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. 2011 Jan 24;589(Pt 6):1455–1462. doi: 10.1113/jphysiol.2010.201681

Maternal obesity eliminates the neonatal lamb plasma leptin peak

Nathan M Long 1, Stephen P Ford 1, Peter W Nathanielsz 1,2
PMCID: PMC3082103  PMID: 21262878

Non technical summary

Leptin, an adipose tissue hormone, inhibits the brain's central drive to eat, enabling maintenance of normal body weight and composition. The leptin peak present in newborn rodents controls development of brain appetite regulatory areas, and alteration in its timing and amplitude predisposes to obesity in later life. However, unlike humans, rodents are born at an immature stage of development so to determine potential relevance to human development, we examined the leptin peak in newborn lambs, born at a more advanced level of maturity equivalent to humans. The normal peak was absent in lambs born to obese mothers who showed higher newborn levels of plasma cortisol. We conclude that similarities and differences exist in neonatal leptin in species born immature or mature. This information aids understanding of effects of the obesity epidemic in women on their offspring and will help promote diagnosis, prevention and therapy.

Abstract

Abstract

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.

Introduction

The fat cell hormone leptin acts on hypothalamic appetitive centres to inhibit food intake (Yura et al. 2005). Correct regulation of leptin feedback is central to maintenance of normal postnatal body weight and composition, and dysregulation leads to obesity. In neonatal, altricial rodents (e.g. rats and mice) leptin has a characteristic peak at postnatal day 8–21 (Elias et al. 1998; Elmquist et al. 1998; Proulx et al. 2001; Yura et al. 2005; Delahaye et al. 2008; Kirk et al. 2009) whose precise timing and duration varies between studies, strains and species. This leptin peak programs the activity balance of orexigenic and anorexigenic appetitive centres and influences leptin sensitivity (Yura et al. 2005). The leptin peak is amplified and prolonged in offspring of obese rats (Kirk et al. 2009).

The rodent species used in the reported studies of postnatal leptin are all altricial species in which offspring are born very immature. As a result, events taking place in the neonatal period in rodents may well have occurred in utero in precocial species including man and the well-characterized animal model we have used in this study, the sheep. There are many fundamental physiological differences in the prenatal period in the characteristics of the environment in utero where the partial pressure of O2 (Inline graphic) is approximately 40 mmHg and glucose at 40 m dl−1 compared with the postnatal environment where both of these values are around 100.

We have developed a model of maternal obesity in sheep pregnancy, a species commonly studied to evaluate developmental programming. Sixty days before conception, through pregnancy, parturition and lactation, control multiparous ewes were fed 100% of National Research Council (NRC) recommendations and obese ewes were fed 150% of the control diet. We have previously reported the results of a feeding trial on offspring of these ewes in which lambs were weaned at 120 days of age, maintained as a single group, with lambs delivered by both control and obese ewes fed the same requirements for maintenance and growth until maturity (Long et al. 2010). At 19.5 months of age offspring from both groups were individually penned and fed ad libitum in a feeding trial lasting 12 weeks. At the start of the feeding trial body weight and body fat were similar in the two groups using dual X-ray absorptiometry and there were only minor indications of impaired glucose metabolism. However, during the feeding trial, blood concentrations of leptin increased significantly more in offspring of obese vs. control mothers. Offspring of obese mothers also consumed approximately 10% more feed and tended to have increased weight gain compared with offspring of control ewes. At the end of the feeding trial, offspring from obese ewes exhibited decreased acute insulin response to glucose as well as glucose disposition in a frequently sampled intravenous glucose tolerance test, and an increased percentage body fat when compared to control lambs. Thus, our model of diet-induced maternal obesity before and during gestation programs offspring appetite, glucose, insulin dysregulation and offspring adiposity at maturity.

Several factors have been implicated in the control of fetal and adult leptin production including glucocorticoids, glucose, insulin, thyroid hormones and IGF-1 (Soret et al. 1999). However, very little is known about the role of these regulatory factors in the control of the leptin peak that occurs in the early postnatal period in either altricial or precocial species. In this study we took the indispensible first step of characterizing changes in the circulating blood of these five factors and leptin in the neonatal period of lambs born to control and obese mothers. We hypothesized that maternal obesity and nutrient excess throughout gestation would alter the timing and amplitude of the plasma leptin peak as shown in rodents.

Methods

All procedures were approved by the University of Wyoming Animal Care and Use Committee. Selection of ewes and maternal feeding procedures used in this experiment along with the highly palatable diets fed to ewes have been described in detail (Zhu et al. 2008). Briefly, from 60 days before conception (day 0) to parturition, multiparous Rambouillet–Columbia cross ewes were fed a ration at 100% of NRC recommendations for energy based on metabolic body weight of individual ewes (wt.0.75) (control group) or 150% of NRC requirements (obese group). Ewes were individually fed and consumed 100% of their diet each day. Ewes were hand mated to a single intact Columbia ram, weighed weekly and rations adjusted for weight gain. A Body Condition Score was assigned to each ewe by two trained individuals before the start of the experiment, before conception, at the midpoint of gestation, and the end of gestation. Body condition is scored as a 1 to 9 system (1 being emaciated and 9 severely obese) that estimates energy reserves and is highly related to carcass lipids (Sanson et al. 1993). Ewes were allowed to lamb unassisted after which all ewes were given free choice access to high quality alfalfa hay and corn to meet NRC requirements of a lactating ewe. Birth weight was recorded for all lambs. Lambs from singleton pregnancies (controls, n = 6 and obese, n = 6) were weighed and bled at birth, then daily at 06.00 h from postnatal day 1 to 7, and again on postnatal days 9 and 11. Neonatal lamb sex ratio was three males and three females in the control group and five males and one female offspring of obese ewes.

Measurement of hormones and metabolites

Glucose was measured colourimetrically in triplicate (Liquid Glucose Hexokinase Reagent, Pointe Scientific, Inc., Canton, MI, USA) as previously described (Ford et al. 2009). Mean intra-assay coefficient of variation (CV) was 1.2% and inter-assay CV was 2.0%. Plasma leptin was measured by radioimmunoassay (Multispecies leptin RIA, Linco Reseach, St Charles, MO, USA) as previously described with an intra-assay CV <4% and inter-assay CV of <6% (Ford et al. 2007). Insulin was measured in duplicate by commercial RIA (Ford et al. 2009; Siemens Medical Solutions Diagnostics, Los Angeles, CA, USA) with a mean intra-assay CV of 8.9% and inter-assay CV of 6.7%, and a sensitivity of 2.40 μIU ml−1. Concentrations of cortisol were determined as described previously (Ford et al. 2009) using Coat-A-Count Cortisol RIA with a sensitivity of 5 ng ml−1 (Siemens Medical Solutions Diagnostics) with an intra-assay CV of 8.7% and inter-assay CV of 10.2%. Tri-iodothyronine was determined by RIA according to manufacturer's specifications (Coat-a-Count Total T3) with a sensitivity of 16.2 ng dl−1 and previously published in our laboratory (Vonnahme et al. 2003) with an intra-assay CV of 4.1% and inter-assay CV of 3.9%. Plasma IGF-1 was measured on an Immulite 1000 (Siemens Medical Solutions Diagnostics) in a single assay and previously validated for sheep (Ford et al. 2009). The sensitivity of the IGF-1 assay was 20 ng ml−1 with intra-assay CV of 5.1%.

Statistical analysis

Ewe body weight, body condition scores and lamb birth weights were compared using the GLM procedure of SAS (SAS Institute Inc., Cary, NC, USA), and glucose and hormone data were analysed as repeated measures using the Mixed procedure of SAS. Significance was set at P < 0.05. Post hoc t tests were performed to determine difference between obese and control values within a time point and also differences between adjacent time points for control and obese lambs. Area under the curve was calculated using Graphpad Prism (GraphPad Software Inc., La Jolla, CA, USA) for plasma leptin concentrations from postnatal days 0 to 4 and 6 to 11.

Results

Maternal weight and lamb characteristics at birth

Ewe body weight was similar between control and obese ewes at the start of the experiment (Table 1). However, at conception and throughout gestation obese ewes were heavier (P < 0.01) than control ewes. Body condition scores followed a similar pattern to ewe body weight (Table 1). Lamb birth weight was similar between lambs from control and obese ewes (5.7 ± 0.4 vs. 6.5 ± 0.5 kg, respectively).

Table 1.

Ewe body weight (BW) and body condition score (BCS) from control and obese ewes throughout the experiment

Control Obese
BW (kg) BCS BW (kg) BCS
Diet initiation 69.7 ± 2.0 4.9 ± 0.1 73.0 ± 2.7 5.1 ± 0.1
Conception 71.2 ± 3.2a 5.2 ± 0.1a 93.5 ± 3.4b 6.5 ± 0.1b
Mid gestation 75.7 ± 1.9a 5.5 ± 0.1a 109.4 ± 3.2b 7.4 ± 0.1b
Late gestation 80.8 ± 2.6a 5.1 ± 0.2a 118.7 ± 4.2b 7.5 ± 0.4b
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a,bMean ± SEM differ within a measurement, P < 0.01; n = 6 for control and obese.

In lambs born to control mothers, plasma leptin increased markedly (P < 0.05) from postnatal day 5 to 6 and remained higher than values of lambs from obese mothers from day 6 to 9 (P < 0.05), returning to levels seen in obese lambs by day 11 (Fig. 1A). Area under the curve from postnatal day 6 to 11 was greater in lambs from control ewes compared to lambs from obese ewes (2.3 ± 0.5 vs. 1.3 ± 0.3, respectively; P = 0.03). In lambs from obese mothers but not control mothers, plasma leptin increased (P < 0.05) from birth to postnatal day 1. Area under the curve from postnatal day 0 to 4 tended (P = 0.08) to be greater in lambs from obese ewes compared to lambs from control mothers (1.6 + 0.3 vs. 1.2 ± 0.2, respectively). Plasma cortisol was elevated at birth and on day 1 (P < 0.01) of age in lambs from obese compared with control ewes (Fig. 1B). Plasma insulin was increased in lambs from obese ewes compared to control ewes from postnatal day 4 to 8 (Fig. 1C; P < 0.01). Plasma triiodothyronine (Fig. 1D), IGF-1 (Fig. 1E) and glucose (Fig. 1F) in lambs from birth to postnatal day 11 were unaffected by the level of maternal nutrition.

Figure 1. Circulating plasma levels.

Figure 1

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Circulating plasma levels (mean ± SEM) from birth until postnatal day 11 in lambs from obese mothers (filled circles; n = 6) and control mothers (open circles; n = 6). A, plasma leptin (treatment × day, *P < 0.01 control vs. obese lambs within a time point; longitudinal comparisons P < 0.05 from the preceding period are indicated by † for control lambs and ‡ for obese lambs); B, cortisol (treatment × day, *P < 0.01 control vs. obese lambs within a time point); C, insulin (treatment, *P < 0.01 control vs. obese lambs within a time point); D, triiodothyronine, E, IGF-1 and F, glucose.

Discussion

Morphometrics of newborn lambs

The absence of any difference in birth weight between the two groups of lambs is of interest in terms of the common association of macrosomia with obesity in human pregnancy. Macrosomia is not always associated with maternal obesity in rodent models. In one study, birth weight was lower in offspring of mothers with diet-induced obesity due primarily to larger litter sizes of 14.5 pups as against 10.6 per litter in control litters (Nivoit et al. 2009). In other studies no difference was reported in birth weights of pups from obese and control-fed mothers (Zambrano et al. 2010). In a carefully controlled non-human primate model, a 10% reduction has been reported in late gestation fetal weight (McCurdy et al. 2009). The eventual outcome in birth weight is clearly the result of the nature and extent of gene–environment interactions in the placenta and fetus.

Effects of maternal obesity on the ontogeny of neonatal leptin concentrations

An early neonatal plasma leptin peak has been well documented in rodents (Ahima et al. 1998; Yura et al. 2005; Kirk et al. 2009). Most studies on maternal nutritional interventions that alter the timing and/or characteristics of the peak have also been conducted in rodents. In one model of maternal under-nutrition in which under-nourished pregnant rats were fed 70% of the global intake of controls from post-conceptional day 10.5 to 18.5, the leptin peak occurred earlier and exceeded control levels for several days (Yura et al. 2005). In the only published study in rats of the effects of maternal obesity and over-nutrition, the major change in the leptin peak in offspring of obese mothers was an increase in the obese pups peak that occurred mostly after the control peak (postnatal day 8). However, pups born to obese rats also had a higher plasma leptin concentration than controls on postnatal day 7 (Kirk et al. 2009).

In contrast to the extensive data from neonatal rodents, to our knowledge, the only published study on neonatal leptin concentrations in a precocial species is, like ours, in the lamb (McFadin et al. 2002). In this study, samples were obtained on postnatal days 1, 5, 12, 19, 26, 33, 40 and 47. Values were low at birth and doubled from approximately 2–4 ng ml−1 on the first postnatal day of life to reach a maximum on postnatal day 5 at around 7 ng ml−1. They then fell until they reached a low stable baseline of about 4 ng ml−1 at day 19. Although the values are twice those reported here, and the frequency of sampling too infrequent to assess any peak with only one sample in the critical period between postnatal day 1 and postnatal day 12, the presence of the maximum value at 5 days of postnatal life agrees with the data we have obtained. Another study in which neonatal lamb samples were taken at 1 h after birth, and 1, 2, 4, 7, 14, 21 and 30 days after birth, showed the highest plasma leptin value on postnatal day 7, agreeing with our more frequent sampling (Bispham et al. 2002). Importantly, these authors also noted that there were no differences observed in plasma leptin according to the sex of the lamb. Our more frequent sampling protocol shows that the leptin peak in control lambs occurs after day 5 rather than before. More frequent sampling has allowed us to show that maternal obesity eliminates the normal peak at 6–9 days and produced values on postnatal days 0–4 that showed a trend to being higher than in controls (P = 0.08).

Leptin plays a critical role in programming the maturation of neural connections in the hypothalamus that regulate appetitive behaviour in later life (Bouret & Simerly, 2007). The precise timing of the leptin peak is critical to programming of life-time appetitive behaviour. Leptin administration to rats in the first 10 days of postnatal life reduces hypothalamic leptin receptors (Toste et al. 2006) and neonatal leptin treatment programs hypothalamic leptin resistance and intermediary metabolic parameters in adult rats (Ahima & Hileman, 2000). Leptin administration to mice neonatally from 5.5 to 10.5 days produced leptin resistance in adulthood (Yura et al. 2005). These findings indicate that higher than normal leptin concentrations occurring earlier than the normal peak, as occurs in the lambs born to our obese ewes, can disorganize the normal control of appetite. Our data suggest that there are similarities and differences between altricial and precocial species. As mentioned above, offspring born to ewes fed to become obese eat more and put on more adipose tissue when allowed access to increased nutrition in adult life (Long et al. 2010). The absence of the normal neonatal leptin peak, together with the increase on day 1 and a trend towards a greater area under curve on days 0–4 clearly show dysregulation of the normal ontogeny in circulating leptin. What is clear is that the normal neonatal leptin peak is eliminated in the offspring of the obese ewes, a change that is accompanied by a subsequent increase in appetite in the lambs born to our obese mothers (Long et al. 2010). This pattern of developmental programming fits with the increased appetite seen in mice in which the leptin peak occurs earlier as a result of exogenous leptin administration (Yura et al. 2005).

Adipose tissue is the most likely source of the leptin that produces the peak. The demonstration that neonatal adipose tissue in offspring of obese rats shows elevated leptin mRNA supports this view (Kirk et al. 2009). An indication of potential regulators of fetal adipose tissue development that may stimulate more leptin production comes from an in vitro study of differentiation of fetal sheep subcutaneous and abdominal pre-adipocytes obtained from omental or peri-renal sites from fetal lambs in a serum-free cell culture system. Insulin and IGF-I were required for differentiation assessed by changes in activity of glycerol 3-phosphate dehydrogenase. The most effective agonist combination that stimulated pre-adipocyte differentiation, was dexamethasone, insulin, triiodothyronine and rosiglitazone (a peroxisome proliferator-activated receptor-gamma agonist) (Soret et al. 1999).

In sheep, many of the changes that prepare the fetus for the challenges of neonatal life are driven by the late gestational exponential increase in fetal cortisol that increases steadily during the final 20 days of fetal life, from 125 days of gestation (Magyar et al. 1980). Thus, fetal and neonatal cortisol may be important in regulating the perinatal changes in leptin in offspring of control sheep as well as the modifications seen here in the setting of obesity (Fowden et al. 1998). In support of this view, fetal sheep plasma leptin and peri-renal adipose tissue leptin mRNA increase in the last 15 days of gestation (O’Connor et al. 2007). Removal of the fetal adrenals prevents these changes while exposure of the intact fetus to high normal late gestation levels of glucocorticoids reproduces the leptin changes (O’Connor et al. 2007). While fetal cortisol was elevated at 78 days of gestation in fetuses of our obese ewes (Ford et al. 2009) it was not changed at 135 days (Zhang et al. 2011). Although we have not measured fetal cortisol over the final 2 weeks of fetal life in our maternal obesity model, parturition occurred about 3 days earlier in these obese ewes (Long et al. 2010), which would be compatible with elevated fetal plasma cortisol concentrations over the final 2 week period of gestation in the setting of maternal obesity in pregnancy. If the fetal cortisol is increased that would provide an explanation for the higher neonatal cortisol in the first day of life as well as the tendency for the leptin to be higher than in control lambs as a result of the effect of cortisol on leptin production by fetal sheep adipose tissue (O’Connor et al. 2007). A further effect of elevated cortisol in late fetal life would be to activate the thyroid axis. Cortisol administration to the fetus raises plasma triiodothyronine levels as a result of increased cortisol-driven conversion of thyroxine to triiodothyronine (Thomas et al. 1978). In the late gestation fetal sheep, infusions that produce physiological levels of triiodothyronine inhibit leptin production (O’Connor et al. 2007), suggesting that increases in fetal plasma cortisol may indirectly inhibit cortisol's own stimulatory action on leptin production by stimulating triiodothyronine production, perhaps acting as a brake.

In control lambs there was no increase in plasma insulin prior to the leptin peak suggesting that normal insulin levels do not affect the peak. Interestingly in offspring of obese ewes, plasma insulin was elevated on day 4 and remained elevated throughout the period of the leptin peak in offspring of control ewes. It has been suggested that insulin may play a role in programming of dysfunction in appetite control (Plagemann, 2008). Plagemann writes in support of the view that insulin in elevated concentrations in early life, may program the development of obesity – possibly by increasing glucose and amino acid uptake in sensitive tissues. Thus, we speculate that the increased insulin in the offspring of the obese ewes may play a role in eliminating the normal leptin peak and/or programming the increased appetite we have shown in offspring from ewes made obese with this model (Long et al. 2010).

The growth factor IGF1 is important for development of adipose tissue. In one study, IGFR1 was variably suppressed (5–82%) by Cre-lox-mediated dosage of a floxed IGF-IR gene (Holzenberger et al. 2001). Adipose tissue growth was also variably suppressed by an average of 56% in female and 81% in males, indicating that reduced IGF-IR has major effects on development of adipose tissue. Physiological levels of IGF1 stimulate proliferation and differentiation of pre-adipocytes in cell culture in both serum-containing and serum-free media (Gregoire et al. 1998; Soret et al. 1999). Further, when placental restriction is produced in sheep pregnancy in a model in which the majority of caruncular sites of placental attachment are removed prior to pregnancy, fetuses are growth restricted and IGF1 and leptin mRNA expression in peri-renal visceral adipose tissue are decreased (Duffield et al. 2008).

Milk components have been suggested as factors that regulate neonatal leptin production since their intake varies with maternal nutritional state. Glucose and fatty acids can affect leptin release and their delivery to the neonate in milk might affect leptin levels circulating in neonatal blood (Ailhaud et al. 2006; Bautista et al. 2008). We have reported that milk leptin is not a determinant of circulating leptin in rat pups (Bautista et al. 2008), an observation in keeping with the report by Kirk et al. (2009) who showed no correlation between pup leptin intake in milk and neonatal leptin levels. Plasma glucose concentrations were not different in our two groups of lambs. Thus, while glucose infusion does increase leptin production (Benedict et al. 2009), glucose does not appear to be involved in the leptin peak although alterations in sensitivity to insulin with subsequent increase in glucose uptake might play a role that remains to be investigated.

In summary, we have demonstrated, for the first time, a clear neonatal peak in plasma leptin in a precocial species. The peak appears to bear no relationship to plasma insulin, IGF-1, glucose, triiodothyronine or cortisol. However, at birth plasma cortisol is elevated in lambs born to obese ewes. The elevated neonatal cortisol may well cause dysregulation of the leptin peak in the offspring of obese ewes We hypothesize that adipose tissue in the fetuses of obese ewes have been exposed to elevated cortisol prior to delivery compared to controls since they were born about 3 days early. We put forward the testable hypothesis that the normal rise in fetal cortisol (possibly in conjunction with other changes) prepares fetal adipose tissue to secrete the leptin that produces the normal leptin peak at days 6–9. However, in the presence of elevated cortisol on the first day of life (and possibly in fetal life) an increased stimulus to fat cell leptin production occurs early, at a time when capacity to secrete leptin is rapidly exhausted. An alternative explanation would be that glucocorticoid receptors on adipose tissue are down-regulated by elevated levels of cortisol before and immediately after birth. Support is available for this hypothesis when we evaluate our data in the light of the values obtained in the study by O’Connor et al. (2007). In this study, the highest fetal plasma cortisol levels achieved in cortisol infusions to the fetus were around 115 ng ml−1. This level of cortisol produced an elevation in leptin from 0.8 ng ml−1 to 1.1 ng ml−1. Neonatal plasma cortisol values in the lambs of our obese sheep were about 50% higher (160 ng ml−1) and plasma leptin also reached approximately 50% more (1.5 ng ml−1). Cortisol plays a central role in preparing key physiological systems for postnatal function in both the fetus and neonate. Glucocorticoids have also been shown to regulate developmental maturation in rodents. Although the major increase in corticosterone in rats begins around day 14, there is a minor peak between day 7 and 14 that may well be involved in the neonatal leptin peak (Daniels et al. 1972). The coordinating role of cortisol in several key developing tissues ensures adequate preparation of the vital systems required for independent life – the lungs, gut, kidneys as well as adipose tissue stores for thermogenesis and nutritional purposes etc. Future studies in this important precocial species need to span the last weeks of fetal life and the immediate postnatal period. The ability to instrument the sheep fetus long-term makes it a very powerful model in which to follow up the findings presented here.

Acknowledgments

This work was supported by NIH INBRE P20RR016474 and HD 21350.

Author contributions

All authors contributed to the experimental design. N.L. and S.P.F. conducted the study and P.W.N. and N.L. wrote the manuscript.

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