established as an important factor that optimally regulates the infant's body weight through BF.	There is little evidence of how the micronutrient content of the BF influences the infant gut microbiome and pediatric obesity. Further research should consider the role of BF and its hormone content in the development of the infant microbiome to attenuate the risk of pediatric obesity.
Marseglia et al. (2015)¹⁴	Bibliographic review summarizing the available findings on the possible relationship between BF and the prevention of obesity development through different meta-analyzes and main and recent existing reviews.	The role of BF in protecting against the development of obesity can be attributed to different factors. The duration of BF can directly influence the baby's ability to self-regulate milk intake and infant growth. The hormones present in the HM have a positive effect on satiety, basal metabolism, and are correlated with the weight gain of infants.	There are certain confounding factors in several studies, such as overweight before pregnancy, which may influence the effects of BF. These factors can hide and/or change the critical role of BF. The studies remain controversial and are often conducted in different populations.
Briffa et al. (2015)¹⁶	Bibliographic review summarizing the evidence for leptin in playing an important role in organogenesis, which can negatively affect the risk of developing many diseases in adulthood.	Leptin's main physiological role is to regulate hunger and satiety by crossing the blood–brain barrier and acting on different neurons, decreasing hunger and satiety and increasing energy expenditure.	There appears to be an emerging link between leptin dysregulation in pregnancy and development and altered organ function that can lead to disease in adulthood. Numerous investigations on these subjects were carried out in animal models. The need for further studies in human models is suggested to more clearly conclude the role of leptin in humans in preventing obesity.
Socha et al. (2016)¹⁷	This literature review summarizes data from a RCT showing that low-protein infantile formula milk produces a lower BMI at 2 and 6 years. The hormone leptin was considered important as an endocrine regulator of obesity. Leptin was related through various studies to BMI.	One of the many parameters evaluated in the RCT study showed that leptin concentration was higher in girls than in boys. Leptin was also investigated in babies whose obesity was assessed in adulthood. Many authors concluded that higher leptin levels may be inversely associated with BMI in childhood.	It is difficult to interpret the results related to leptin and other hormones present in HM, since they come mainly from observational studies. The role of these hormones in relation to obesity is unclear. Many results are conflicting, and the authors identified several risk factors for altered levels of childhood adipokines, including increased maternal consumption of sugary drinks during pregnancy and increased birth weight.
Nouri and Tarighat-Esfanjani (2016)⁸	In this systematic review, we searched for terms in the PubMed and Science direct databases: “BF” plus obesity, and “HM” plus obesity from 2005 to March 2015. The search was limited to articles with English language. Review articles, case reports, abstracts at symposia and conferences, studies on preterm infants and unhealthy infants, nonhuman studies, and unpublished studies were excluded. Based on a critical evaluation, the eligibility of the included articles was evaluated.	We reviewed 18 studies on the comparison of the effects of the type of diet, 7 studies on hormones and bioactive compounds in BF, and 2 studies on the content of macronutrients in BF. Most of the studies showed a positive association between hormones and bioactive compounds in BF and the prevention of obesity.	In the present study, little research was evaluated on the content of macronutrients in BF and its bioactive components, and therefore it is difficult to conclude about the effectiveness of BF in the prevention of obesity.

BF, breastfeeding; ELISA, enzyme-linked immunoassay; FA, fatty acids; FM, fat mass; GE, gastric emptying; LCPUFA, long chain polyunsaturated fatty acids; RCT, randomized controlled trial.

Leptin in HM and infant anthropometry

Brunner et al.¹² observed that the leptin concentration in HM at 4 months after delivery was inversely associated with the weight and body mass of the infant, but no relationship was found at later stages.¹² Similar results were obtained in another study carried out by Nuss et al.,² where the results showed that, in the women with normal weights, total leptin values present in HM were negatively correlated with the measures of infant growth.² In the nonexperimental field study carried out by Verzura et al.,⁴ there was a negative correlation between leptin in mature milk and the weight of infants at 1 month and a positive correlation at 3 and 6 months. Meanwhile for height, the correlation was negative at months 1 and 6 and positive at month 3.⁴ However, these variations in the correlation records with weight and height were not statistically significant.⁴

In the review carried out by Lemas et al.¹³ on BF and the development of childhood obesity, the included studies reported that leptin concentrations in HM at the age of 1 month were associated with lower body weight and fat in exclusively breastfed infants. Leptin was established as an important factor that optimally regulates infant body weight through BF.¹³ The study by Larrosa-Haro et al.⁵ showed that the concentration of leptin in milk was significantly higher at 8 weeks postpartum than at 16 weeks in the exclusive BF group, and related these results to other studies that reported the higher adiposity that characterizes the infant in the fourth month of life.⁵ Other reviews, such as that carried out by Eriksen et al.,⁷ suggested a functional relevance of hormone concentrations in HM in the growth of infants.

The systematic review by Nouri and Tarighat-Esfanjani⁸ reviewed studies based on the comparison of the type of infant feeding, hormones, and bioactive compounds in HM, macronutrient content, and infant body composition. The review included studies that indicated that leptin present in HM was negatively correlated with infant body mass index (BMI) at 18 and 24 months of age when compared against formula-fed infants. However, at the same time, the authors reported that the risk of obesity is not yet clearly associated with leptin concentrations in HM.⁸

Leptin in HM, satiety, and self-regulation in the infant

Although the research on leptin in HM and its effects on self-regulation is still unclear, some studies included in this review highlighted the possible effect on appetite and satiety signals in the infant fed with HM.

The study carried out by Verzura et al.,⁴ suggested that BF influences the infant's appetite, satiety, and body weight, possibly due to the hormones contained in HM and not in formula.⁴ Along the same lines, in the bibliographic review carried out by Marseglia et al.,¹⁴ the authors indicated that the role of BF in protecting against obesity could be attributed to different factors; one of the main ones being the duration of BF, which could directly influence the baby's ability to self-regulate its intake and growth, due to the ARHs present in HM. This review also described that the ARHs presented in HM exerted a positive effect on satiety and basal metabolism and correlated with the weight gain of infants.¹⁴

The study by Larrosa-Haro et al.,⁵ attributed the ability for BF infants to better self-regulate to the composition of HM. However, the authors reported that the mechanisms of self-regulation associated with the presence of ARH in HM are still unclear.⁵ In the study by Patel et al.,¹⁵ where feeding was assessed using the Baby-Eating Behavior Questionnaire, did not observe any difference in satiety between the different modes of infant feeding.¹⁵ On the other hand, in the review carried out by Briffa et al.,¹⁶ the authors described the physiological role of leptin in regulating hunger and satiety in the individual, and concluded that the effects of this ARH on two types of neurons of the hypothalamus, result in a decrease in food intake, and an increase in satiety and in energy expenditure.¹⁶

Leptin concentration in blood serum and type of infant feeding

A group of studies comparing the concentration of leptin and other appetite regulators in blood serum, according to the type of diet the infant received, was also reviewed.

The bibliographic review of Socha et al.¹⁷ summarized the results of a randomized controlled trial (Childhood Obesity Project), where the findings on leptin concentration in blood serum were compared with the findings of other studies. Higher levels of leptin in blood serum were found in infants fed exclusively with HM and, consequently, formula-fed infants had higher BMI values at follow-up.¹⁷

In contrast to the previous results, in the study by Breij et al.¹⁸ involving 197 infants, blood serum leptin levels were significantly higher in the formula-fed group at 3 months of age. Leptin levels were positively correlated with the percentage of subcutaneous fat at 3 months of age, but not with the percentage of visceral fat.¹⁸

Meanwhile, the study by Vásquez-Garibay et al.,¹⁹ carried out in 167 mothers with their babies, found that there were no significant differences in blood serum leptin concentration in 4-month-old infants depending on their feeding type. The prospective study by Kaya et al.²⁰ could neither observe any significant difference in terms of leptin values in infants and their type of diet, nor could any correlation be found between weight, length, or BMI and serum leptin levels, indicating the need for more research in this field.²⁰

Discussion

Association between the concentration of leptin in HM and infant growth

In this literature review, information was collected on the presence of the ARH leptin in HM and its relationship with growth and weight gain in children. Studies with information on the concentration of this hormone in blood serum depending on the type of feeding have also been evaluated. The results of this review show that the concentration of leptin in HM has been inversely associated with infant growth and weight gain and a difference in the serum concentration of leptin with type of feeding has also been observed. Furthermore, leptin in HM appears to aid in self-regulating infant intake and to influence the center of satiety, however, these findings remain controversial.

Some studies have shown a significant correlation between leptin concentration in HM and childhood growth. The research carried out by Brunner et al.¹² and Nuss et al.,² found an inverse relation between the values of this hormone in HM and the weight of infants, which is consistent with the theory that the authors put forward that leptin plays a direct role in regulation of infant appetite and weight early on.^2,12

However, in the study carried out by Verzura et al.,⁴ the variations in the correlation records with weight and height in relation to the concentration of leptin in mature milk were not statistically significant, and the authors concluded that the results of their work suggested that in the first month of life, the nutrients and bioactive molecules contained in milk had not yet reached stable concentrations, and confirmed the possible effect of HM leptin on weight gain from the first month of life of the infant onward.

Other studies that compared these results did not report a correlation between leptin concentrations in mature milk and the weight of infants, and this reinforced the hypothesis that in addition to leptin, other molecules and bioactive components present in milk would be involved in the anthropometric development of the infant and should be studied.⁴

Lemas et al.,¹³ in their review on BF and the development of childhood obesity, reported the association of the concentration of leptin in HM with the body weight and adiposity of the infant, although the mechanisms are often defined in animal and nonhuman models, and these authors highlight the importance of more research in this field in human subjects.¹³ The study carried out by Lemas et al.¹³ reported that maternal BMI can be a confounding factor in the relationship of these hormones with infant weight. This study also reported that the composition of macronutrients in HM, as well as bioactive components, also depends on other factors that include the maternal environment, the time of delivery, the stage of lactation, the maternal diet, and the frequency of lactation.

For the study of this hormone in HM and its relationship with the anthropometry of the infant, variables such as the mother's diet and eating pattern, both in the prepregnancy period and during pregnancy and lactation, have been considered as relevant.¹³

Eriksen et al.⁷ included in their review studies that examined the hormonal concentrations in HM, where they concluded that the evidence on the composition of HM in relation to infant growth is limited. The authors report that the few observational studies available suggest functional implications of the composition of the mother's milk and a significant importance for infant weight gain.⁷

The importance of further research in this field must be highlighted as there remains some controversy regarding the association of the components of HM, especially ARHs, with childhood growth. For example, the aforementioned review by Eriksen et al.,⁷ reported that the association of bioactive components of HM in relation to infant growth needed further investigation.

Leptin in HM: satiety and self-regulation of the infant's intake

Another aspect identified in some research selected for this review is the self-regulation of intake in the infant for the prevention of obesity in adulthood. In the study by Patel et al.,¹⁵ it was reported that infants exclusively fed with HM can self-regulate energy intake according to their needs, unlike FF babies. They could observe a better relationship of the infant with food, as well as a greater enjoyment and satiety capacity in those fed exclusively with HM, thanks to the composition of HM compared with FF.¹⁵ This result agrees with the bibliographic review carried out by Marseglia et al.,¹⁴ where several included studies indicated that the duration of BF could directly influence the baby's ability to self-regulate its milk intake and growth, due to the hormones present in milk.

These ARHs have a positive effect on satiety and basal metabolism and are correlated with weight gain in infants. Therefore, these authors conclude that the protective role of BF against the development of obesity could be explained in part by the composition of HM and by the presence of ARH.¹⁴

On the other hand, in a cohort study, Larrosa-Haro et al.⁵ demonstrated that, in the group of mothers who fed with exclusive BF, the concentration of leptin in HM was significantly higher at 8 weeks postpartum than at 16 weeks. The authors mentioned that these results could be due to the greater adiposity that characterizes the baby in the fourth month of life. Furthermore, another aspect that these authors highlighted was the baby's ability to self-regulate its intake due to the composition of the HM, unlike infants fed with formula milk. However, these mechanisms are not yet precisely known.⁵

Other investigations reported on the form of transmission of leptin to the infant. This hormone is produced and secreted by the mammary epithelial cells in the milk fat globules, and this is how it is transmitted to the infant. The review by Gila-Diaz et al.,³ reported that the highest levels of ARH are found in colostrum, results that the authors interpret as a great importance of the first hours of BF for the transmission of these hormones, especially leptin, to the infant.³

Concentration of leptin in blood serum of the infant in accordance with their type of feed

Other studies wanted to compare the concentration of leptin in blood serum according to the type of feeding of the infant, and in a systematic review on the mechanisms of BF in the prevention of obesity, the authors reported that the leptin present in HM negatively correlates with infantile BMI in exclusively breastfed infants,⁸ a result that is also supported by other studies summarizing the role of this hormone in infantile anthropometry, where their findings show higher levels of leptin in blood serum in fed infants exclusively with HM compared with those fed with formula milk, and as a consequence, formula-fed infants have higher BMI values in the study follow-up.¹⁷ The authors conclude that leptin is transferred from the HM to the infant's blood serum and consequently exerts a direct effect on the regulation of infant weight.

However, the results are often conflicting. The studies carried out by Gila-Diaz et al.³ and Breij et al.¹⁸ showed higher serum leptin values in the infant fed with formula milk compared with infants exclusively fed with HM at 3 months of age, and these values were directly correlated with the percentage of fat mass (FM) in the infant, which explains that the serum leptin values directly reflect the content of body FM.^3,18

The different results of the studies are often controversial and can be explained by numerous confounding factors, because the investigations have been conducted differently and the recruited population does not meet the same inclusion criteria. Due to this contradiction, it is necessary to carry out more studies where a population with the same inclusion criteria is included and if possible, with a higher number of participants, so that there is a more exhaustive analysis of the relationship of the leptin with growth and weight gain in children.

However, the results found in the different investigations are still controversial. The review study by Kaya et al.,²⁰ which also aimed to compare several studies that investigated serum leptin values in the infant and their diet, were unable to find any type of relationship between these two variables, nor to establish a correlation with infant weight.²⁰ This is because the evidence currently available comes from observational studies, and often does not meet well-defined and common inclusion criteria, nor does it have many participants. Several authors report the need to carry out more studies on the ARH present in HM and its influence on the growth and increase of infant weight, in a well-defined population, controlling for several confounding factors and, if it is possible, with a larger sample size.

Conclusion

This review highlights some studies on the composition of hormones in HM and their association with infant growth. Evidence shows that the ARH leptin present in HM has a direct effect on the growth and development of infant weight. In evaluating the studies included in this review, it has been concluded that leptin present in HM, among other bioactive components, has an important role in the basal metabolism of the infant. The highest levels of this hormone have been found in colostrum, compared with other times of lactation. Several authors argue that the duration of BF is a key point that directly influences the baby's ability to self-regulate its intake and growth, due to the components present in the mother's milk.

However, the mechanism by which leptin is related to infant weight gain is still unclear, as the results are often controversial. The authors agree that more research is needed on the role of this hormone in the regulation of the infant's body weight, carrying out more interventional studies, with a higher number of participants and well-established inclusion criteria. A variety of maternal confounding factors, such as BMI, diet, and lifestyle, among many others, are often neglected.

Footnotes

Authorship Confirmation Statement

All authors meet ICMJE criteria for authorship, including approval of the final article, and are able to take public responsibility for the work and have full confidence in the accuracy and integrity of the work of other authors.

Disclosure Statement

No competing financial interests exist.

Funding Information

No funding was received for this article.

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