Neonatal Leptin Research Articles

Sugaring appetite development: mechanisms of neuroendocrine programming.

Gestational diabetes is one of the most common complications of pregnancy occurring in up to 10% of women in the Western world. The short-term risks of gestational diabetes to both mother and child, including preeclampsia, preterm delivery, and increased perinatal mortality, are well established (1). However, there is now strong evidence from both human and animal models that exposure to a diabetic environment during fetal life has substantial long-term health consequences for the child, including increased risk of type 2 diabetes and obesity (2). Much research effort has therefore been directed toward understanding the mechanisms by which such metabolic programming arises. In this issue of Endocrinology, Steculorum and Bouret demonstrate that maternal diabetes leads to impaired neonatal leptin signaling and structural disorganization of hypothalamic feeding pathways in the offspring. This is associated with leptin resistance in adulthood resulting in increased food intake and increased risk of metabolic disease (3). The concept of metabolic programming has been recognized for many years (reviewed in Ref. 4). Although initial focus was directed toward the long-term detrimental effects of fetal undernutrition and low birth weight (5), in light of the global epidemic of obesity and diabetes in women of child-bearing age, recent attention has shifted toward fetal overnutrition and high birth weight (6). Both ends of the birth weight spectrum have been associated with increased risk of type 2 diabetes and other features of the metabolic syndrome that may indicate common mechanistic pathways (7). Low birth weight is often followed by accelerated postnatal growth (frequently referred to as “catch-up growth”) and this has been shown to be particularly detrimental in terms of later obesity risk, highlighting the neonatal period as a critical time window for establishment of long-term regulation of energy balance (8). It is therefore possible that accelerated early postnatal growth may represent a commonality between animal models of low birth weight followed by catch-up growth (9) and models of maternal diabetes/obesity where suckling by such dams leads to increased weight gain during the lactation period (3, 10). The hypothalamus plays a central role in regulation of energy balance and has therefore been a major focus of experiments aimed at dissecting the mechanisms underlying the programming of obesity. Early experiments that manipulated neonatal growth and nutrient intake by variation of litter size showed programmed changes in crude measures of hypothalamic function and structure, including RNA content (11) and neuronal density (12). However, as understanding of the molecular mechanisms underlying hypothalamic regulation of energy balance has increased, more detailed information on programmed changes in the hypothalamus has emerged. These include programmed changes in neuropeptide expression (13–15) that could result from altered epigenetic regulation of gene transcription (15). A common phenotypic outcome that has been reported in a number of programming models, including those of neonatal overfeeding (16, 17), intrauterine undernutrition (18), maternal high fat feeding (19), and maternal diet-induced obesity (13), is resistance to leptin in adulthood in relation to inhibition of food intake. However, there has been less focus on whether leptin resistance during the very early stages of life, at a time when leptin has no effect on food intake (20, 21), plays a mechanistic role in metabolic programming (13, 17).

Effects of Acute Changes in Neonatal Leptin Levels on Food Intake and Long-Term Metabolic Profiles in Rats

In rodents there is a rise in serum leptin levels between postnatal days (PND) 5 and 14, with this neonatal leptin surge reported to modulate the maturation of hypothalamic circuits involved in appetite regulation. We hypothesized that acute changes in neonatal leptin levels have different long-term metabolic effects depending on how and when this surge is modified. To advance the timing of the normal leptin peak, male Wistar rats were injected with leptin (sc, 3 μg/g) on PND 2. To ablate the leptin peak on PND 10, a pegylated leptin antagonist (sc, 9 μg/g) was injected. Controls received vehicle. All rats were allowed to eat ad libitum until PND 150. Increased leptin on PND 2 reduced food intake (P<0.01) after 3 months of age with no effect on body weight. Levels of total ghrelin were reduced (P<0.001) and acylated ghrelin increased (P<0.05), with no other modifications in metabolic hormones. In contrast, treatment with the leptin antagonist on PND 9 did not affect food intake but reduced body weight beginning around PND 60 (P<0.02). This was associated with a reduction in fat mass, insulin (P<0.01), and leptin (P<0.007) levels and an increase in testosterone levels (P<0.01). Hypothalamic neuropeptide Y (P<0.05) and leptin receptor (P<0.005) mRNA levels were reduced, whereas mRNA levels for uncoupling protein 2 (P<0.005) were increased in visceral fat, which may indicate an increase in energy expenditure. In conclusion, acute changes in neonatal leptin levels induce different metabolic profiles depending on how and when leptin levels are modified.

Leptin-programmed rats respond to cold exposure changing hypothalamic leptin receptor and thyroid function differently from cold-exposed controls

We showed that neonatal leptin treatment programmes for hyperleptinemia and central leptin resistance both at 30days-old and adulthood, while programmes for lower serum T3 at 30days-old, but higher thyroid hormones (TH) at adulthood. As in these animals, acute cold at 30days-old normalized leptinemia and restored the expression of hypothalamic leptin receptor (OBR), here we evaluate the effect of cold exposure on the thyroid function and OBR in adult rats programmed by neonatal hyperleptinemia. Pups were divided into 2 groups: Lep-injected with leptin (8μg/100g/BW, sc) for the first 10days of lactation, and C-injected with saline. At 150days, both groups were subdivided into: LepC and CC, which were exposed to 8°C for 12h. Serum leptin, TH, TSH, liver type I and brown adipose tissue (BAT) type II deiodinases (D1 and D2) activities, liver mitochondrial alpha-glycerol-3-phosphate dehydrogenase (mGPD) activity and adrenal catecholamine content were measured. Hypothalamic and thyroid OBR protein contents were evaluated. Differences were significant when p<0.05. Lep group had hyperleptinemia (+19%), higher T4 (+20%) and T3 (+30%) with lower TSH (−55%), higher liver D1 (1.4 fold-increase), lower BAT D2 (−44%) and liver mGPD activities (−55%), higher adrenal catecholamines (+44%), lower hypothalamic OBR (−51%) and normal thyroid OBR. Cold exposure normalized leptinemia, D1, mGPD, catecholamine and hypothalamic OBR. However, cold exposure further increased TH and decreased D2. Thus, cold exposure normalizes most of the changes programmed by neonatal hyperleptinemia, at the expense of worsening the hyperthyroidism and BAT thermogenesis.

Fetal Hypothalamic Neuroprogenitor Cell Culture: Preferential Differentiation Paths Induced by Leptin and Insulin

In response to temporally orchestrated growth factor stimulation, developing neural stem/progenitor cells undergo extensive self-renewal and then generate neurons and astrocytes. Fetal neonatal leptin and insulin deficiency results in reduced hypothalamic axonal pathways regulating appetite, which may predispose to offspring hyperphagia and obesity. Neural development of the arcuate nucleus, a key target of adiposity signals, leptin and insulin, is immature at birth. Hence, to explore proximate effects of leptin/insulin on hypothalamic development, we determined trophic and differentiation effects on neural stem/progenitor cells using a model of fetal hypothalamic neurospheres (NS). NS cultures were produced from embryonic d 20 fetal rats and passage 1 and passage 2 cells examined for proliferation and differentiation into neurons (neuronal nuclei, class IIIβ-tubulin, and doublecortin) and astrocytes (glial fibrillary acidic protein). Leptin-induced NS proliferation was significantly greater than that induced by insulin, although both effects were blocked by Notch, extracellular signal-regulated kinase, or signal transducer and activator of transcription 3 inhibition. Leptin preferentially induced neuronal, whereas insulin promoted astrocyte differentiation. Extracellular signal-regulated kinase inhibition suppressed both leptin and insulin-mediated differentiation, whereas signal transducer and activator of transcription inhibition only affected leptin-mediated responses. These findings demonstrate preferential and disparate differentiation paths induced by leptin and insulin. Altered fetal exposure to leptin or insulin, resulting from fetal growth restriction, macrosomia, or maternal diabetes, may potentially have marked effects on fetal brain development.

Neonatal Leptin Administration Alters Regional Brain Volumes and Blocks Neonatal Growth Restriction-Induced Behavioral and Cardiovascular Dysfunction in Male Mice

Premature delivery is often complicated by neonatal growth restriction (GR) and neurodevelopmental impairment. Because global overnutrition increases the risk of adult metabolic syndrome, we sought a targeted intervention. Premature delivery and perinatal GR decrease circulating levels of the neurotrophic hormone leptin. We hypothesized that leptin supplementation would normalize the outcomes of mice with incipient neonatal GR. Pups were fostered into litters of 6 or 12 to elicit divergent growth patterns. Pups in each litter received injections of saline or leptin from d 4 to 14. At 4 mo, mice underwent tail cuff blood pressure measurement, behavioral testing, and MRI. Mice fostered in litters of 12 had decreased weanling weights and leptin levels. Neonatal leptin administration normalized plasma leptin levels without influencing neonatal growth. Leptin replacement also normalized the hypertension, stress-linked immobility, conditioned fear, and amygdala enlargement seen in neonatal growth restricted male mice. In control males, neonatal leptin administration led to hypothalamic enlargement, without overt neurocardiovascular alterations. Female mice were less susceptible to the effects of neonatal GR or leptin supplementation. In conclusion, the effects of neonatal leptin administration are modulated by concurrent growth and gender. In growth restricted male mice, physiologic leptin replacement improves adult neurocardiovascular outcomes.

Neonatal exposure to leptin reduces glucose tolerance in adult mice

The aim of this study was to evaluate the effect of leptin treatment in mouse neonates on glucose metabolism in adulthood. Leptin was administered subcutaneously to normally nourished neonates, from 5.5 to 10.5 days of age, to mimic the premature surge observed in neonates undernourished in utero. At 15-16 weeks of age, we measured blood glucose or insulin levels after the intraperitoneal administration of glucose or insulin. After the intraperitoneal administration of glucose, the levels of blood glucose, but not insulin, in adult mice that received the neonatal leptin treatment were significantly higher than that of those which received vehicle control. After the intraperitoneal administration of insulin, the levels of blood glucose in adult mice that underwent neonatal leptin treatment were significantly higher than that of those which received vehicle control. These findings suggest that the premature leptin surge plays an essential role, as a programming signal during the early neonatal period, as well as in the developmental origins of impaired insulin sensitivity.

Leptin withdrawal after birth: A neglected factor account for cognitive deficit in offspring of GDM mother

Pregnancy in the diabetic woman has long been associated with an increased risk of cognitive deficit in the offspring, which might be associated with the poor intrauterine environment for the developing fetal brain. Leptin, as an important hormone regulating the intrauterine and early extrauterine life growth and development, greatly elevated during diabetic pregnancy. The current results indicate that leptin exerts neurotrophic actions during the critical period of development of hippocampus, and acts as a cognitive enhancer. Leptin resistance was a common phenomenon in diabetic pregnancies resulting reduced leptin receptors and signaling. With sudden withdrawal of placenta-derived leptin after birth, neonatal leptin levels declined sharply. The declined leptin could not work normally with the reduced leptin receptor and thus affected the newborn’s brain development, which at least partly accounted for later cognitive deficits of offspring of GDM mother. Our hypothesis provides an alternative strategy to decrease the risk of cognitive deficit of offspring of diabetic mother, by exogenously supplementing leptin after birth for some period.

Maternal obesity eliminates the neonatal lamb plasma leptin peak

A neonatal peak in rodent plasma leptin plays a central role in regulating development of the hypothalamic appetite control centres. Maternal obesity lengthens and amplifies the peak in altricial rodent species. The precise timing and characteristics of the neonatal leptin peak have not been established in offspring of either normal or obese mothers in any precocial species. We induced obesity by feeding female sheep for 60 days before conception, and throughout pregnancy and parturition with 150% of the diet consumed by control ewes fed to National Research Council recommendations.We have reported that mature offspring of obese sheep fed similarly exhibited increased appetite, weight gain and obesity in response to ad libitum feeding at 19 months of age. We observed a leptin peak in lambs of control ewes between days 6 and 9 of postnatal life, earlier than reported in rodents. This peak was not present in lambs born to obese ewes. The leptin peak in lambs born to control ewes was not clearly related to any changes in plasma cortisol, insulin, triiodothyronine, IGF-1 or glucose. However, there was a significant increase in cortisol at birth in lambs born to obese ewes related to an increase in leptin in the first day of life. We conclude that the increased cortisol seen in lambs of obese sheep plays a role in disrupting the normal peak of leptin in lambs born to obese ewes thereby predisposing them to increased appetite and weight gain in later life.

Increased Adiposity Programmed by Catch-Up Growth: Requirement for Leptin Signals?

Low birth weight (LBW) followed by accelerated growth during infancy and childhood are associated with increased risk of obesity, insulin resistance, and cardiovascular disease in adulthood (1–4). Recent efforts to characterize the mechanism underlying this phenomenon of metabolic programming have largely focused on the effects of leptin treatment during the period of catch-up growth. A report in this issue of Endocrinology is the first to examine whether leptin signals are required for programming of increased adiposity due to accelerated catch-up growth (5). Rodent models have provided a useful means to parse the respective contributions of LBW vs. increased growth rates in the postnatal period to program adverse metabolic outcomes. Since the 1950s, manipulations of litter size have been used to control nutrient intake and growth rates in neonates (6). Animals that receive more nutrients as a consequence of lactation in small litters are heavier at weaning and gain more weight as adults; conversely, those reared in large litters are smaller at weaning and gain less weight as adults (6–8). Persistent effects of neonatal overnutrition on adiposity are concomitant with decreased sensitivity to leptin (9). The observations that blunting catch-up growth during the lactation period or delaying it to the postweaning period can prevent adverse metabolic outcomes support the idea that both the rate and time window of catch-up growth are critical determinants of the degree of programming in LBW models (10). Studies to identify molecular mechanisms underlying metabolic programming due to catch-up growth initially focused on the potential role of hyperinsulinemia (11, 12); however, two seminal discoveries shifted the focus to leptin. First, Ahima et al. (13) characterized a surge in plasma leptin levels in the first 2 wk of life, a period when leptin does not influence food intake or body weight (13–16). Second, the demonstration that leptin can influence the establishment of patterns of connectivity in hypothalamic circuits regulating energy balance during the neonatal period (17) led many to investigate leptin’s role in programming increased adiposity during the neonatal period. It has been difficult to evaluate the role of neonatal leptin in mediating persistent effects of catch-up growth on metabolic phenotypes. Differences in the sex and background strain of rodent models, as well as in the mode of leptin administration, result in a wide variation in the severity (and sometimes direction) of reported metabolic outcomes.Whereasperipheral leptinadministration inneonates often leads to leptin resistance and increased susceptibility to high-fat diet (HFD)-induced obesity in male mice (18–20), the degree of effects vary, as increased adiposity on chow has been observed in some studies (20) and not others (18). Both acute and persistent effects of neonatal leptin treatment are sexually dimorphic. In contrast to its effects in males, neonatal leptin treatment is reported to acutely reduce body weight as well as to protect against programming effects of small litter size in females (9, 21, 22). Several labs are using rodent models to examine the role of leptin in the context of catch-up growth associated with LBW. Intrauterine growth restriction (IUGR), achieved by reductions in either caloric intake or protein in the maternal diet, is followed by catch-up growth in the postnatal period (23). The nutrient status of the dam during lactation (restricted vs. unrestricted) and litter size influence the rate of catch-up growth achieved under different experimental paradigms, such that the body weight and adiposity of weanlings reflect the nutrient availability during lactation (23, 24). A premature leptin surge has been reported

Gestational Glucose Tolerance and Cord Blood Leptin Levels Predict Slower Weight Gain in Early Infancy

To determine the extent to which known prenatal and perinatal predictors of childhood obesity also predict weight gain in early infancy. We studied 690 infants participating in the prospective cohort Project Viva. We measured length and weight at birth and at 6 months. Using multivariable linear regression, we examined relationships of selected maternal and infant factors with change in weight-for-length z-score (WFL-z) from 0 to 6 months. Mean (standard deviation) change in WFL-z from 0 to 6 months was 0.23 (1.11), which translates to 4500 grams gained from birth to 6 months of life in an infant with average birth weight and length. After adjustment for confounding variables and birth weight-for-gestational age z-score (-0.28 [95% confidence interval, -0.37, -0.19] per unit), cord blood leptin (-0.40 [95%confidence interval, -0.61, -0.19] per 10 ng/mL), and gestational diabetes -0.50 [95%confidence interval, -0.88, -0.11] versus normal glucose tolerance)were each associated with slower gain in WFL-z from 0 to 6 months. Higher neonatal leptin and gestational diabetes predicted slower weight gain in the first 6 months of life. The hormonal milieu of the intrauterine environment may determine growth patterns in early infancy and thus later obesity.

Programming of Adiposity in Offspring of Mothers With Type 1 Diabetes at Age 7 Years

OBJECTIVEThe goals of this study were to examine the influence of maternal type 1 diabetes during pregnancy on offspring adiposity and glucose tolerance at age 7 years and to assess whether metabolic factors at birth (neonatal leptin and insulin) predict adverse outcomes.RESEARCH DESIGN AND METHODSWe examined 100 offspring of mothers with type 1 diabetes (OT1DM) and 45 offspring of control mothers. Mothers had previously been recruited during pregnancy, and, where possible, birth weight, umbilical cord insulin, and leptin were measured. Children were classed as overweight and obese using age-specific reference ranges.RESULTSOT1DM had similar height (control, 1.25 ± 0. 06 m; OT1DM, 1.24 ± 0.06 m; P = 0.81) but were heavier (control, 25.5 ± 3.8 kg; OT1DM, 27.1 ± 5.7 kg; P = 0.048) and had an increased BMI (control, 16.4 kg/m2; OT1DM, 17.4 ± 2.6 kg/m2, P = 0.005). Waist circumference (control, 56.0 ± 3.7 cm; OT1DM, 58 ± 6.8 cm; P = 0.02) and sum of skinfolds were increased (control, 37.5 ± 17.0 mm [n = 42]; OT1DM, 46.1 ± 24.2 mm [n = 91]; P = 0.02), and there was a marked increase in the prevalence of overweight and obese children (OT1DM, 22% overweight and 12% obese; control, 0% overweight and 7% obese; χ2 P = 0.001). Glucose tolerance was not different compared with that in control subjects. BMI at age 7 years correlated with cord leptin (OT1DM, r = 0.25; n = 61, P = 0.047), weakly with adjusted birth weight (r = 0.19; P = 0.06) and hematocrit (r = 0.25; n = 50, P = 0.07), but not cord insulin (OT1DM, r = −0.08; P = 0.54).CONCLUSIONSOT1DM are at increased risk of overweight and obesity in childhood. This risk appears to relate, in part, to fetal leptin and hematocrit but not insulin.

Association of Plasma Leptin Levels With Maternal Body Weight and Body Mass Index in Premature and Term Newborns

Leptin plays an important role in the regulation of body weight and energy metabolism in adults; its role in neonates also needs to be explored. The current study aims to determine the correlation between serum leptin concentrations and anthropometric variables in newborns and their mothers, and to examine the effects of sex, gestational age and antenatal steroid use on neonatal leptin levels. This was a retrospective study. Blood samples were collected from 55 newborns within 24 hours of birth. Plasma leptin levels were measured by immunometric assay. The relationship between neonatal leptin levels and anthropometric parameters was determined using Pearson's correlation and further evaluated by linear regression analysis. Neonatal leptin was significantly correlated with maternal body weight (p < 0.002) and maternal body mass index (BMI) (p < 0.001). However, it was not correlated with gestational age (p = 0.130), birth weight (p = 0.097), or birth BMI (p = 0.336). The leptin levels in premature newborns (gestational age < 37 weeks; 0.69 +/- 1.82ng/mL) were significantly less than those in term newborns (gestational age > or = 37 weeks; 2.09 +/- 2.30 ng/mL, p = 0.031). There were no significant differences between sexes (p = 0.277) or in relation to antenatal steroid use (p = 0.611). Neonatal serum leptin concentrations within 24 hours of birth correlated with maternal body weight and BMI, especially in premature newborns. Premature newborns had significantly lower leptin levels than full-term newborns.

Metabolic programming of lipid profile and reproductive organs weight by leptin treatment on early life

To evaluate whether the neonatal leptin treatment during the first days of life can program the male reproductive organs weight and the lipid profile. At birth 6 dams were divided into 2 groups: Leptin - each pup was injected with 50microL of recombinant rat leptin (80ng/g BW, sc), for the first 10 d of lactation; Control - each pup received the same volume of saline. After weaning, all pups received unlimited access to food until 190 days of age when they were killed. Values are given as mean + or - SEM of 6 animals and Test t Student was used to analyze the results. The leptin treatment resulted in a significant increase in body weight (Control= 411.8 + or - 16.31; Leptin= 481.8 + or - 11.29, p=0.005) and food consumption (Control= 25.32 + or - 0.09; Leptin= 32.42 + or - 0.15, p=0.0001) and a significant reduction in triglycerides levels (Control= 540.0 + or - 117.9; Leptin= 93.25 + or - 15.21, p=0.006) and in the weight of hypothalamus (Control= 0.234 + or - 0.016; Leptin= 0.154 + or - 0.015, p=0.007), pituitary (Control= 0.104 + or - 0.0120; Leptin= 0.033 + or - 0.012, p=0.003), testis (Control= 3.75 + or - 0.055; Leptin= 3.19 + or - 0.10, p=0.002) and prostate (Control=1.641 + or - 0.1389; Leptin= 0.91 + or - 0.07, p=0.001). Leptin treatment on the first days of life can program the reproductive organs weight and the lipid profile of the progeny.

Neonatal exposure to parathion alters lipid metabolism in adulthood: Interactions with dietary fat intake and implications for neurodevelopmental deficits

Organophosphates are developmental neurotoxicants but recent evidence also points to metabolic dysfunction. We determined whether neonatal parathion exposure in rats has long-term effects on regulation of adipokines and lipid peroxidation. We also assessed the interaction of these effects with increased fat intake. Rats were given parathion on postnatal days 1–4 using doses (0.1 or 0.2 mg/kg/day) that straddle the threshold for barely detectable cholinesterase inhibition and the first signs of systemic toxicity. In adulthood, animals were either maintained on standard chow or switched to a high-fat diet for 7 weeks. We assessed serum leptin and adiponectin, tumor necrosis factor-α (TNFα) in adipose tissues, and thiobarbituric acid reactive species (TBARS) in peripheral tissues and brain regions. Neonatal parathion exposure uncoupled serum leptin levels from their dependence on body weight, suppressed adiponectin and elevated TNFα in white adipose tissue. Some of the effects were offset by a high-fat diet. Parathion reduced TBARS in the adipose tissues, skeletal muscle and temporal/occipital cortex but not in heart, liver, kidney or frontal/parietal cortex; it elevated TBARS in the cerebellum; the high-fat diet again reversed many of the effects. Neonatal parathion exposure disrupts the regulation of adipokines that communicate metabolic status between adipose tissues and the brain, while also evoking an inflammatory adipose response. Our results are consistent with impaired fat utilization and prediabetes, as well as exposing a potential relationship between effects on fat metabolism and on synaptic function in the brain.

Maternal obesity induced by diet in rats permanently influences central processes regulating food intake in offspring.

Hypothalamic systems which regulate appetite may be permanently modified during early development. We have previously reported hyperphagia and increased adiposity in the adult offspring of rodents fed an obesogenic diet prior to and throughout pregnancy and lactation. We now report that offspring of obese (OffOb) rats display an amplified and prolonged neonatal leptin surge, which is accompanied by elevated leptin mRNA expression in their abdominal white adipose tissue. At postnatal Day 30, before the onset of hyperphagia in these animals, serum leptin is normal, but leptin-induced appetite suppression and phosphorylation of STAT3 in the arcuate nucleus (ARC) are attenuated; the level of AgRP-immunoreactivity in the hypothalamic paraventricular nucleus (PVH), which derives from neurones in the ARC and is developmentally dependent on leptin, is also diminished. We hypothesise that prolonged release of abnormally high levels of leptin by neonatal OffOb rats leads to leptin resistance and permanently affects hypothalamic functions involving the ARC and PVH. Such effects may underlie the developmental programming of hyperphagia and obesity in these rats.

Milk leptin in sows and blood leptin and growth of their offspring1,2

Twenty-one mixed-parity (average 2.4 +/- 0.49) crossbred sows and their offspring were used to determine whether sow milk leptin at farrowing was related to neonatal serum leptin and pig growth to weaning. During farrowing, pigs were randomly allotted to suckling (n = 99) or delayed suckling (n = 89) groups, with delayed suckling pigs placed in a group pen apart from the dam before suckling. Both groups had access to heat lamps. Colostrum samples were collected no more than 2 h after farrowing the first pig. Blood samples were collected from all pigs approximately 2 h after farrowing was complete; pigs were then ear notched and returned to their dams. Pig BW was recorded at 1.2 +/- 0.04 d of age and again at weaning. Milk and blood serum were collected after centrifugation; leptin concentrations were estimated using RIA. Leptin was detected in colostral milk, as expected, and averaged 46.0 +/- 1.1 ng/mL. Pig serum leptin (P < 0.02) was greater in suckling pigs than in delayed suckling pigs, averaging 0.69 +/- 0.08 and 0.54 +/- 0.07 ng/mL, respectively. Although male pigs were heavier (P < 0.01) at birth than female pigs (1,507 +/- 52 vs. 1,381 +/- 43 g), ADG to weaning and weaning weights were similar for both sexes, averaging 229 +/- 14 g and 5,829 +/- 323 g, respectively, for all pigs; serum leptin concentrations were not affected by sex of the pig. Milk serum leptin was not associated with litter size, parity, pig birth weight, ADG to weaning, or weaning weight. Suckling status did not influence ADG to weaning or weaning weight of pigs; neonatal pig serum leptin was not related to birth weight, weaning weight, or ADG to weaning. These results indicate that leptin is not directly related to early neonatal growth in the pig; however, more in-depth studies are needed to determine possible indirect or long-term effects of early leptin exposure.

The influence of leptin on early life programming of obesity

Epidemiological evidence together with experimental models shows a direct relationship between fetal and early postnatal growth patterns and an increased risk of adult metabolic disease. Maternal health and nutrition are key determinants in influencing infant growth but the precise molecular mechanisms underlying this relationship are unclear, although it is evident that there are critical time windows when these effects are important. Animal models show mechanistic parallels with human populations and highlight that the early environment represents a therapeutic window for protection from obesity and metabolic disease. The observation that developmental programming can be reversed has been demonstrated in studies in which both maternal and neonatal leptin treatment prevents the induction of the adverse metabolic phenotype. Given that orally administered peptides are absorbed intact by the new born, the prospect of providing supplemental leptin either as drops or in milk deserves serious consideration as a means of reducing or reversing the obesity and type 2 diabetes epidemic.

Role of neonatal hyperleptinaemia on serum adiponectin and suppressor of cytokine signalling-3 expression in young rats

Previously we had shown that neonatal leptin treatment programmes for both hyperleptinaemia and hyperinsulinaemia, which lead to leptin resistance and low expression of the hypothalamic leptin receptor (OB-Rb) of rats aged 150 d. Here we investigated in young post-weaned rats (age 30 d) if leptin treatment during lactation induces leptin and insulin resistance and if those changes are accompanied by changes in the suppressor of cytokine signalling-3 (SOCS-3) expression and serum adiponectin concentration. After delivery, the pups were divided into two groups: (1) a leptin group (Lep) that were injected with leptin daily (8 microg/100 g body weight subcutaneously) for the first 10 d of lactation; (2) a control (C) group, receiving saline. After weaning (day 21), body weight was monitored until the animals were age 30 d. They were tested for food intake in response to either leptin (0.5 mg/kg body weight intraperitoneally) (CL, LepL) or saline (CSal, LepSal) when they were aged 30 d. The CL group showed lower food intake, but no response was observed in the LepL group, suggesting leptin resistance. The Lep group had hyperleptinaemia (five-fold), hyperinsulinaemia (+42.5%) and lower levels of serum adiponectin (-43.2%). The hypothalamic expression of OB-Rb was lower (-22%) and SOCS-3 was higher (+52.8%) in the Lep group. We conclude that neonatal leptin treatment programmes for leptin resistance as soon as 30 d and suggests that SOCS-3 appears to be of particular importance in this event. In the Lep group, the lower serum adiponectin levels were accompanied by higher serum insulin, indicating a probable insulin resistance.

Neonatal food restriction permanently alters rat body dimensions and energy intake

Neonatal food restriction (FR) in rats, by means of increased litter size, has been used as a model for developmental programming by several investigators. However, the results reported have been inconsistent and difficult to compare between studies. In the present study, we aim to characterize the effects of this model throughout life in both sexes of one particular strain. On the second day of life, Wistar rat pups were randomly assigned to a litter of 10 (control) or 20 (FR). All litters had an equal number of males and females, and pups were weaned on day 25. Body dimensions and food intake were measured regularly until the age of one year. Serum leptin levels were determined in four subsets of different ages. FR acutely reduced growth in all body dimensions and serum leptin levels. Despite catch-up after weaning, all these parameters remained reduced throughout life. Male and female FR rats had a significantly reduced absolute energy intake throughout life. Male FR rats had significantly higher energy intake adjusted for body weight immediately after weaning. During catch-up growth, both FR males and females showed significantly enhanced feed efficiency. These results suggest that neonatal food restriction programmed both male and female Wistar rats to remain small and lean in adult life, with a lower food intake. Low neonatal leptin levels may play a mechanistic role in this process.

Effects of prenatal betamethasone administration on leptin and adiponectin concentrations in maternal and fetal circulation

The aim of this study was to determine the effects of in vivo administration of prenatal betamethasone on leptin and adiponectin concentration in maternal and fetal circulation. Blood samples were collected from 35 pregnant women receiving betamethasone for threatened preterm delivery before and at different time points after drug administration. Cord blood was collected at delivery in infants born from mothers treated with betamethasone and in 15 infants who delivered at the same gestational age not receiving betamethasone. Betamethasone caused an approximately 170% increase in maternal leptin at 24 hours after betamethasone, whereas it had no effects on adiponectin concentration. Betamethasone affects neonatal leptin and adiponectin levels in a time-dependent manner. The glucocorticoid-induced changes in the relationship between these adipokines in maternal and fetal circulation was long lasting. These results provide the first evidence for in vivo effects of glucocorticoids on maternal and fetal adipokines relationship in human pregnancy.