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Clinic of Obstetrics, Division of Experimental Obstetrics, Charité—University Medicine Berlin, Campus Virchow-Klinikum, Berlin, Germany
2To whom correspondence should be addressed. E-mail: andreas.plagemann{at}charite.de.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • gestational diabetes • breastfeeding • nutritional programming • hypothalamus • regulation of food intake and body weight
Experimental and clinical investigations have shown that offspring of mothers with diabetes during pregnancy are at increased risk of developing obesity and diabetogenic disturbances in later life (1–8). Offspring of streptozotocin-diabetic rat dams, a well-established animal model for gestational diabetes (GD),3 display hyperphagia and become overweight in later life (6,7). This is associated with malformations of the ventromedial hypothalamic nucleus (VMN) (9), a key regulator of food intake, body weight, and metabolism (10). Moreover, juvenile and adult offspring of GD rat dams show persisting malorganization of the hypothalamic neurons that express orexigenic neuropeptides in the arcuate hypothalamic nucleus (ARC) (6,7). We hypothezised that these hypothalamic alterations could be coresponsible for the lasting alterations in food intake, body weight, and metabolism observed in the offspring of GD dams.
Within the mediobasal hypothalamus, a network of orexigenic and anorexigenic neuropeptides is critically involved in the complex regulation of food intake, body weight, and metabolism [for review, see Kalra et al. (11)]. Neuropeptide Y (NPY) and galanin (GAL) are probably the most intensively investigated neuropeptides that stimulate food intake and body weight gain (11,12). Proopiomelanocortin (POMC) and its splice-product 
-melanocyte-stimulating hormone (MSH) are the main functional antagonists, which decrease food intake and consequently weight (13). Within the anorexigenic POMC-MSH system, agouti-related peptide (AGRP) acts as a physiological antagonist at the melanocortin-4 (MC-4) receptor, thereby exerting orexigenic effects (14).
Physiologically, insulin and leptin act as peripheral satiety signals by regulating the expression and release of both orexigenic and anorexigenic neuropeptides within the ARC, the major site of expression: Increased concentration of both hormones causes downregulation of expression and release of the orexigenic neuropeptides NPY, GAL, and AGRP and simultaneous upregulation of the anorexigenic peptides POMC and MSH (11,12).
We recently showed that neonatal exposure to breast milk from diabetic mothers might be coresponsible for an increased risk of developing obesity and consequent diabetogenic disturbances in the offspring of mothers that were diabetic during pregnancy (15). Reifsnyder et al. (16) demonstrated that New Zealand obese mouse pups (a genetic animal model for obesity and type 2 diabetes) suckled by diabetic mothers became more obese and had higher insulin and leptin levels in adulthood than did those reared by control dams, independent of their genetic background. Against this background, we hypothesized that the functional and hypothalamic alterations in the offspring of diabetic rat dams described above might be at least partly a direct consequence of exposure to milk from diabetic dams. The possible role of maternal milk in the development of short- and long-term alterations in the offspring of diabetic rat dams has rarely been investigated. Therefore, we investigated whether exposing rat pups to milk from diabetic mothers affects the development of the neurons involved in lifelong hypothalamic regulation of food intake, body weight, and metabolism.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Cross-fostering-schedule. Immediately after birth (d 1 of life), offspring of CO rat dams were randomly cross-fostered either to CO rat dams (CO-CO group; n = 6 litters) or to GD rat dams (CO-GD group; n = 4 litters). Pups born to GD mothers were not studied further in this experiment. Litter sizes were adjusted to 10–12 pups per nest. Pups were reared in these nests until weaning (d 21 of life). Maternal blood samples for determination of whole blood glucose concentration (glucoseoxidase-peroxidase method; Dr. Lange GmbH) were taken during lactation, on d 16 of the suckling period.
Experimental procedures in the offspring. Body weight was monitored from d 1 to 21 of life. Offspring were killed by rapid decapitation on d 21. Body weight, body length, and blood glucose, plasma insulin, and plasma leptin concentrations were measured. Offspring (6 CO-CO and 8 CO-GD) were randomly assigned to neuromorphometric investigations. The brain volume index (BVI), the absolute and relative volume of the VMN and of the paraventricular hypothalamic nucleus (PVN), the numerical density of Nissl+ neurons, and the absolute number of neurons within the VMN and PVN were determined using cresyl violet–stained coronary brain sections. Stained sections of the ARC were assayed for neurons positive for NPY, POMC, MSH, AGRP, and GAL by semiquantitative immunocytochemistry.
Metabolic variables. Blood glucose concentration was measured in trunk blood as described above. Immunoreactive plasma insulin was measured using a modified double antibody radioimmunoassay performed within one assay (insulin RIA kit, BioChem Immunosystems). Rat insulin (Novo Nordisk Biolabs) with a biological potency of 21.3 U/mg served as the standard preparation. The intraassay variation was 4.5 to 7.4% in a concentration range of 63.7 to 659.4 pmol/L (n = 10). Leptin concentration was measured using a commercial radioimmunoassay (rat leptin RIA kit, Linco). Recombinant rat leptin (Linco) served as the standard preparation. The intraassay variation was 2.0 to 4.6% in a concentration range of 1.6 to 11.6 µg/L (n = 20).
Conventional and immunocytochemical staining. Neuromorphological investigations were performed as previously described (6,7,9,17). In brief, 5-µm-thick serial coronal sections were cut through the hypothalamus at planes 24 to 32 (18). Alternate slides were stained with cresyl violet (Nissl+) or immunostained for NPY, POMC, MSH, AGRP, or GAL, using the avidin-biotin-peroxidase complex (ABC) method (Vectastain Kit; Vector Laboratories). Samples were incubated with a rabbit antibody to rat NPY (1:6000; Peninsula), POMC (1:5000; Phoenix), MSH (1:500; DPC Biermann), AGRP (1:1300; Phoenix), or GAL (1:5000; Peninsula) for 48 h in a humid chamber at 4°C. After washing, slides were treated with biotinylated antimouse IgG (2.00 mg/L; Vector), then incubated with ABC for 2 h. Sections were exposed to a 0.05% solution of 3,3'-diaminobenzidine tetrahydrochloride (Sigma) for 20 min. Specificity of the labeling procedure was verified by the absence of immunocytochemical reaction in sections in which the primary antibody was omitted or was replaced with normal serum.
Neuromorphometric analysis. Morphometric analyses of the VMN, PVN, and ARC were performed using an image analyzing system (KS 400 V.3.0; Zeiss) connected to a light microscope (Axioscope; Zeiss) by a video camera (DXC-390P; Sony). The BVI, a measure of whole-brain volume (19), was calculated from measurements at the level of the mediobasal hypothalamus (20). The areas of the VMN and PVN were calculated by interactively drawing their boundaries in all Nissl-stained serial sections at a final magnification of 90X. The volume of each hypothalamic nucleus was calculated from these values using the Simpson rule (21). The relative volumes of the VMN and the PVN were calculated by dividing the volume of the nucleus by the BVI (20).
In all successive sections showing these nuclei, neurons were identified by a distinct nucleolus and soma appearance (22). They were counted in the VMN and the PVN at a final magnification of 2000X. Localization of measurement was chosen as described previously (17). At planes 24 to 28 (18), 4 microscopic fields (MF) in the anterior part of the VMN and 3 MF in the magnocellular and parvocellular parts of the PVN, respectively, were counted in both hemispheres of the brain in each section (Fig. 1). At planes 30 to 31, 4 MF were counted bilaterally in each part of the VMN (central, ventrolateral, and dorsomedial), and 3 MF were counted bilaterally in the ARC. From these measurements, the total number of neurons in the VMN and PVN was calculated as previously described (23).
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Statistical analysis. Data are presented as means ± SEM. One-way ANOVA analyses followed by unpaired t tests were used to evaluate differences between the groups. Relations between variables were analyzed using Spearman’s rank correlation tests. Values of P < 0.05 were considered significant. All evaluations were performed using SPSS for Windows 10.0 (SPSS).
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Furthermore, the area of AGRP immunopositivity was markedly larger in CO-GD rats, whereas neither the absolute nor the relative numerical density of AGRP neurons differed between groups (Fig. 4D). The area of AGRP immunopositivity was positively correlated with maternal blood glucose on d 16 of lactation (r = 0.80; P < 0.001; n = 14).
Finally, the absolute and relative numerical density of GAL-immunopositive neurons was markedly lower, and the GAL-immunopositive area within the ARC was smaller, in CO-GD than in CO-CO rats (Fig. 4E). Maternal blood glucose on d16 of lactation was negatively correlated with the absolute (r = -0.84; P < 0.001) and relative (r = -0.91; P < 0.001) numerical density of GAL-positive neurons and the GAL-immunopositive area (r = -0.85; P < 0.001; all n = 14). Furthermore, body weight on d 21 was positively correlated with the absolute (r = 0.64; P < 0.01) and relative (r = 0.68; P < 0.01) numerical density of GAL-positive neurons and the GAL-immunopositive area (r = 0.55; P < 0.05; all n = 14).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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We observed a progressive delay in growth during neonatal life in the rats reared by diabetic dams, which has rarely been taken into account in this model. In humans, neonatal ingestion of breast milk from diabetic mothers may dose-dependently increase the risk of obesity in early childhood (15). Breast milk from diabetic mothers is characterized by increased levels of glucose and insulin, which both diffuse from maternal circulation into milk [(28); for review, see Neubauer (29)]. In nontreated diabetic rat dams, this is combined with a marked decrease in milk synthesis and milk ejection (30), which apparently led to quantitative undernutrition in the offspring in our experiment. However, factors other than maternal milk that are altered in this model may contribute to the outcome to a certain degree. For example, alterations in maternal behavior caused by maternal diabetes might affect neurodevelopment in the offspring.
In previous studies, we observed a decreased numerical density and a decreased total number of neurons in the VMN in offspring of GD rat dams, which persisted from weaning (d21 of life) into adulthood (2,4,9). These general neuronal alterations were restricted to the VMN, whereas other hypothalamic nuclei such as the PVN were not affected (9,23). Moreover, we showed that these alterations could be prevented by treatment of maternal gestational hyperglycemia (23,31). Because the VMN inhibits food intake, body weight gain, and insulin secretion (10), we concluded that the decreased numerical density and number of neurons might lead to impaired function of this nucleus. Impaired function of the VMN may contribute to the development of hyperphagia, obesity, and diabetogenic disturbances in the offspring of GD rat dams [(2,9); for review, see Dörner and Plagemann (4)].
Remarkably, there were no general morphometric alterations in the VMN in the current experiment. In rats, the critical differentiation period for the VMN begins in the second half of gestation, and continues until the end of wk 3 of neonatal life (32). Unlike our previous studies, exposure to maternal diabetes was restricted to the suckling period in the present experiment. Therefore, we conclude that exposure to a diabetic intrauterine milieu is crucial for the development of a general malorganization of the VMN in the offspring of diabetic rat dams, whereas exposure to altered lactation and milk alone is not sufficient.
On the contrary, exclusive exposure to milk from diabetic dams resulted in general neural alterations in the PVN. These morphometric changes could be the result of neonatal malnutrition, as similar changes occurred in underweight weanling offspring of rat dams fed a low-protein diet during gestation and lactation (17). Remarkably, similar to milk from rat dams fed a low-protein diet, milk from diabetic mothers contains decreased concentrations of amino acids (33). Aside from its role in body weight control, the PVN is crucially involved in the regulation of blood pressure (34,35). Therefore, malorganization of this nucleus might also contribute to long-term cardiovascular disturbances. Notably, we reported an association between the neonatal ingestion of breast milk from diabetic mothers and increased blood pressure during childhood in a recent clinical study (36).
Using the NPY-immunopositive area as a crucial indicator of orexigenic activity, we observed an upregulation of NPY-ergic activity under basal conditions in weanling rats reared by GD mothers. This supports previous studies with the offspring of GD rat dams (6,7). Notably, because blood glucose and, especially, plasma leptin and insulin concentrations did not differ between groups under basal conditions, the nonstimulated basal upregulation of NPY in CO-GD rats strongly suggests that exposure to milk from diabetic mothers alone may be sufficient to cause "malprogramming" of the NPY-ergic system, regardless of the intrauterine period. This malprogramming indicates a kind of uncoupling or resistance of this important orexigenic neuropeptidergic system to the physiological effects of leptin and insulin, obviously caused by the altered neonatal nutrition. The expression of NPY in the diencephalon begins 
14 d postconception in rats (37). During the neonatal period, NPY expression in the ARC is strongly enhanced in rats, indicating a particular critical period in the development of this neuropeptidergic system (38). Notably, a causal relation between the ingestion of glucose-enriched milk from diabetic mothers and the hypothalamic NPY expression in the weanling offspring is further supported by the positive correlation between maternal blood glucose during lactation and NPY immunopositivity in the offspring.
However, the numerical density of NPY neurons did not change, as it did in previous studies with offspring of GD rat dams (6,7). The severity of maternal diabetes might explain this phenomenon, as it obviously leads to a growth delay during neonatal development, which is probably caused by reduced maternal lactational performance (30). Therefore, we conclude that intrauterine as well as neonatal exposure are crucial for functional and structural malorganization of NPY-ergic neurons in this animal model. This interpretation is supported by animal-model studies of perinatal undernutrition, in which the number of NPY-expressing neurons did not differ between groups (39). Rather, one study even reported decreased numerical densities of NPY-positive neurons (17). Therefore, in newborn rats exposed to milk from diabetic mothers, the effects of neonatal undernutrition (i.e., reduced milk intake) might have interacted with the effects of neonatal ingestion of milk enriched with glucose and insulin.
There was a similar phenomenon regarding the GAL-expressing neurons in the ARC. Rats in the CO-GD group had a lower numerical density of GAL-positive neurons and a smaller GAL-immunopositive area, indicating both structural and functional inhibition or hypoactivity of this neuropeptidergic system. In addition to acting as an orexigenic neuropeptide, GAL plays an important role in the regulation of growth, by stimulating growth hormone secretion (40,41). On one hand, early neonatal overnutrition stimulates GAL in the ARC (42). On the other hand, studies report a reduced numerical density of GAL-immunopositive neurons in animal models of perinatal growth retardation, such as the offspring of rat dams fed a low-protein diet (17,43) or rats raised in large litters (44). The expression of GAL in the ARC begins during late neonatal life, 11 d after birth (45), corresponding to the period of exposure to milk from diabetic dams in our model. Despite increased concentrations of glucose and insulin (46), milk from diabetic rat dams can induce a growth delay in the newborn offspring, probably due to decreased milk volume and decreased amino acid concentrations (33), which interact crucially with the growth hormone–somatostatin–GAL network during development (47). Consequently, GAL expression was positively correlated to body weight and inversely correlated to maternal blood glucose concentration during lactation in our model.
Both POMC and its splice product MSH showed structural disorganization and functional downregulation in CO-GD rats. This suppression occurred despite normal plasma leptin and insulin concentrations. Together with the inverse correlation between maternal blood glucose during midlactation and MSH expression, this might indicate that exposure to milk from diabetic mothers causes malprogramming of the POMC/MSH-ergic hypothalamic system. The point at which MSH-ergic neurons appear in the ARC, around d 16 of postnatal life (48), might provide an anatomical and physiological basis for such a malprogramming, due to the kind of neonatal nutrition used in the present study. In addition, we attempted to characterize neurons expressing the neuropeptide AGRP, which acts as a physiological antagonist at the MC-4 receptor within the melanocortinergic system. Again, as in the case of NPY, there was an upregulation of this orexigenic neuropeptide in the ARC of weanling CO-GD rats. The expression of AGRP increases markedly during neonatal life, beginning on d 2 (38). In principle, it is possible that the increased expression of AGRP in the present study was induced by increased expression of NPY or vice versa, because these neuropeptides stimulate each other and are coexpressed to a high degree (49). However, the differing extent of hyperactivity and the positive correlation between maternal blood glucose during lactation and AGRP immunopositivity in the offspring seem to indicate an independent malprogramming of this orexigenic neuropeptidergic system due to ingestion of milk from diabetic mothers.
In summary, this study indicates that neonatal exposure to maternal diabetes, especially exposure to milk from diabetic mothers, causes a complex malorganization and malprogramming of hypothalamic orexigenic and anorexigenic neuropeptidergic systems in the offspring. This could contribute to the development of hyperphagia, obesity, and diabetogenic disturbances in infancy and in later life. Notably, even subtle alterations in these neuropeptidergic circuits might initiate a vicious circle, as similarly suggested by Lustig (50). Hypothalamic malprogramming due to altered organization of neuropeptidergic regulatory systems may initially lead to more or less discrete functional consequences, such as moderate hyperphagia, hyperglycemia, hyperinsulinemia and hyperleptinemia, and insulin and leptin resistance. However, this may result in further (e.g., age-accelerated) dysfunction or even damage to hypothalamic neurons due to, e.g., glucotoxicity and/or a progressive induction of hypothalamic resistance to insulin and leptin, which further augments functional consequences, and so on.
Therefore, the data seem to support clinical observations showing a crucial role of neonatal exposure to breast milk from diabetic mothers in the pathogenesis of later obesity (15). Further research on the possible long-term effects of breast feeding on the offspring of diabetic mothers is obviously needed.
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FOOTNOTES |
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3 Abbreviations used: ABC, avidin-biotin-peroxidase complex; AGRP, agouti-related peptide; ARC, arcuate hypothalamic nucleus; BVI, brain volume index; CO, control group; CO-CO, offspring of control rat dams cross-fostered to control rat dams; CO-GD, offspring of control rat dams cross-fostered to diabetic rat dams; GAL, galanin; GD, gestational diabetes; MC-4, melanocortin-4; MF, microscopic field; MSH, -melanocyte-stimulating hormone; NPY, neuropeptide Y; POMC, proopiomelanocortin; PVN, paraventricular hypothalamic nucleus; STZ, streptozotocin; VMN, ventromedial hypothalamic nucleus.
Manuscript received 27 August 2003. Initial review completed 26 September 2003. Revision accepted 17 November 2003.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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1. Pettitt, D. J., Baird, H. R., Aleck, K. A., Bennett, P. H. & Knowler, W. C. (1983) Excessive obesity in offspring of Pima Indian women with diabetes during pregnancy. N. Eng. J. Med. 308:242-245.[Abstract]
2. Dörner, G., Plagemann, A., Rückert, J. C., Götz, F., Rohde, W., Stahl, F., Kürschner, U., Gottschalk, J., Mohnike, A. & Steindel, E. (1988) Teratogenetic maternofetal transmission and prevention of diabetes susceptibility. Exp. Clin. Endocrinol. 91:247-258.[Medline]
3. Aerts, L., Holemans, K. & Van Assche, F. A. (1990) Maternal diabetes during pregnancy: consequences for the offspring. Diab. Metab. Rev. 6:147-167.[Medline]
4. Dörner, G. & Plagemann, A. (1994) Perinatal hyperinsulinism as a possible predisposing factor for diabetes mellitus, obesity and enhanced cardiovascular risk in later life. Horm. Metab. Res. 26:213-221.[Medline]
5. Silverman, B. L., Purdy, L. P. & Metzger, B. E. (1996) The intrauterine environment: implications for the offspring of diabetic mothers. Diabetes Rev. 4:21-35.
6. Plagemann, A., Harder, T., Rake, A., Melchior, K., Rittel, F., Rohde, W. & Dörner, G. (1998) Hypothalamic insulin and neuropeptide Y in the offspring of gestational diabetic mother rats. NeuroReport 9:4069-4073.[Medline]
7. Plagemann, A., Harder, T., Melchior, K., Rake, A., Rohde, W. & Dörner, G. (1999) Elevation of hypothalamic neuropeptide Y-neurons in adult offspring of diabetic mother rats. NeuroReport 10:3211-3216.[Medline]
8. Dabelea, D., Hanson, R. L., Lindsay, R. S., Pettitt, D. J., Imperatore, G., Gabir, M. M., Roumain, J., Bennett, P. H. & Knowler, W. C. (2000) Intrauterine exposure to diabetes conveys risks for type 2 diabetes and obesity: a study of discordant sibships. Diabetes 49:2208-2211.
9. Plagemann, A., Harder, T., Janert, U., Rake, A., Rittel, F., Rohde, W. & Dörner, G. (1999) Malformation of hypothalamic nuclei in hyperinsulinaemic offspring of gestational diabetic mother rats. Dev. Neurosci. 21:58-67.[Medline]
10. Bray, G. A., Fisler, J. & York, D. A. (1990) Neuroendocrine control of the development of obesity: understanding gained from studies in experimental animal models. Front. Neuroendocrinol. 11:128-181.
11. Kalra, S. P., Dube, M. G., Pu, S., Xu, B., Horvath, T. L. & Kalra, P. S. (1999) Interacting appetite-regulating pathways in the hypothalamic regulation of body weight. Endocr. Rev. 20:68-100.
12. Spiegelman, B. M. & Flier, J. S. (2001) Obesity and the regulation of energy balance. Cell 104:531-543.[Medline]
13. Tritos, N. A., Vincent, D., Gillette, J., Ludwig, D. S., Flier, E. S. & Maratos-Flier, E. (1998) Functional interactions between melanin-concentrating hormone, neuropeptide Y, and anorectic neuropeptides in the rat hypothalamus. Diabetes 47:1687-1692.[Abstract]
14. Rossi, M., Kim, M. S., Morgan, D.G.A., Small, C. J., Edwards, C.M.B., Sunter, D., Abusnana, S., Goldstone, A. P. & Russel, S. H., et al (1998) A c-terminal fragment of agouti-related protein increases feeding and antagonizes the effect of alpha-melanocyte stimulating hormone in vivo. Endocrinology 139:4428-4431.
15. Plagemann, A., Harder, T., Franke, K. & Kohlhoff, R. (2002) Long-term impact of neonatal breast feeding on body weight and glucose tolerance in children of diabetic mothers. Diabetes Care 25:16-22.
16. Reifsnyder, P. C., Churchill, G. & Leiter, E. H. (2000) Maternal environment and genotype interact to establish diabesity in mice. Genome Res. 10:1568-1578.
17. Plagemann, A., Harder, T., Rake, A., Melchior, K., Rohde, W. & Dörner, G. (2000) Hypothalamic nuclei are malformed in weanling offspring of low-protein malnourished rat dams. J. Nutr. 130:2582-2590.
18. Paxinos, G. & Watson, C. (1986) The rat brain in stereotaxic coordinates 1986 Academic Press San Diego, CA.
19. Jacobson, C. D., Shryne, J. E., Shapiro, R. & Gorski, R. A. (1980) Ontogeny of the sexually dimorphic nucleus of the preoptic area. J. Comp. Neurol. 193:541-548.[Medline]
20. Maecker, H. L. (1993) Perinatal cocaine exposure inhibits the development of the male SDN. Dev. Brain Res. 76:288-292.[Medline]
21. Gottlieb, M. D., Pasik, P. & Pasik, T. (1985) Early postnatal development of the monkey visual system. I. Growth of the lateral geniculate nucleus and striate cortex. Brain Res. 349:53-62.[Medline]
22. Erskine, M. S. & Miller, S. (1995) Ultrastructural effects of estradiol and 5-alpha-androstane-3-alpha, 17-beta-diol on neurons within the ventromedial nucleus of the hypothalamus. Neuroendocrinology 61:669-679.[Medline]
23. Harder, T., Aerts, L., Franke, K., Van Bree, R., Van Assche, F. A. & Plagemann, A. (2001) Pancreatic islet transplantation in diabetic pregnant rats prevents acquired malformation of the ventromedial hypothalamic nucleus in their offspring. Neurosci. Lett. 299:85-88.[Medline]
24. Gundersen, H.J.G. (1986) Stereology of arbitrary particles. J. Microsc. 143:3-45.[Medline]
25. Leibowitz, S. F., Akabayashi, A. & Wang, J. (1998) Obesity on a high-fat diet: role of hypothalamic galanin in neurons of the anterior paraventricular nucleus projecting to the median eminence. J. Neurosci. 18:2709-2719.
26. Bestetti, G. E., Abramo, F., Guillaume-Gentil, C., Rohner-Jeanrenaud, F., Jeanrenaud, B. & Rossi, G. L. (1990) Changes in the hypothalamo-pituitary-adrenal axis of genetically obese fa/fa rats: a structural, immunocytochemical, and morphometrical study. Endocrinology 126:1880-1887.
27. Zoli, M., Pich, E. M., Cimino, M., Lombardelli, G., Peruzzi, G., Fuxe, K., Agnati, L. F. & Cattabeni, F. (1990) Morphometrical and microdensitometrical studies on peptide- and tyrosine hydroxylase-like immunoreactivities in the forebrain of rats prenatally exposed to methylazoxymethanol acetate. Dev. Brain Res. 51:45-61.[Medline]
28. Neville, M. C., Allen, J. C., Archer, P., Casey, C. E., Seacat, J., Keller, R. P., Lutes, V., Rasbach, J. & Neifert, M. (1991) Studies in human lactation: milk volume and nutrient composition during weaning and lactogenesis. Am. J. Clin. Nutr. 54:81-92.
29. Neubauer, S. H. (1990) Lactation in insulin-dependent diabetes. Prog. Food Nutr. Sci. 14:333-370.[Medline]
30. Lau, C., Sullivan, M. K. & Hazelwood, R. L. (1993) Effects of diabetes mellitus on lactation in the rat. Proc. Soc. Exp. Biol. Med. 204:81-89.[Medline]
31. Harder, T., Franke, K., Fahrenkrog, S., Aerts, L., Van Bree, R., Van Assche, F. A. & Plagemann, A. (2003) Prevention by maternal pancreatic islet transplantation of hypothalamic malformation in offspring of diabetic mother rats is detectable already at weaning. Neurosci. Lett. 352:163-166.[Medline]
32. Pozzo-Miller, L. D. & Aoki, A. (1992) Postnatal development of the ventromedial hypothalamic nucleus: neurons and synapses. Cell Mol. Neurobiol. 12:121-129.[Medline]
33. Nowak, J. & Dzialoszynski, L. (1967) Effect of experimental alloxan diabetes on the secretion and composition of goat milk. Acta Physiol. Polon. 18:488-497.
34. Krukoff, T. L., Harris, K. H., Linetsky, E. & Jhamandas, J. H. (1994) Expression of c-fos protein in rat brain elicited by electrical and chemical stimulation of the hypothalamic paraventricular nucleus. Neuroendocrinology 59:590-602.[Medline]
35. Dampney, R.A.L., Coleman, M. J., Fontes, M.A.P., Hirooka, Y., Horiuchi, J., Li, Y. W., Polson, J. W., Potts, R. D. & Tagawa, T. (2002) Central mechanisms underlying short- and long-term regulation of the cardiovascular system. Clin. Exp. Pharmacol. Physiol. 29:261-268.[Medline]
36. Harder, T., Kohlhoff, R., Franke, K. & Plagemann, A. (2001) Early nutrition and later blood pressure: effect of maternal diabetes. J. Pediatr. 139:905-906.[Medline]
37. Allen, J. M., McGregor, G. P., Woodhams, P. L., Polak, J. M. & Bloom, S. R. (1984) Ontogeny of a novel peptide, neuropeptide Y (NPY) in the rat brain. Brain Res. 303:197-200.[Medline]
38. Grove, K. L., Allen, S., Grayson, B. E. & Smith, M. S. (2003) Postnatal development of the hypothalamic neuropeptide Y system. Neuroscience 116:393-406.[Medline]
39. Huizinga, C. T., Oudejans, C. B. M. & Delemarre-van de Waal, H. A. (2001) Persistent changes in somatostatin and neuropeptide Y mRNA levels but not in growth hormone-releasing hormone levels in adult rats after intrauterine growth retardation. J. Endocrinol. 168:273-281.[Abstract]
40. Ottlecz, A., Snyder, G. D. & McCann, S. M. (1988) Regulatory role of galanin in the control of hypothalamic-anterior pituitary functions. Proc. Natl. Acad. Sci. U.S.A. 85:9861-9865.
41. Niimi, M., Takahara, J., Sato, M. & Kawanishi, K. (1990) Immunohistochemical identification of galanin and growth hormone-releasing factor-containing neurons projecting to the median eminence of the rat. Neuroendocrinology 51:572-575.[Medline]
42. Plagemann, A., Harder, T., Rake, A., Voits, M., Fink, H., Rohde, W. & Dörner, G. (1999) Perinatal increase of hypothalamic insulin, acquired malformation of hypothalamic galaninergic neurons, and syndrome X-like alterations in adulthood of neonatally overfed rats. Brain Res. 836:146-155.[Medline]
43. Plagemann, A., Rittel, F., Harder, T., Waas, T., Ziska, T. & Rohde, W. (2000) Hypothalamic galanin levels in weanling rats exposed to maternal low-protein diet. Nutr. Res. 20:977-983.
44. Huizinga, C. T., Oudejans, C.B.M. & Delemarre-van de Waal, H. A. (2001) Decreased galanin mRNA levels in growth hormone-releasing hormone neurons after perinatally induced growth retardation. J. Endocrinol. 170:521-528.[Abstract]
45. Sizer, A. R., Rökäeus, A. & Foster, G. A. (1990) Analysis of the ontogeny of galanin in the rat central nervous system by immunohistochemistry and radioimmunoassay. Int. J. Dev. Neurosci. 8:81-97.[Medline]
46. Jovanovic-Peterson, L., Fuhrmann, K., Hedden, K., Walker, L. & Peterson, C. M. (1989) Maternal milk and plasma glucose and insulin levels: studies in normal and diabetic subjects. J. Am. Coll. Nutr. 8:125-131.[Abstract]
47. Ghigo, E., Arvat, E., Gianotti, L., Ramunni, J., DiVito, L., Maccagno, B., Grottoli, S. & Camanni, F. (1996) Human aging and the GH-IGF-I axis. J. Pediatr. Endocrinol. Metab. 9(Suppl 3):271-278.
48. Marani, E. & van der Veeken, J. G. (1988) The postnatal developmental localization of pro-opiomelanocortin and alpha melanocyte stimulating hormone in the mediobasal hypothalamus of the rat. Basic Appl. Histochem. 32:171-178.[Medline]
49. Dhillo, W. S., Small, C. J., Stanley, S. A., Jethwa, P. H., Seal, L. J., Murphy, K. G., Ghatei, M. A. & Bloom, S. R. (2002) Hypothalamic interactions between neuropeptide Y, agouti-related protein, cocaine- and amphetamine-regulated transcript and alpha-melanocyte-stimulating hormone in vitro in male rats. J. Neuroendocrinol. 14:725-730.[Medline]
50. Lustig, R. H. (2002) Hypothalamic obesity: the sixth cranial endocrinopathy. Endocrinologist 12:210-217.
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