Milk Leptin Levels Research Articles

The association between maternal factors and milk hormone concentrations: a systematic review.

Breast milk is the gold standard for infant feeding. It is a dynamic biological fluid rich in numerous bioactive components. Emerging research suggests that these components, including hormones, may serve as signals between mother and offspring. From an evolutionary perspective, maternal hormonal signals could allow co-adaptation of maternal and offspring phenotype, with implications for their Darwinian fitness. However, a series of steps need to be considered to establish the role of a component as a signal and this systematic review focuses on one step: 'Do maternal factors influence the concentration of milk hormones?' To systematically review human studies which analyze the association between maternal factors and the concentration of hormones in breast milk. Three databases were searched for studies reporting the association of maternal factors including body mass index (BMI), weight, fat mass, age, ethnicity, smoking with hormones such as adiponectin, leptin, insulin, ghrelin, and cortisol in breast milk. Thirty-three studies were eligible for inclusion. Maternal BMI was positively associated with milk leptin (20/21 studies) and with milk insulin (4/6 studies). Maternal weight also displayed a positive correlation with milk leptin levels, and maternal diabetes status was positively associated with milk insulin concentrations. Conversely, evidence for associations between maternal fat mass, smoking, ethnicity and other maternal factors and hormone levels in breast milk was inconclusive or lacking. Current evidence is consistent with a signaling role for leptin and insulin in breast milk, however other steps need to be investigated to understand the role of these components as definitive signals. This review represents a first step in establishing the role of signaling components in human milk and highlights other issues that need to be considered going forward.

Gestational Diabetes Mellitus and Colostral Appetite-Regulating Adipokines.

Gestational diabetes mellitus (GDM) is a complex metabolic disorder that has short- and long-term effects on maternal and offspring health. This study aimed to assess the impact of maternal hyperglycemia severity, classified as GDM-G1 (diet treatment) and GDM-G2 (insulin treatment) on colostral appetite-regulating molecules. Colostrum samples were collected from hyperglycemic (N = 30) and normoglycemic (N = 21) mothers, and the concentrations of milk hormones were determined by immunoenzymatic assay. A difference was found for milk ghrelin, but not for molecules such as adiponectin, leptin, resistin, or IGF-I levels, in relation to maternal hyperglycemia. The colostral ghrelin in the GDM-G1 cohort (0.21 ng/mL) was significantly lower than for GDM-G2 (0.38 ng/mL) and non-GDM groups (0.36 ng/mL). However, colostral resistin was higher, but not significantly, for GDM-G1 (13.33 ng/mL) and GDM-G2 (12.81 ng/mL) cohorts than for normoglycemic mothers (7.89 ng/mL). The lack of difference in relation to hyperglycemia for milk leptin, adiponectin, leptin-adiponectin ratio, resistin, and IGF-I levels might be the outcome of effective treatment of GDM during pregnancy. The shift between ghrelin and other appetite-regulating hormones might translate into altered ability to regulate energy balance, affecting offspring's metabolic homeostasis.

A Diet Profiling Algorithm (DPA) to Rank Diet Quality Suitable to Implement in Digital Tools—A Test Study in a Cohort of Lactating Women

Although nutrient profiling systems can empower consumers towards healthier food choices, there is still a need to assess diet quality to obtain an overall perspective. The purpose of this study was to develop a diet profiling algorithm (DPA) to evaluate nutritional diet quality, which gives a final score from 1 to 3 with an associated color (green-yellow-orange). It ranks the total carbohydrate/total fiber ratio, and energy from saturated fats and sodium as potentially negative inputs, while fiber and protein are assumed as positive items. Then, the total fat/total carbohydrate ratio is calculated to evaluate the macronutrient distribution, as well as a food group analysis. To test the DPA performance, diets of a lactating women cohort were analyzed, and a correlation analysis between DPA and breast milk leptin levels was performed. Diets classified as low quality showed a higher intake of negative inputs, along with higher energy and fat intakes. This was reflected in body mass index (BMI) and food groups, indicating that women with the worst scores tended to choose tastier and less satiating foods. In conclusion, the DPA was developed and tested in a sample population. This tool can be easily implemented in digital nutrition platforms, contributing to real-time dietary follow-up of patients and progress monitoring, leading to further dietary adjustment.

Maternal exercise and high-fat diet affect hypothalamic neural projections in rat offspring in a sex-specific manner

This study aimed to investigate the effect of maternal high-fat (HF) diet and exercise during gestation and lactation on hypothalamic neural projection development in the offspring. Pregnant Sprague-Dawley rats were fed a CHOW or HF diet during gestation and lactation, and further divided into two subgroups: voluntary exercised and sedentary. Offspring's brains and tissue were collected at weaning and 16 weeks of age. Maternal exercise downregulated dams’ body weight and food intake during lactation, but failed to normalize increased fat weight, plasma and milk leptin levels of HF dams at weaning. Maternal HF diet significantly increased offspring's body weight, adipose depots, plasma insulin, and leptin at weaning and had long-term effect on body weight of male offspring, while maternal exercise decreased offspring's body weight from 3 to 5 weeks of age in both sexes. At weaning, maternal exercise decreased αMSH fiber density and maternal HF diet impaired agouti-related peptide fiber density in the paraventricular nucleus of hypothalamus of male pups, while maternal HF diet disrupted αMSH fiber density in the paraventricular nucleus of hypothalamus of female pups. The impaired αMSH fiber density was consistent with reduced STAT3 signaling in the arcuate nucleus of hypothalamus, while the reduced agouti-related peptide fiber density was consistent with reduced ERK1/2 signaling in the arcuate nucleus of hypothalamus. The impaired hypothalamic projections were compensated in adulthood in both sexes. Our findings suggest that maternal HF diet and exercise exerts different effects on hypothalamic neural projections development through distinct signaling pathways in a sex-specific manner.

Human Milk Hormone Intake in the First Month of Life and Physical Growth Outcomes in Preterm Infants

Human milk contains hormones that regulate metabolism. Extrauterine growth restriction remains common among preterm infants, but the effect of ingesting milk hormones on preterm infant growth is poorly understood. To quantify associations of longitudinal exposure to leptin, adiponectin, and insulin in milk with physical growth of preterm infants. In 50 preterm neonates (median gestational age 29.4 weeks), we sampled maternal milk on day-of-life 7, 14, 21, and 28 and measured hormone levels in whole milk by ELISA. Milk leptin levels were available for a subset of 18 infants. We calculated milk hormone doses by multiplying the hormone level by the milk volume ingested on each day and estimated the area under the curve (AUC) to reflect longitudinal exposure. We analyzed associations of milk hormone exposure with growth outcomes in generalized estimated equations. Weight gain velocity and z-scores in weight, length, head circumference, and body mass index at 36 weeks' postmenstrual age (PMA). Higher leptin intake was associated with greater weight gain (2.17g/kg/day [95% CI, 1.31, 3.02]) and weight z-score at 36 weeks' PMA (0.30 [0.08, 0.53] higher z-score per tertile). Higher adiponectin intake was associated with greater length z-score (0.41 [0.13, 0.69]), however, this association was nullified after adjustment of protein and calorie intake. Higher adiponectin was associated with smaller head circumference z-score (-0.36 [-0.64, -0.07]). Insulin was not associated with growth outcomes. Milk leptin and adiponectin exposures may affect growth of preterm infants. The long-term effects of milk hormones warrant further investigation.

Nutrient and hormone composition of milk is altered in rodent dams post-bariatric surgery.

Although bariatric surgery is approved for a woman of child-bearing age with an interest in subsequent pregnancy, reports of in utero growth issues during pregnancy have garnered a closer look at the impact of maternal surgical weight loss on the pre- and postpartum periods. Offspring of dams having received vertical sleeve gastrectomy (VSG) are born small-for-gestational age and have increased risk for metabolic syndrome later in life. Here, we aimed to determine whether the postnatal catch-up growth trajectory of bariatric offspring may be affected by milk composition. Milk samples were collected at postnatal day 15/16 from dams having received VSG surgery and fed a high-fat diet (HFD) (H-VSG), Sham surgery and fed chow (C-Sham), or Sham surgery and fed HFD (H-Sham). Milk obtained from H-VSG dams had elevated glucose (P < 0.05) and significantly reduced triglyceride content (P < 0.01). Milk from H-Sham dams had the lowest amount of milk protein (P < 0.05). Fatty acid composition measured by fractionation was largely not affected by surgery but rather maternal diet. No difference was observed in milk leptin levels; however, insulin, adiponectin, and growth hormone levels were significantly increased in milk from H-VSG animals. H-Sham had the lowest level of immunoglobulin (Ig)A, whereas IgG was significantly reduced in H-VSG. Taken together, the quality of milk from H-VSG dams suggests that milk composition could be a factor in reducing the rate of growth during the lactation period.

Could a remarkable decrease in leptin and insulin levels from colostrum to mature milk contribute to early growth catch-up of SGA infants?

BackgroundBreast milk is known to contain many bioactive hormones and peptides, which can influence infant growth and development. In this context, the purpose of this study was to evaluate the influence of different clinical pregnancy conditions on hormone concentrations in colostrum and mature breast milk.MethodsAn observational study was performed with mother-newborn pairs divided into five groups according to maternal clinical background: diabetes (12), hypertension (5), smoking (19), intrauterine growth restriction of unknown causes with small-for-gestational-age newborns at delivery (12), and controls (21). Socioeconomic data, anthropometric measurements and breast milk samples were collected between the first 24 and 48 h and 30 days postpartum. Leptin, adiponectin, and insulin levels in breast milk were measured by immunoassays.ResultsA significant decrease in leptin (p = 0.050) and insulin (p = 0.012) levels from colostrum to mature breast milk in mothers of small-for-gestational-age infants was observed. Maternal body mass index was correlated with both leptin and insulin, but not with adiponectin. Insulin levels were negatively correlated to infant weight gain from birth to one month (p = 0.050). In addition, catch-up growth was verified for small-for-gestational-age infants throughout the first month of life.ConclusionsThis study suggests that a remarkable decrease in leptin and insulin levels in mature milk of mothers of small-for-gestational-age newborns may be involved in the rapid weight gain of these newborns. The physiological and external mechanisms by which these significant decreases and rapid weight gains occur in this group remain to be elucidated.

Diet-induced modifications to milk composition have long-term effects on offspring growth in rabbits.

It has been clearly demonstrated that the maternal nutritional status during pregnancy and lactation has long-term effects on offspring health. In mammals, milk represents the first maternal support provided to the newborns so that its composition may play a major role in long-term programming. We therefore assessed the effects of maternal high-fat/high-sugar obesogenic (OD) or control (CD) diets on offspring growth and adiposity in the rabbit. Between 7 and 20 wk of age, the BW gain of OD milk-fed rabbits was higher than that of CD milk-fed rabbits ( < 0.05). Body fat mass measurements at 21 wk of age revealed a significant increase in body adiposity as a function of milk ingested during the neonatal period, in both female and male offspring ( < 0.05). A marked weight gain difference was observed according to the milk in both female and male offspring. Moreover, we investigated the composition in major proteins and leptin levels in milk from OD or CD diet-fed dams. Liquid chromatography-mass spectrometry analysis of individual CD skimmed milk samples enabled identification and quantification of the rabbit main milk proteins and of their main phosphorylated isoforms at 2 different stages of lactation (3 and 10 d). Here we show that the OD diet induced a reduction in the whey acidic protein content concomitantly with both an increase in serum albumin and lactoferrin contents and in the phosphorylated isoforms of the main milk proteins. Furthermore, a sharp rise in leptin levels was observed in the milk of OD diet-fed dams on Day 10 of lactation when compared with CD diet animals ( < 0.05). Taken together, these findings provide evidence that lactation is a critical window of development during which exposure to a deleterious diet is highly detrimental to long-term outcomes. Moreover, these insights suggest that it may be possible to prevent at least some of the adverse effects of inadequate maternal nutrition on the long-term metabolic outcomes of the offspring through nutritional interventions applied during the lactation period.

Offspring predisposition to obesity due to maternal-diet-induced obesity in rats is preventable by dietary normalization before mating.

We studied in rats whether the expected detrimental effects in offspring associated to maternal dietary obesity may be reverted by obesogenic diet removal 1 month before mating. Female rats were fed a cafeteria diet (CD) from days 10 to 100 and then a standard diet (SD) (postcafeteria rats). One month after CD removal, postcafeteria rats and a group of SD-fed female rats (controls) were mated with males. At weaning, offspring were fed SD and followed until 4 months old. CD was effective at inducing obesity in dams. Its removal led to a reduction in body weight, although, after 30 days, rats retained excess body weight and fat than controls. During lactation, postcafeteria dams showed greater body fat, and higher leptin and adiponectin levels in milk than controls. From 2 months of life, offspring of postcafeteria dams displayed lower body weight than controls, with no differences in the percentage of fat, homeostatic model assessment for insulin resistance, or circulating parameters. Removal of CD in obese rats before gestation, although without complete reversion of body weight excess, may prevent the expected detrimental effects in offspring associated to an excess fat accumulation in adulthood and the related metabolic disturbances.

Milk Leptin Surge and Biological Rhythms of Leptin and Other Regulatory Proteins in Breastmilk.

A significant number of chronic diseases are linked to perinatal nutrition, and prevention may be associated to naturally occurring components of breast milk. One key hormone in breast milk is leptin, related with the protection from obesity in the adulthood, thus knowing its changes through the day or lactation is crucial. We aimed to investigate the daily rhythms in the milk levels of leptin, together with other two related hormones, ghrelin and adiponectin, during lactation (days 5, 10 and 15) in rat dams, and the relation with morphometric parameters (dams and pups). Summarizing the main results, the existence of biological rhythms, but not daily and maybe circasemidian, was confirmed for the three hormones at the earliest period of lactation. The correlations performed generally showed a possible dependence of milk hormone levels on plasma levels at the early phase of lactation, while with the progression of lactation this dependence may fade and the hormone levels are suggested to be more dependent on mammary gland production/maturation. There was also a correlation between milk leptin and adiponectin levels, especially in the first half of lactation, suggesting a possible parallel regulation. Interestingly, we describe a milk leptin surge around the mid of lactation (at day 10) which may be related with pup´s growth (males and females) and with the well-known (in the literature) plasma leptin surge in pups. All this knowledge may be crucial for future applications in the development of formula milk and in relation with the role of leptin surge during lactation.

Assay of adiponectin, leptin, true insulin and ghrelin levels in preterm human milk, and its relationship with infants growth

To understand adiponectin, leptin, insulin and ghrelin levels in preterm colostrum and mature milk and their influence on the growth and development of the premature infant. The study subjects were divided into two groups: preterm group and control group. Specimens of colostrum and mature milk on 42nd day after delivery were collected, the general situation of maternal and infants growth parameters at birth and at postnatal 42 days were recorded. Leptin, adiponectin, insulin and ghrelin levels in colustrum and mature milk were determined and compared. A total of 128 mother-infant pairs were involved. There were 128 specimens of colostrums (80 from preterm group, 48 from control group) and 94 specimens of mature milk(50 from premature group, 44 from control group). The levels of colostrum, mature milk adiponectin, leptin, and insulin were not significantly different between the 2 groups; ghrelin levels in colostrum and mature milk of premature group were significantly lower than those in control group (P = 0.038), adiponectin and leptin levels in colostrum were higher than those of the mature milk (P < 0.05), colostrum ghrelin levels were lower than those of mature milk (P < 0.05). Adiponectin, leptin, and ghrelin showed no significant difference between different gestational age groups ( ≤ 34 weeks group vs. > 34 weeks group). True insulin level of mature milk in 34 weeks group was higher than that of > 34 weeks group (29.3 vs. 21.6 mU/L, P = 0.045); true insulin level in colostrums in ≤ 34 weeks group was lower than that in mature milk (21.7 vs. 29.3 mU/L, P = 0.000). Adiponectin levels in colostrum and 42 days weight gain were negatively correlated (r = -0.362, P = 0.025) . Insulin level in mature milk had a negative correlation with birth weight (r = -0.319, P = 0.029) . Ghrelin levels in colostrum and birth weight, length, head circumference, head circumference on 42(nd) day were positively correlated (r = 0.271,0.261,0.360, P < 0.05); weight, length at 42(nd) day and ghrelin levels showed borderline positive correlation (P = 0.050, 0.058). Many bioactive hormones in milk might participate in the regulation of suitable growth after birth. Premature birth affects hormone levels in breast milk. Breast feeding is very important in preterm infants.

Is variation in total antioxidant capacity of human milk associated with levels of bio-active proteins?

As the antioxidant properties of human milk may be beneficial for very preterm-born infants, it is important to identify the association between total antioxidant capacity (TAC) and bio-active proteins. Breast milk was prospectively collected (four times) on postpartum days 6 to 8, 13 to 15, 20 to 22 and 27 to 29 from 15 mothers who had delivered between 24 and 31 weeks of gestation. Skimmed milk was assayed to measure TAC and bio-active proteins (lysozyme, lactoferrin, leptin and adiponectin). The association between TAC and levels of bio-active proteins during the first month of lactation was analyzed in a regression model. Coefficient of determinations (R(2)) revealed an overall effect of bio-active proteins on breast milk TAC (R(2)=0.635+/-0.102, P<0.0001). Breast milk leptin, lysozyme and lactoferrin levels were identified as independent factors that significantly predict the concentration of TAC. The identified enhancement of the antioxidant capacity of human milk by bio-active proteins that are lacking in commercial formula supports consideration of breast milk as ideal nutrition for preterm-born neonates.

Leptin and ghrelin levels in colostrum, milk and blood plasma of sows and pig neonates during the first week of lactation

Radioimmunology was used to determine leptin and ghrelin levels in sow colostrum and milk in relation to those in sow and neonatal pig blood plasma and to the body weight of piglets during the first week of lactation. The highest concentration of leptin was found in colostrum on the second day of lactation (69.3 ± 6.3 ng/mL). Leptin concentrations in sow plasma were significantly lower than in colostrum/milk (2.19 ± 0.9 ng/mL, P = 0.7692) and were stable in the first 7 days of lactation. Total and active ghrelin concentrations in colostrum/milk were stable in the measured time points (6734 ± 261 pg/mL, P = 0.3397; 831 ± 242 pg/mL, P = 0.3988, respectively). Total ghrelin concentrations in sow plasma were lower than in colostrum/milk. These results indicate that pigs follow a unique species-specific pattern of leptin and ghrelin synthesis, release and existence, and that the mammary gland is an important source of leptin and ghrelin contained in colostrum/milk.

Developmental Plasticity in Thyroid Function Primed by Maternal Hyperleptinemia in Early Lactation: A Time-course Study in Rats

Pups whose mothers were leptin-treated during the last 3 days of lactation have thyroid dysfunction at adulthood. However, there was no report about leptin treatment in the first days of life or about its action on thyroid function during development. Here, we evaluated the effects of maternal leptin treatment on the first 10 days of lactation upon thyroid function of the offspring at 21, 30, and 180 days old. At birth, lactating Wistar rats were divided into: Leptin (Lep) - leptin-treated (8 μg/100 g of body weight, s.c.) for the first 10 days of lactation and Control (C, saline-treated). Mothers were killed at the end of lactation and their offspring at 21, 30, and 180 days old. Triiodothyronine (T3), thyroxine (T4), thyrotropin (TSH), and leptin levels in serum and milk were measured. Liver mitochondrial glycerolphosphate dehydrogenase (mGPD) activity was determined. Significant differences had p<0.05. At the end of lactation, Lep mothers had higher milk T3 (+ 30%), while their offspring had higher serum T3 (+ 20%) and TSH (+ 84%). At 30 days-old, Lep offspring showed lower TSH ( - 48%), T3 ( - 20%), and mGPDm ( - 42%). At 180 days-old, Lep group presented hyperleptinemia (1.4-fold increase), higher serum T3 (+ 22%), and lower mGPD activity ( - 57%). Maternal hyperleptinemia on lactation causes hypothyroidism in the pups at 30 days, which may program for higher serum T3 at adulthood. In conclusion, maternal hyperleptinemia during lactation, that is common in obese mothers, may have an impact in future disease development, such as thyroid dysfunction.

Leptin in Maternal Serum and Breast Milk: Association With Infants' Body Weight Gain in a Longitudinal Study Over 6 Months of Lactation

The adipokine leptin has been detected in human breast milk, but its effect on postnatal growth and development remains largely unclear. We hypothesized that leptin could affect infant's body weight gain during early lactation in the first 6 mo of life. Therefore, we evaluated leptin levels in maternal serum and breast milk of 23 healthy, lactating mothers and their neonates in a prospective, longitudinal study. Leptin concentration was quantified by a commercially available human leptin RIA. Our results showed that leptin levels in breast milk were 22-fold lower than in maternal serum, but both parameters were positively correlated to each other (r = 0.431, p = 0.001) and to maternal BMI (serum: r = 0.512, p < 0.001; milk: r = 0.298, p < 0.001) over 6 mo of lactation. A negative association was found between breast milk leptin levels during the first week after delivery and the infant weight gain from the end of the first to the sixth month (r = -0.681, p = 0.007). This suggests that milk-borne leptin provides a link between maternal body composition and infant growth and development and plays a critical role in regulating appetite and food intake during early infancy.

Leptin determination in colostrum and early human milk from mothers of preterm and term infants

Background Leptin is involved in the regulation of food intake and energy expenditure and is therefore important for growth and brain development. Analytical methods used for leptin measurement in human milk differ widely in the literature and yield varying results. Aims To compare different preparation methods for the analysis of leptin in human milk and to investigate the leptin levels in colostrum and mature human milk from mothers of preterm or term infants. Methods Mothers delivering a preterm (n = 37) or a term infant (n = 40) were recruited for a prospective study and were ask to collect breast milk on the 3rd and 28th day of lactation. Leptin, protein and fat concentrations were analysed. Clinical data of mother and child were recorded prospectively. Results Skim milk was most appropriate for leptin analysis. Human milk leptin concentrations did not differ between preterm and term human milk. In term milk, leptin concentration on day 28 was lower than on day 3 (p < 0.05). Milk leptin levels on the 3rd and 28th day were positively correlated with mothers' body mass index, but not with fat content in milk. Conclusion Skim milk was the most stabile preparation for leptin analysis. Preterm and term human milk contain leptin in equal concentrations. Human milk leptin depends on mothers' body mass index.

Evaluation of leptin in breast milk, lactating mothers and their infants

Leptin is present in human milk, but it is not clear what the relationship between breast milk (BM) leptin levels and maternal and infant serum leptin concentrations is. The objective of this study was to evaluate the leptin concentration in BM and to investigate its relationship with infants' and mothers' anthropometric parameters and with serum leptin concentration in breast-fed (BF) infants and lactating mothers. We enrolled 36 adequate for gestational age healthy, exclusively BF, term infants aged <6 months. Leptin concentration in serum and BM was determined by radioimmunoassay (RIA) test (human-leptin-RIA-sensitive, Mediagnost). Infants' and mothers' weights, lengths and body mass indexes (BMI) were measured. The median leptin concentration was 3.42 ng/ml (interquartile range (IR): 2.65) in BF infants' serum, 3.02 ng/ml (IR: 2.85) in mothers' serum (n=17) and 0.51 ng/ml (IR: 0.34) in BM (n=24). BM leptin concentrations were significantly lower than serum BF infant (P<0.001) and maternal (P<0.001) leptin levels. Infant serum leptin concentration correlated positively with infant weight (r=0.437, P=0.008) and BMI (r=0.561, P=0.004). Mother serum leptin levels correlated positively with weight (r=0.755, P<0.001) and BMI (r=0.661, P=0.007). No correlations were found between BM leptin and serum leptin concentrations in BF infants and mothers. We confirmed the presence of leptin in BM at a lower concentration than that found in infant and lactating mother serum. We observed a positive correlation between serum leptin levels in BF infants and their growth parameters.

Prolactin Inhibition at Mid-lactation Influences Adiposity and Thyroid Function in Adult Rats

Maternal hypoprolactinemia at the end of lactation (a precocious weaning model) increases milk leptin transfer and results in overweight, leptin resistance, and secondary hypothyroidism at adulthood. We studied the effects of prolactin (PRL) inhibition during mid-lactation (a partial malnutrition model) on milk leptin transfer, leptinemia, body composition, and thyroid function. Lactating rats were treated with bromocryptine (BRO, 1 mg/twice daily) or saline on days 7, 8, and 9 of lactation. Offspring were sacrificed 10, 21, and 90 days after birth. After treatment, BRO-treated dams showed hypoprolactinemia and hyperleptinemia, and produced less milk with lower levels of lactose and higher milk triglycerides. Milk leptin levels were lower at weaning. Offspring of BRO-treated dams had lower body weight and length as well as less visceral fat during lactation and adulthood. Total fat was also lower at weaning and adult life, whereas total protein was higher at 90 days-old. BRO offspring presented lower serum T4 and TSH at 10 days-old and weaning, respectively. When adults, these rats exhibited hypoleptinemia, lower levels of thyroid hormones, and higher TSH. Early inhibition of PRL therefore leads to offspring malnutrition and affects subsequent growth. Also, inhibition of PRL during lactation predisposes offspring to hypothyroidism; however, when the inhibition occurs during late lactation, the hypothyroidism is secondary, whereas when it is restricted to mid-lactation, the thyroid hypofunction is primary. The programming effect of milk suppression thus depends on the developmental stage of offspring.

Maternal obesity during pregnancy and lactation programs the development of offspring non-alcoholic fatty liver disease in mice

Obesity induced, non-alcoholic fatty liver disease (NAFLD), is now the major cause in affluent countries, of the spectrum of steatosis-to-cirrhosis. Obesity and NAFLD rates in reproductive age women, and adolescents, are rising worldwide. Our hypothesis was that maternal obesity and lactation transmit to the offspring a pre-disposition to dysmetabolism, obesity and NAFLD. Female mice were fed standard or obesogenic chow, before, throughout pregnancy, and during lactation. The critical developmental period was studied by cross-fostering offspring of lean and obese dams. Offspring were then weaned onto standard chow and studied at 3months. Read-outs included markers of metabolic dysfunction, biochemical and histological indicators of NAFLD, induction of liver fibrogenesis, and activation of pro-fibrotic pathways. Mechanisms involved in programming a dysmetabolic and NAFLD phenotype were investigated by assaying breast milk components. Offspring of obese dams had a dysmetabolic, insulin resistant and NAFLD phenotype compared to offspring of lean dams. Offspring of lean dams that were suckled by obese dams showed an exaggerated dysmetabolic and NAFLD phenotype, with increased body weight, as well as increased levels of insulin, leptin, aspartate transaminase, interleukin-6, tumour necrosis factor-alpha, liver triglycerides, steatosis, hepatic fibrogenesis, renal norepinephrine, and liver alpha1-D plus beta1-adrenoceptors, indicative of sympathetic nervous system activation. Obese dams also had raised breast milk leptin levels compared to lean dams. Maternal obesity programs development of a dysmetabolic and NAFLD phenotype, which is critically dependent on the early postnatal period and possibly involving alteration of hypothalamic appetite nuclei signalling by maternal breast milk and neonatal adipose tissue derived, leptin.

Role of leptin in early metabolic programming

Experimental studies in rodents have highlighted the relationship between early postnatal events, undernutrition during pregnancy and/or lactation and the subsequent development of metabolic syndrome, a phenomenon termed developmental programming. However, appearance of metabolic syndrome is dependent not only on prenatal or postnatal predisposition but also on type of nutrition throughout the life cycle. Those experimental findings have been supported by epidemiological data in humans, born to mothers who suffered undernutrition during pregnancy. Leptin is likely involved is such programming and maintaining a critical leptin level during development may allow normal maturation of tissues and pathways involved in metabolic homeostasis, reversing the undesired effects. Leptin disruption during a critical neonatal or prenatal window is sufficient to permanently alter long-term metabolic regulation. Thus, in rodents (in the early postnatal phase), and likely in other species such as primates, and including humans (in the prenatal period), leptin plays a major role in the development of brain circuits which affect future developmental programming of metabolic disease. As postnatal nutritional or therapeutic intervention can ameliorate the consequences of developmental malprogramming, use of leptin as an additive to milk in infant formula which, in contrast to maternal milk, which is devoid of this protein, has been suggested. Alternatively, identification of potential factors elevating leptin levels in maternal milk may also be beneficial. In conclusion, the present data highlight the importance of leptin in the developmental induction of metabolic disease and offer exciting new strategies for therapeutic intervention, by either maternal or neonatal intervention or targeted nutritional manipulation in postnatal life. Adipobiology 2009; 1: 27-34.