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Neonatal Leptin Treatment Reverses Developmental Programming

Liggins Institute (M.H.V., P.D.G., A.H.C., P.L.H., W.S.C., B.H.B., M.H.), University of Auckland and National Research Centre for Growth and Development (M.H.V., P.D.G., A.H.C., P.L.H., W.S.C., B.H.B.), Auckland 1020, New Zealand; and Institute of Biochemistry (A.G.), Food Science and Nutrition, the Hebrew University of Jerusalem, Rehovot 76100, Israel

Address all correspondence and requests for reprints to: Dr. Mark Vickers, Liggins Institute, Faculty of Medical and Health Science, University of Auckland, Auckland 1020, New Zealand. E-mail: m.vickers{at}auckland.ac.nz.

	Abstract

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An adverse prenatal environment may induce long-term metabolic consequences, in particular obesity and insulin resistance. Although the mechanisms are unclear, this programming has generally been considered an irreversible change in developmental trajectory. Adult offspring of rats subjected to undernutrition during pregnancy develop obesity, hyperinsulinemia, and hyperleptinemia, especially in the presence of a high-fat diet. Reduced locomotor activity and hyperphagia contribute to the increased fat mass. Using this model of maternal undernutrition, we investigated the effects of neonatal leptin treatment on the metabolic phenotype of adult female offspring. Leptin treatment (rec-rat leptin, 2.5 µg/g·d, sc) from postnatal d 3–13 resulted in a transient slowing of neonatal weight gain, particularly in programmed offspring, and normalized caloric intake, locomotor activity, body weight, fat mass, and fasting plasma glucose, insulin, and leptin concentrations in programmed offspring in adult life in contrast to saline-treated offspring of undernourished mothers who developed all these features on a high-fat diet. Neonatal leptin had no demonstrable effects on the adult offspring of normally fed mothers. This study suggests that developmental metabolic programming is potentially reversible by an intervention late in the phase of developmental plasticity. The complete normalization of the programmed phenotype by neonatal leptin treatment implies that leptin has effects that reverse the prenatal adaptations resulting from relative fetal undernutrition.

	Introduction

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AN ADVERSE INTRAUTERINE environment is associated with long-term metabolic consequences, in particular obesity, insulin resistance, and type 2 diabetes (1, 2, 3, 4, 5, 6). Data from epidemiological as well as in vivo animal studies have given rise to the concept of developmental programming, whereby an unfavourable prenatal environment is believed to trigger adaptations that improve fetal survival or prepare the fetus in expectation of a particular range of environments postnatally (1). These adaptations may later prove to be a disadvantage, however, when the pre- and postnatal environments are widely discrepant (2). Although the mechanisms underlying developmental programming are unclear, epigenetic modification of gene expression is increasingly implicated (3, 4). The cues inducing such long-term changes leading to such postnatal metabolic phenotypes may either be nutritional or involve the glucocorticoid system (5, 6, 7). The general premise underlying the concept of developmental programming is that although it is induced by the processes of developmental plasticity (8), once induced the organism has a reduced capacity to reverse the developmental trajectory chosen, making developmental programming irreversible in a particular nutritional range (8).

Using one experimental approach to induce developmental programming, we have previously shown that maternal undernutrition during pregnancy results in the offspring developing obesity, hyperinsulinemia, and hyperleptinemia in adult life, particularly when fed a high-fat diet (9). Inactivity and hyperphagia contribute to the obesity phenotype in the adult offspring of undernourished mothers (10, 11).

The field of metabolic physiology has been profoundly altered by the discovery of the adipokines (12, 13). The initial view was that leptin was an anti-obesity hormone, preventing the storage of excess adipose tissue by feeding back to the hypothalamus to reduce food intake and increase energy expenditure (14, 15). In most humans with obesity, however, systemic leptin levels are elevated, in keeping with a state of leptin resistance (16, 17). Although a chronic elevation in leptin may not prevent weight gain, a sudden decrease in leptin coordinates adaptations aimed at protecting body weight during fasting. Restoring circulating leptin levels in fasting mice normalizes all of the neuroendocrine responses elicited by fasting (18).

Recent data suggest that leptin may have a broader range of actions, particularly during growth and development (19). Serum levels of leptin vary dramatically during intrauterine and early postnatal life, with a 5- to 10-fold increase in leptin occurring between postnatal d 4 and 10 in female mice (20). Leptin mRNA is expressed in the placenta, and the human leptin gene has a placental-specific upstream enhancer (21). Breast milk also contains significant amounts of leptin (22), and it may contribute to circulating levels in the neonate. Although cord blood leptin levels tend to reflect neonatal fat mass, low cord blood leptin levels are associated with rapid postnatal weight gain in small-for-gestational-age infants (23). The temporal coexpression of the long isoform of the leptin receptor and its ligand in mesenchymal tissues during fetal development (19) raises the possibility that leptin may act as a paracrine or autocrine factor during fetal life.

Studies of developmental programming suggest that both central and peripheral mechanisms are involved (11, 24, 25, 26), and we hypothesized that leptin might affect developmental programming by virtue of either its central or peripheral effects. Hypothalamic arcuate nucleus projections that regulate body weight mature during the first 2 wk after birth in rodents (27). In leptin-deficient (ob/ob) mice, these projections remain immature. Exogenous leptin has a neurotrophic effect on these hypothalamic projections but only during the neonatal period (27). Leptin may also influence the normal proliferation of pancreatic ß-cells that occurs in the neonatal period. Pancreatic ß-cells express the long form of the leptin receptor, and leptin increases the viability of isolated rat pancreatic islets by suppressing apoptosis and increasing islet cell proliferation (28). In addition, leptin provides a functional link with insulin to form the adipoinsular axis (29, 30, 31) and plays an important role in the control of ß-cell function in vivo via inhibition of insulin secretion and reduction of insulin transcript levels (32, 33, 34) It is possible that maintaining a critical leptin level during development allows the normal maturation of tissues involved in metabolic homeostasis and that a period of relative hypoleptinemia may induce some of the metabolic adaptations that underlie developmental programming. The aim of the present study was to establish whether neonatal leptin treatment can alleviate postnatal obesity and the associated metabolic sequelae that occur in the offspring of undernourished mothers.

	Materials and Methods

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Study design
A previously developed maternal undernutrition model of fetal programming was used in this study (6). Virgin Wistar rats (age 100 ± 5 d) were time mated using a rat estrous cycle monitor to assess the stage of estrous of the animals before introducing the male. After confirmation of mating, rats were housed individually in standard rat cages with free access to water. All rats were kept in the same room with a constant temperature maintained at 25 C and a 12-h light, 12-h dark cycle. Animals were assigned to one of two nutritional groups: 1) undernutrition (30% of ad libitum) of a standard diet throughout gestation (UN group) and 2) standard diet ad libitum throughout gestation (AD group). Food intake and maternal weights were recorded daily until the end of pregnancy. After birth, pups were weighed and litter size was adjusted to eight pups per litter to assure adequate and standardized nutrition until weaning. Pups from undernourished mothers were cross-fostered onto dams that had received AD feeding throughout pregnancy. At postnatal d 3, female AD and UN pups were randomized to receive either saline or recombinant rat leptin (2.5 µg/g·d) for 10 d by sc injection (n = 16 per group). During and after treatment, all animals were maintained on ad libitum feeding until weaning. At weaning, saline- or leptin-treated AD and UN offspring were weight matched and placed on either standard rat chow or a high-fat diet [HF; Research Diets Inc. (New Brunswick, NJ) no. 12451, 45% kcal as fat]. At postnatal d 170, rats were fasted overnight and killed by halothane anesthesia followed by decapitation. Blood was collected into heparinized vacutainers and stored on ice until centrifugation and removal of supernatant for analysis. All animal work was approved by the Animal Ethics Committee of the University of Auckland.

Measurements
Body composition was assessed using dual-energy x-ray absorptiometry (DEXA) (Hologic, Waltham, MA). Food intake was measured over a 5-d period before the end of the trial. Plasma leptin was measured by RIA as described previously (35) The ED₅₀ was 0.31 ng/ml, and the intraassay coefficient of variation was less than 10% (all samples measured within a single assay). Fasting plasma insulin was measured using a rat insulin ELISA (no. 10-1124-10; Mercodia, Uppsala, Sweden). C-peptide was measured using a rat C-peptide RIA (RCP-21K; Linco Research Inc., St. Charles, MO). Fasting plasma glucose was measured using a YSI glucose analyzer (model 2300; Yellow Springs Instrument Co., Yellow Springs, OH). Voluntary locomotor activity was assessed at d 165 in trials of 20 min duration after three habituation trials using Optimax behavioral testing apparatus (Columbus Instruments, Columbus, OH) as described previously (10). Statistical analyses were carried out using SigmaStat (Jandel Scientific, San Rafael, CA) and StatView (SAS Institute Inc., Cary, NC) statistical packages. Differences between groups were determined by three-way ANOVA (prenatal nutrition, treatment, and postnatal diet as factors) followed by Bonferonni post hoc analysis, and data are shown as mean ± SEM.

	Results

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As reported previously (9), maternal undernutrition resulted in fetal growth retardation reflected by significantly decreased birth weight in the offspring from UN dams (UN, 4.02 ± 0.03 g; AD, 6.13 ± 0.04 g; P < 0.0001). Litter size was not different between the two groups (AD, 12.3 ± 1.8; UN, 11.9 ± 2.0).

Neonatal leptin treatment resulted in a transient reduction in pup weight gain in both AD and UN pups (Fig. 1), although the response was more acute and more marked in the UN group (mean relative weight loss over treatment period: AD, 3.8 ± 0.5%; UN, 14.8 ± 1.2%; P < 0.0001) (mean relative weight loss in first 72 h after treatment: AD, 3.2 + 1.9%; UN, 22.9 + 1.7%; P < 0.0001).

View larger version (34K): [in this window] [in a new window]   FIG. 1. Change in body weight gain in leptin-treated AD and UN neonates relative to saline-treated animals. UN offspring showed an acute response to leptin treatment compared with offspring born of normally nourished mothers. P < 0.0001 for effect of leptin; P < 0.0001 for effect of programming. Data are shown as mean + SEM; n = 8 per group.

View larger version (17K): [in this window] [in a new window]   FIG. 2. A, Diet-induced weight gain ( high fat – chow fed) at postnatal d 170 in AD and UN animals treated with either saline or leptin in the neonatal period. Neonatal leptin in UN animals normalized diet-induced weight gain to match that of AD animals. Neonatal leptin had no effect on diet-induced weight gain in AD animals. , UN saline; , UN leptin; , AD saline; , AD leptin. Differences in AD saline vs. AD leptin, UN leptin vs. AD saline, UN leptin vs. AD leptin were not significant; P < 0.001 for UN saline vs. all other groups. B, Absolute body weight gain at postnatal d 170 in AD and UN animals on chow (C) or high-fat (HF) diet treated with either saline (S) or leptin (L) in the neonatal period. Leptin treatment had no effect on weight gain in chow or HF-fed AD animals. The diet-induced weight gain in UN saline-treated HF animals (UN SHF) was significantly reduced in UN leptin-treated HF (UN LHF) animals to a level below that of AD HF animals (programming x treatment interaction, P < 0.05).

View larger version (22K): [in this window] [in a new window]   FIG. 3. Representative DEXA scans from adult UN offspring at postnatal d 170 treated as neonates with either saline (top) or leptin (bottom); total fat mass as assessed by DEXA. Neonatal leptin treatment reduced total fat mass by 30% in UN HF offspring to match that of AD animals; also shown are locomotor activity and caloric intake in adult AD and UN HF animals after saline (S) or leptin (L) treatment as neonates. Data are mean ± SEM; n = 8 per group. For total body fat and locomotor activity, P < 0.001 for UN saline-treated HF animals (UNSHF) vs. all other groups; for food intake, P < 0.05 for UNSHF vs. all other groups.

At postnatal d 170, fasting plasma leptin, C-peptide, and insulin concentrations were elevated in UN saline-treated HF animals compared with AD saline-treated HF animals (programming x postnatal diet interaction, P < 0.005) (Fig. 4). Neonatal leptin treatment normalized plasma leptin, C-peptide, and insulin in UN leptin-treated HF animals to match that of AD HF animals. In contrast, neonatal leptin treatment had no statistically significant effect on adult leptin, C-peptide, and insulin levels in AD animals fed chow, AD animals fed a high-fat diet, or UN animals fed chow. However, a trend toward an increase in plasma leptin, insulin, and C-peptide concentrations was noted in AD leptin-treated animals on both the chow and high-fat diets, but these did not reach statistical significance (P = 0.11, 0.08, and 0.07, respectively). Fasting plasma glucose concentrations were in the normal range for all treatment groups (data not shown).

View larger version (17K): [in this window] [in a new window]   FIG. 4. A, Fasting plasma insulin concentrations at d 170 in AD and UN animals on either a chow (C) or high-fat (HF) diet after neonatal saline or leptin treatment. Neonatal leptin treatment normalized fasting plasma insulin concentrations in UN leptin-treated HF (UN LHF) animals compared with saline-treated animals (P < 0.05 for effect of programming and diet; programming x treatment, programming x diet, and treatment x diet interactions, P < 0.05). B, Fasting plasma leptin concentrations at d 170. Neonatal leptin treatment normalized fasting plasma leptin concentrations in UN LHF animals compared with saline-treated animals (P < 0.05 for effect of diet and treatment; programming x diet, programming x treatment, treatment x diet, and programming x treatment x diet interactions, all P < 0.05). C, Fasting plasma C-peptide concentrations at d 170. Neonatal leptin treatment normalized fasting plasma C-peptide concentrations in UN LHF animals compared with saline-treated animals (P < 0.05 for effect of programming; P < 0.0001 for effect of diet; programming x treatment, programming x diet, and treatment x diet interactions, P < 0.05). Data were analyzed by three-way factorial ANOVA, mean ± SEM; n = 8 per group.

	Discussion

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Although the mechanisms underlying developmental programming are unclear, the process has been considered irreversible. The current findings indicate that, at least in the rat, there is an early postnatal window during which the process can be reversed. SGA (small for gestational age) children have been shown to have low cord blood and plasma leptin levels (36, 37) and a predisposition to develop the metabolic syndrome in adult life (38), although very little is known about the leptin surge in these cohorts. Our animal model closely resembles the increased weight gain and metabolic abnormalities seen in humans born of low birth weight, and thus we propose that the underlying mechanistic basis proposed in the present study will have parallels in the clinical setting. Defining the postnatal age limit after which a potential intervention would be ineffective and the underlying mechanisms will require further study. However, the continuing developmental plasticity of the hypothalamus (27), and the pancreas in the rodent (39), provides the opportunity to alter developmental programming. The timing of neonatal leptin treatment in the current study, from d 3–13, was an attempt to replicate the normal postnatal leptin surge (20).

Long-term effects of neonatal leptin treatment were restricted to the programmed animals. Energy homeostasis in the offspring of normally fed mothers was not significantly altered by neonatal leptin treatment. This specificity of leptin’s action argues in favor of neonatal leptin treatment correcting the mechanism of programming rather than having a general effect on metabolic determination. Additional work will be required to define the relationship between maternal undernutrition and leptin levels during fetal life and also in the immediate postnatal period. It is possible, however, that maternal undernutrition results in hypoleptinemia during a critical period of development and that this reduction in leptin is the cue that initiates the programming cascade. Gluckman and Hanson (2) have suggested that developmental programming is the consequence of a mismatch between the environment seen during the period of developmental plasticity and the mature environment. Maternal undernutrition has indicated to the fetus that the current and therefore future nutritional environments are likely to be poor, but the high-fat diet applied after weaning creates a severe metabolic mismatch. It is notable in the present study in females that the programmed phenotype is expressed only in the presence of a high-fat diet postnatally, whereas we have previously shown in the male that programming can manifest independently of postnatal nutrition (9). Irrespective of the mechanism that the fetus uses to read the nutritional cue, a high leptin level in the neonate might be interpreted as a high nutritional state (because leptin levels and fat mass generally correlate in the neonate), and given that there is still potential for plastic response, the organism readjusts from its earlier trajectory. Neonatal leptin caused a very different weight response in the pups of undernourished mothers. This suggests that sensitivity to leptin is affected by prenatal undernutrition and again might infer a central role for perinatal leptin levels having a key role in metabolic programming.

The concomitant reduction in caloric intake and increased locomotor activity in programmed animals treated with neonatal leptin may reflect a direct effect of leptin on the hypothalamus. Leptin-deficient animals have reduced neural projections from the arcuate nucleus to a number of other hypothalamic nuclei involved in energy homeostasis (27, 40). These projections can be normalized by exogenous leptin treatment but only if leptin is given during the neonatal period (27). It has also been shown that fetal hypothalamic development can be modified by maternal nutrition, and weanling offspring of rat dams fed a low-protein diet during pregnancy are reported to have malformed hypothalamic nuclei (24).

As well as having a central hypothalamic effect, neonatal leptin treatment may have reversed developmental programming by modifying postnatal pancreatic organogenesis. Fetal malnutrition causes a reduction in ß-cell number and pancreatic islet size in rat pups by suppressing islet cell proliferation (41) and increasing ß-cell apoptosis (25). Pancreatic ß-cells express the long form of the leptin receptor, and leptin increases the viability of isolated rat pancreatic islets by suppressing apoptosis (28). Work in our laboratory has described a dysregulation of the feedback loop between insulin and leptin in the pancreatic islet in adult offspring after maternal undernutrition (11). The normalization of insulin and C-peptide levels in adult programmed animals given neonatal leptin may be primary but could alternatively be secondary to the reduction in fat mass in these animals.

The results of this study indicate that developmental adaptations during fetal life can be reversed by interventions in the neonatal period, at least in an altricial species, and that alterations in perinatal leptin levels may play a crucial role in determining the occurrence of long-term metabolic sequelae. Given the implications of these findings, it will be important to determine leptin’s ontogeny in infants born prematurely or small for gestational age.

	Footnotes

 
This work was funded by the Health Research Council of New Zealand and the National Research Centre for Growth and Development.

First Published Online July 14, 2005

Abbreviation: DEXA, Dual-energy x-ray absorptiometry.

Received May 12, 2005.

Accepted for publication July 7, 2005.

	References

Top Abstract Introduction Materials and Methods Results Discussion References

 

1. Hales CN, Barker DJ 2001 The thrifty phenotype hypothesis. Br Med Bull. 60:5–20
2. Gluckman PD, Hanson MA 2004 Living with the past: evolution, development and patterns of disease. Science 305:1773–1776[Abstract/Free Full Text]
3. Waterland RA, Garza C 1999 Potential mechanisms of metabolic imprinting that lead to chronic disease. Am J Clin Nutr. 69:179–197
4. Waterland RA, Jirtle RL 2004 Early nutrition, epigenetic changes at transposons and imprinted genes, and enhanced susceptibility to adult chronic diseases. Nutrition 20:63–68[CrossRef][Medline]
5. Armitage JA, Taylor PD, Poston L 2005 Experimental models of developmental programming: consequences of exposure to an energy rich diet during development. J Physiol. 15:3–8 (First Published 3 Feb 2005; 10.1113/jphysiol.2004.079756)
6. Ozanne SE 2001 Metabolic programming in animals. Br Med Bull. 60:143–152
7. McMillen IC, Adam CL, Muhlhausler BS 2005 Early origins of obesity: programming the appetite regulatory system. J Physiol. 15:9–17 (First Published 10 Feb 2005; 10.1113/jphysiol.2004.081992)
8. Bateson P, Barker D, Clutton-Brock T, Deb D, D’Udine B, Foley RA, Gluckman P, Godfrey K, Kirkwood T, Mirazon Lahr M, McNamara J, Metcalfe NB, Monaghan P, Spencer HG, Sultan SE 2004 Developmental plasticity and human health. Nature 430:419–421[CrossRef][Medline]
9. Vickers MH, Breier BH, Cutfield WS, Hofman PL, Gluckman PD 2000 Fetal origins of hyperphagia, obesity and hypertension and its postnatal amplification by hypercaloric nutrition. Am J Physiol. 279:E83–E87
10. Vickers M, Breier B, McCarthy D, Gluckman P 2003 Sedentary behavior during postnatal life is determined by the prenatal environment and exacerbated by postnatal hypercaloric nutrition. Am J Physiol. 285:R271–R273
11. Vickers MH, Reddy S, Ikenasio BA, Breier BH 2001 Dysregulation of the adipoinsular axis: a mechanism for the pathogenesis of hyperleptinemia and adipogenic diabetes induced by fetal programming. J Endocrinol. 170:323–332
12. Zhang Y, Proenca R, Maffei M, Barone M, Leopold L, Friedman JM 1994 Positional cloning of the mouse obese gene and its human homologue. Nature 372:425–432[CrossRef][Medline]
13. Elmquist JK, Flier JS 2004 The fat-brain axis enters a new dimension. Science 304:63–64[Abstract/Free Full Text]
14. Hamann A, Matthaei S 1996 Regulation of energy balance by leptin. Exp Clin Endocrinol Diabetes 104:293–300[Medline]
15. Ahima RS, Flier JS 2000 Leptin. Annu Rev Physiol. 62:413–437
16. Considine RV, Sinha MK, Heiman ML, Kriauciunas A, Stephens TW, Nyce MR, Ohannesian JP, Marco CC, McKee LJ, Bauer TL 1996 Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 334:292–295
17. Caro JF, Kolaczynski JW, Nyce MR, Ohannesian JP, Opentanova I, Goldman WH, Lynn RB, Zhang PL, Sinha MK, Considine RV 1996 Decreased cerebrospinal-fluid/serum leptin ratio in obesity: a possible mechanism for leptin resistance. Lancet 348:159–161[CrossRef][Medline]
18. Ahima RS, Prabakaran D, Mantzoros C, Qu D, Lowell B, Maratos-Flier E, Flier JS 1996 Role of leptin in the neuroendocrine response to fasting. Nature 382:250–252[CrossRef][Medline]
19. Hoggard N, Hunter L, Duncan JS, Williams LM, Trayhurn P, Mercer JG 1997 Leptin and leptin receptor mRNA and protein expression in the murine fetus and placenta. Proc Natl Acad Sci USA. 94:11073–11078
20. Ahima RS, Prabakaran D, Flier JS 1998 Postnatal leptin surge and regulation of circadian rhythm of leptin by feeding. Implications for energy homeostasis and neuroendocrine function. J Clin Invest. 101:1020–1027
21. Bi S, Gavrilova O, Gong DW, Mason MM, Reitman M 1997 Identification of a placental enhancer for the human leptin gene. J Biol Chem. 272:30583–30588
22. Houseknecht KL, McGuire MK, Portocarrero CP, McGuire MA, Beerman K 1997 Leptin is present in human milk and is related to maternal plasma leptin concentration and adiposity. Biochem Biophys Res Commun. 240:742–747
23. Iniguez G, Soto N, Avila A, Salazar T, Ong K, Dunger D, Mericq V 2004 Adiponectin levels in the first two years of life in a prospective cohort: relations with weight gain, leptin levels and insulin sensitivity. J Clin Endocrinol Metab. 89:5500–5503
24. Plagemann A, Harder T, Rake A, Melchior K, Rohde W, Dorner G 2000 Hypothalamic nuclei are malformed in weanling offspring of low protein malnourished rat dams. J Nutr. 130:2582–2589
25. Petrik J, Reusens B, Arany E, Remacle C, Coelho C, Hoet JJ, Hill DJ 1999 A low protein diet alters the balance of islet cell replication and apoptosis in the fetal and neonatal rat and is associated with a reduced pancreatic expression of insulin-like growth factor-II. Endocrinology 140:4861–4873[Abstract/Free Full Text]
26. Ozanne SE, Olsen GS, Hansen LL, Tingey KJ, Nave BT, Wang CL, Hartil K, Petry CJ, Buckley AJ, Mosthaf-Seedorf L 2003 Early growth restriction leads to down regulation of protein kinase C and insulin resistance in skeletal muscle. J Endocrinol. 177:235–241
27. Bouret SG, Draper SJ, Simerly RB 2004 Trophic action of leptin on hypothalamic neurons that regulate feeding. Science 304:108–110[Abstract/Free Full Text]
28. Islam M, Sjöholm Å, Emilsson V 2000 Fetal pancreatic islets express functional leptin receptors and leptin stimulates proliferation of fetal islet cells. Int J Obes Relat Metab Disord. 24:1246–1253
29. Cohen P, Friedman JM 2004 Leptin and the control of metabolism: role for stearoyl-CoA desaturase-1 (SCD-1). J Nutr. 134:2455S–2463S
30. Marx J 2003 Cellular warriors at the battle of the bulge. Science 299:846–849[Abstract/Free Full Text]
31. Seufert J, Kieffer TJ, Leech CA, Holz GG, Moritz W, Ricordi C, Habener JF 1999 Leptin suppression of insulin secretion and gene expression in human pancreatic islets: implications for the development of adipogenic diabetes mellitus. J Clin Endocrinal Metab. 84:670–676
32. Kieffer TJ, Habener JF 2000 The adipoinsular axis: effects of leptin on pancreatic ß-cells. Am J Physiol. 278:E1–E14
33. Poitout V, Rouault C, Guerre-Millo M, Briaud I, Reach G 1998 Inhibition of insulin secretion by leptin in normal rodent islets of Langerhans. Endocrinology 139:822–826[Abstract/Free Full Text]
34. Pallett AL, Morton NM, Cawthorne MA, Emilsson V 1997 Leptin inhibits insulin secretion and reduces insulin mRNA levels in rat isolated pancreatic islets. Biochem Biophys Res Commun. 238:267–270
35. Vickers MH, Ikenasio BA, Breier BH 2001 IGF-I treatment reduces hyperphagia, obesity, and hypertension in metabolic disorders induced by fetal programming. Endocrinology 142:3964–3973[Abstract/Free Full Text]
36. Koistinen HA, Koivisto VA, Andersson S, Karonen SL, Kontula K, Oksanen L, Teramo KA 1997 Leptin concentration in cord blood correlates with intrauterine growth. J Clin Endocrinol Metab. 82:3328–3330
37. Harigaya A, Hagashima K, Nako Y, Morikawa A 1997 Relationship between concentration of serum leptin and fetal growth. J Clin Endocrinol Metab. 82:3281–3284
38. Levy-Marchal C, Jaquet D 2004 Long-term metabolic consequences of being born small for gestational age. Pediatr Diabetes 5:147–153[CrossRef][Medline]
39. Stoffers DA 2004 The development of ß-cell mass: recent progress and potential role of GLP-1. Horm Metab Res. 36:811–821
40. Bouret SG, Simerly RB 2004 Leptin and development of hypothalamic feeding circuits. Endocrinology 145:2621–2626[Abstract/Free Full Text]
41. Snoeck A, Remacle C, Reusens B, Hoet JJ 1990 Effect of a low protein diet during pregnancy on the fetal rat endocrine pancreas. Biol Neonate. 57:107–118

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				D. A. Nugent, D. M. Smith, and H. B. Jones A Review of Islet of Langerhans Degeneration in Rodent Models of Type 2 Diabetes Toxicol Pathol, June 1, 2008; 36(4): 529 - 551. [Abstract] [Full Text] [PDF]

				M. H. Vickers, P. D. Gluckman, A. H. Coveny, P. L. Hofman, W. S. Cutfield, A. Gertler, B. H. Breier, and M. Harris The Effect of Neonatal Leptin Treatment on Postnatal Weight Gain in Male Rats Is Dependent on Maternal Nutritional Status during Pregnancy Endocrinology, April 1, 2008; 149(4): 1906 - 1913. [Abstract] [Full Text] [PDF]

				M. M. Elahi, F. R. Cagampang, F. W. Anthony, N. Curzen, S. K. Ohri, and M. A. Hanson Statin Treatment in Hypercholesterolemic Pregnant Mice Reduces Cardiovascular Risk Factors in Their Offspring Hypertension, April 1, 2008; 51(4): 939 - 944. [Abstract] [Full Text] [PDF]

				S. G. Bouret Crossing the Border: Developmental Regulation of Leptin Transport to the Brain Endocrinology, March 1, 2008; 149(3): 875 - 876. [Full Text] [PDF]

				F. Delahaye, C. Breton, P.-Y. Risold, M. Enache, I. Dutriez-Casteloot, C. Laborie, J. Lesage, and D. Vieau Maternal Perinatal Undernutrition Drastically Reduces Postnatal Leptin Surge and Affects the Development of Arcuate Nucleus Proopiomelanocortin Neurons in Neonatal Male Rat Pups Endocrinology, February 1, 2008; 149(2): 470 - 475. [Abstract] [Full Text] [PDF]

				P. D. Gluckman, K. A. Lillycrop, M. H. Vickers, A. B. Pleasants, E. S. Phillips, A. S. Beedle, G. C. Burdge, and M. A. Hanson Metabolic plasticity during mammalian development is directionally dependent on early nutritional status PNAS, July 31, 2007; 104(31): 12796 - 12800. [Abstract] [Full Text] [PDF]

				M. Thamotharan, M. Garg, S. Oak, L. M. Rogers, G. Pan, F. Sangiorgi, P. W. N. Lee, and S. U. Devaskar Transgenerational inheritance of the insulin-resistant phenotype in embryo-transferred intrauterine growth-restricted adult female rat offspring Am J Physiol Endocrinol Metab, May 1, 2007; 292(5): E1270 - E1279. [Abstract] [Full Text] [PDF]

				C. J. Stocker, E. Wargent, J. O'Dowd, C. Cornick, J. R. Speakman, J. R. S. Arch, and M. A. Cawthorne Prevention of diet-induced obesity and impaired glucose tolerance in rats following administration of leptin to their mothers Am J Physiol Regulatory Integrative Comp Physiol, May 1, 2007; 292(5): R1810 - R1818. [Abstract] [Full Text] [PDF]

				I. H. Trevenzoli, M. M. R. Valle, F. B. Machado, R. M. G. Garcia, M. C. F. Passos, P. C. Lisboa, and E. G. Moura Neonatal hyperleptinaemia programmes adrenal medullary function in adult rats: effects on cardiovascular parameters J. Physiol., April 15, 2007; 580(2): 629 - 637. [Abstract] [Full Text] [PDF]

				B. A Ikenasio-Thorpe, B. H Breier, M. H Vickers, and M. Fraser Prenatal influences on susceptibility to diet-induced obesity are mediated by altered neuroendocrine gene expression J. Endocrinol., April 1, 2007; 193(1): 31 - 37. [Abstract] [Full Text] [PDF]

				P. Saenger, P. Czernichow, I. Hughes, and E. O. Reiter Small for Gestational Age: Short Stature and Beyond Endocr. Rev., April 1, 2007; 28(2): 219 - 251. [Abstract] [Full Text] [PDF]

				P. D. Taylor and L. Poston Developmental programming of obesity in mammals Exp Physiol, March 1, 2007; 92(2): 287 - 298. [Abstract] [Full Text] [PDF]

				B. N. Van Vliet and L. L. Chafe Maternal Endothelial Nitric Oxide Synthase Genotype Influences Offspring Blood Pressure and Activity in Mice Hypertension, March 1, 2007; 49(3): 556 - 562. [Abstract] [Full Text] [PDF]

				P D Gluckman and M A Hanson Adult disease: echoes of the past Eur. J. Endocrinol., November 1, 2006; 155(suppl_1): S47 - S50. [Abstract] [Full Text] [PDF]

				S. O Krechowec, M. Vickers, A. Gertler, and B. H Breier Prenatal influences on leptin sensitivity and susceptibility to diet-induced obesity. J. Endocrinol., May 1, 2006; 189(2): 355 - 363. [Abstract] [Full Text] [PDF]

				E. Zambrano, C. J. Bautista, M. Deas, P. M. Martinez-Samayoa, M. Gonzalez-Zamorano, H. Ledesma, J. Morales, F. Larrea, and P. W. Nathanielsz A low maternal protein diet during pregnancy and lactation has sex- and window of exposure-specific effects on offspring growth and food intake, glucose metabolism and serum leptin in the rat J. Physiol., February 15, 2006; 571(1): 221 - 230. [Abstract] [Full Text] [PDF]

				M. C. Henson and V. D. Castracane Leptin in Pregnancy: An Update Biol Reprod, February 1, 2006; 74(2): 218 - 229. [Abstract] [Full Text] [PDF]

				M. G. Myers Jr., M. E. Patti, and R. L. Leshan Hitting the Target: Leptin and Perinatal Nutrition in the Predisposition to Obesity Endocrinology, October 1, 2005; 146(10): 4209 - 4210. [Full Text] [PDF]

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