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McGill University (K.P., C.-D.W.), Department of Psychiatry, Douglas Hospital Research Center, Montréal, Québec, Canada H4H 1R3; and Department of Physiology (D.R.), Université Laval, Ste-Foy, Québec, Canada H4H 1R3
Address all correspondence and requests for reprints to: Dr. Claire-Dominique Walker, Douglas Hospital Research Center, 6875 Lasalle Boulevard, Verdun, Québec, Canada H4H 1R3. E-mail: waldom{at}douglas.mcgill.ca.
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Abstract |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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-MSH (by way of reducing expression of the precursor POMC) in the rostral arcuate nucleus (ARC) (10), and corticotropin-releasing factor (CRF) from the paraventricular portion of the hypothalamus (PVN) (8, 11). In the arcuate nucleus, NPY and POMC neurons express Ob-Rb (the long form of leptin receptor) that are functionally coupled to the Janus kinase-signal transducer and activator of transcription intracellular signaling cascade and produce an endogenous inhibitor [suppressor of cytokine signaling (SOCS)-3] upon activation (12). Reduced POMC mRNA expression has been reported in animal models of reduced (ob/ob mouse) or defective (fa/fa Zucker rat) leptin signaling (13). In neonates, hypothalamic NPY levels are initially low, dramatically increase at postnatal d 16 (PND16), and subsequently decline to reach adult levels after weaning (14). Recently, Grove et al. (15) demonstrated that the ARC NPY/agouti-related peptide fibers do not start to significantly innervate the PVN until PND10–11 and that even by PND15–16, these fibers have still not reached adult levels in the rostral part of the PVN. However, whether NPY expression is regulated by leptin during development is still unclear. Studies have demonstrated that NPY expression is sensitive to feeding status in developing rats. For instance, the expression of prepro-NPY and NPY is increased by maternal deprivation as early as PND2 in lean Zucker rat pups (16).
In contrast to NPY mRNA expression, POMC mRNA expression is hardly detectable in 5-d-old mice but then increases to reach adult levels around weaning (17). There is indication, however, that POMC mRNA expression in the ARC is not sensitive to the effect of chronic leptin treatment in 10-d-old mice (17). In the rat, adult-like pattern of distribution of POMC perikarya and fibers are observed by late gestation although the peak of POMC immunoreactivity occurs between PND21–28 (18). At present, there is a paucity of information on the regulation of POMC neurons in the ARC during the early neonatal period in this species.
Similarly to POMC, CRF has been demonstrated to induce anorexia in adult rats (19). CRF receptor type 2 (CRFR-2) in the ventromedial hypothalamus (VMH) is the receptor through which CRF is thought to exert its action on feeding (20). Decreased VMH CRFR-2 mRNA levels have been reported in obese Zucker (fa/fa) rats (21) and also in starved and adrenalectomized rats (22). Moreover, both acute and chronic systemic administration of leptin in rats stimulated the expression of CRFR-2 mRNA in the VMH (20). Eghbal-Ahmadi et al. (23) found that CRFR-2 mRNA is expressed in the VMH as early as E16 and seems to follow a gradual pattern of increase, with a peak between PND15–25. Maternal deprivation has been shown to reduce the expression of CRFR-2 mRNA in the VMH of developing rats, whereas artificial feeding increased the expression of CRFR-2 mRNA to an intermediate level between maternally deprived unfed pups and control animals (24). However, to our knowledge, no study has analyzed the effects of leptin on the expression of this receptor during development.
Several authors, including ourselves (6, 25), reported that leptin is already effective in reducing body weight and body fat during early development, although this effect might be due to increased thermogenesis rather than anorexigenic action (26, 27, 28). Although the effects of leptin on NPY, POMC, and CRFR-2 are well established in adults, little is known about the ontogeny and the timing of the functional activation of these neuropeptides by leptin in rat pups. Hence, in our study we tested the effect of acute leptin on food intake in the early postnatal period and determined whether acute or chronic leptin treatment during the first 10 d of life induces functional intracellular responses and modifies the expression of hypothalamic neuropeptides such as NPY and POMC. We also examined leptin-induced changes in CRFR-2 expression in the ventromedial hypothalamus. We found that although acute leptin administration did not modify food intake in pups, leptin signaling was functional in the ARC of 10-d-old pups. Chronic and/or acute leptin treatment reduced the expression of NPY and all forms of Ob-R in the ARC, whereas it increased the expression of POMC in the ARC and CRFR-2 in the VMH.
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Materials and Methods |
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Leptin treatments
Murine leptin was obtained lyophilized from Preprotech Inc. (Rocky Hill, NJ) and reconstituted in 10 mM Tris buffer at a pH of 9.5. After dissolution, the pH was readjusted to 7.4 by addition of 1 N HCl. For the chronic treatment, each litter was subdivided into three groups receiving either no injection (uninjected, n = 2 pups) or daily ip injections of 50 µl of either leptin (3 mg/kg BW, L, n = 4 pups) or vehicle (10 mM Tris-HCl, pH 7.4; V, n = 4 pups) between d 3 and 9 of life. All injections were given in the morning between 0830 and 1000 h.
Tissue collection
At 0900 h on PND10, rat pups from each chronic treatment group (V and L) were weighed and separated into two experimental groups receiving an ip injection of either saline (saline 0.9%, S) or leptin (3 mg/kg BW, L). Injected pups were then returned to their mothers in a quiet room and euthanized 30 or 120 min after the injection. Control pups (uninjected) were euthanized without any injection. The time interval of 30 min was chosen to be optimal for the determination of SOCS-3 induction as shown previously in adults (29), and the 120-min interval was chosen to be more optimal for the detection of stable changes in neuropeptide mRNA expression. Trunk blood was collected in chilled microcentrifuge tubes containing 10 µl of EDTA (60 mg/ml) and plasma was kept frozen at -20 C until assayed for leptin and corticosterone concentrations. Brains were rapidly collected and postfixed in a chilled solution of 4% paraformaldehyde in phosphate buffer (0.1 M, pH 7.4, 4 C) for 2 d followed by immersion in a solution of 10% sucrose in phosphate buffer (0.1 M, pH 7.4) for 2 d at 4 C. Brains were then frozen at -80 C until processed for in situ hybridization. Retroperitoneal fat pads and adrenal glands were dissected and weighed.
To determine the possible down-regulation of leptin receptors (Ob-R) following chronic daily injection, a subset of V and L injected pups were euthanized on PND10, 24 h after the last injection to determine Ob-R mRNA levels in the ARC.
Time course after exogenous leptin injection
To determine the peak and duration of leptin increases in the plasma after exogenous administration, 10-d-old pups from 8 different litters were injected ip with 50 µl of either vehicle (0.9% NaCl) or leptin (3 mg/kg BW). Pups were euthanized at 1, 3, 6, 13, 18, or 24 h after injection (n = 6/treatment and per time point), and trunk blood was collected on EDTA as described above. A control group was euthanized without injection at the beginning of the experiment (t = 0 h, n = 5). Plasma concentrations of leptin and corticosterone were determined by sensitive RIAs.
Determination of food intake in pups
On PND5, PND8, and PND10, pups received an acute injection of leptin (3 mg/kg BW, ip) or saline (NaCl 0.9%) between 0900 and 1000 h, and they were removed from the dam for 3 h thereafter. This interval between injection and testing was chosen because we determined that the peak plasma leptin occurred 3 h after exogenous administration (Fig. 1
). Before testing, pups were stimulated to urinate and defecate by stroking the anogenital region with an artist’s brush wetted with warm water, then pups were weighed. During the intake test, pups were placed individually into plastic containers lined with paper towels wetted with a commercial lukewarm half and half milk solution. Pups were kept on a warming pad at 32–35 C and allowed to consume the milk solution for 30 min during which the paper towels were rewet with warm solution as necessary. Pups were then removed from the containers, dried carefully, and reweighed. Because pups at this age do not readily urinate and defecate spontaneously, unless stimulated manually, the amount of weight gained (expressed as a percentage of the pup’s predeprivation body weight) during the intake test was used as a reliable measure of milk intake (30). Using this method of determination of food intake in neonatal rats, others have demonstrated both stimulatory effects of 2-mercaptoacetate (30) and inhibitory effects of glucose gastric preloads (31)
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For each experimental group, two to six animals were analyzed with an average of three to six sections/animal. Once removed from the autoradiography cassettes, the slides were defatted in xylene and dipped in NTB2 nuclear emulsion (Eastman Kodak Co.) for 5 min. Exposure time to emulsion varied for each transcript. After developing, slides were rinsed in running distilled water for 1–2 h, counterstained with thionin (0.25%), and coverslipped.
For the determination of POMC and NPY mRNA, we used oligonucleotides probes with some variations in the hybridization protocol. Sequences were 5'-ATGAGATGTGGGGGGAAACTAGGAAAAGTC AGGAGAGCAAGTTTCATT-3' and 5'-CTTGCCCACCGGCTTGCCCCAGCG-3' for NPY and POMC, respectively. The brain sections were postfixed for 10 min in paraformaldehyde (4%), washed 3 x 15 min in phosphate buffer 0.1 M, 1 x 1 h in 4x SSC (containing 1% of Denhardt’s solution), and 5 min in a mixture of 1:1 (TEA 0.2 M and NaCl 18%), acetylated 15 min with acetic anhydride (0.25% in a mixture 1:1 of TEA 0.2 M and NaCl 18%), washed 3 x 5 min in 2x SSC, defatted through graded concentrations (70, 95, and 100%) of alcohol, then placed in chloroform 5 min and rehydrated through graded concentrations (100, 95, 70%) of alcohol. After air-drying for at least 2 h, 90 µl of hybridization solution mixture was spotted on each slide. Hybridization buffer contained 5% formamide, 600 mM NaCl, 10 mM Tris-HCl (pH 7.5), 1 M EDTA, 0.02% Denhardt 50x, 100 µg/ml of denatured salmon sperm DNA, 50 µg/ml of yeast tRNA, 10% dextran sulfate, 10 mM dithiothreitol, 1 x 107 cpm/ml of the 35S-labeled POMC or NPY probe and volume was completed to 1 ml with sterile water. The slides were coverslip-sealed and incubated overnight at 40 C. The next day, the coverslips were removed and the slides were rinsed 10 min in 2x SSC, 5 min in 1x SSC, followed by a stringent wash for 60 min in 100 ml of 0.1x SSC with 1.5 ml of ß-mercaptoethanol at 35 C under constant stirring. The sections were quickly rinsed in tap water and dehydrated through graded concentrations (50, 70, and 100%) of alcohol. After at least 2 h of air-drying, slides were exposed to ß-max Hyperfilm (Amersham Pharmacia Biotech) together with radioactive 14C standards for 6 d (POMC) and 12 d (NPY). Matching sections selected at four different levels of the ARC were analyzed. The whole ARC was subdivided into four levels (A through D) as previously described by Steiner and colleagues (3, 37) and adapted according to the atlas of Sherwood and Timiras (38) for 10-d-old pups. Level A corresponded to plate A 3.5 mm to A 3.2 mm (excluded), level B, plate A 3.2 mm to A 2.6 mm (excluded); level C, plate A 2.6 mm to A 2.0 mm (excluded); and level D, plate A 2.0 mm to the end of the ARC plate A 1.6 mm (included). For each experimental group, two to six animals were analyzed with an average of three to nine sections/animal.
Hormone assays
Plasma corticosterone concentrations were determined by RIA using a kit from ICN Biomedicals, Inc. (Costa Mesa, CA) with small modifications. The limit of detection was 0.2 µg/dl, interassay and intraassay variability was 12% and 3%, respectively (25). Plasma leptin levels were measured by specific RIA using a kit from Linco Research, Inc. (St. Charles, MO). The limit of detection was 0.5 ng/ml, and interassay variability was 9% (25).
Statistical analysis
All results were analyzed using the ANOVA followed by post hoc Student-Newman-Keuls or Tukey’s highest significant difference tests where appropriate. Significant differences between two groups were determined by Student’s t test. The level of significance was set as P < 0.05. All values are expressed as mean ± SEM.
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Results |
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). At the time of the peak circulating leptin (i.e. 3 h after injection), food intake in leptin-treated pups was not modified over that of vehicle-treated pups on PND5, PND8, or PND10 of life (V vs. L: PND5, P = 0.890; PND8, P = 0.438; and PND10, P = 0.353, Table 1). When administered chronically between PND3–9, leptin slightly reduced body weight gain in PND10 pups (P = 0.331) but significantly reduced fat pads weight (P < 0.01) compared with vehicle-treated rats in agreement with previous data (6, 25).
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). However, plasma corticosterone was higher at 30 min compared with 120 min following treatment, most likely reflecting the stress of ip injection.
Effects of leptin on NPY, POMC, and SOCS-3 expression in the arcuate nucleus
Consistent with the function of SOCS-3 as an acute marker of leptin’s intracellular response, changes in SOCS-3 mRNA expression were determined 30 min following acute leptin or vehicle treatment in PND10 pups. Thirty minutes after acute treatment, SOCS-3 mRNA expression was seen specifically in the epithelium lining the lateral ventricles, the dentate gyrus of the hippocampus (not shown), and the ARC (Fig. 2, top). In the ARC, SOCS-3 mRNA levels were significantly higher in pups injected with leptin compared with saline-injected pups (P < 0.05) (Fig. 2, bottom) and the increase in SOCS-3 expression was observed independently of the nature of chronic treatment (V/L vs. L/L pups, P = 0.227). In the dentate gyrus of the hippocampus, SOCS-3 mRNA levels were also significantly elevated after leptin treatment (V/S = 233.2 ± 17.2 nCi/g, V/L = 282.5 ± 11.5, P < 0.05). The short increase in corticosterone secretion is unlikely to have contributed significantly to SOCS-3 stimulation because previous reports have failed to document a direct effect of glucocorticoids on SOCS-3 expression throughout the adult rat brain (32).
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). Expression of POMC mRNA was restricted to the ARC, whereas NPY mRNA expression was found both in the ARC and the dorsomedial hypothalamus (Fig. 3C). No NPY mRNA expression was detected in the PVN of PND10 pups.
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, the effects of acute or chronic leptin on NPY mRNA were dependent upon the level of the ARC analyzed and the time point used after the injection. Whereas acute leptin reduced NPY mRNA levels 30 min after the injection in the more rostral portion of the ARC (level A, P < 0.05), it increased the expression of this peptide in a more caudal region (level C, P < 0.05) (Fig. 4, top). However, these effects were only transient because they were observed at 30 min, but not at 120 min after injection (level A, P = 0.737; and level C, P = 0.180 compared with V/S). The effects of an acute injection of leptin in pups chronically treated with leptin were also manifest on different levels of the ARC (Fig. 4, bottom). In this situation, cumulative leptin injection consistently reduced NPY mRNA expression 30 or 120 min after injection in all levels, but the more rostral portion of the ARC. The reduction in NPY mRNA expression after leptin treatment was consistent for both time points (30 and 120 min) only at the more caudal level of the ARC (level D, P < 0.05) (Fig. 5).
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and 6, top, level A). POMC mRNA levels increased both 30 and 120 min after an acute leptin injection in level A (P < 0.05), but were unchanged in other levels (30 min, level B, P = 0.519; level C, P = 0.451; level D, P = 0.347 compared with V/S and 120 min; level B, P = 0.484; level C, P = 0.775; level D, P = 0.057 compared with V/S). Acute leptin-induced stimulation of POMC expression was probably maximum because there was no further increase in POMC mRNA expression when an acute injection was superimposed on chronic leptin treatment (Fig. 6, bottom).
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). In contrast, leptin increased CRFR-2 mRNA levels in the VMH of PND10 pups only when the interval between injection and euthanasia was 30 min (P < 0.05) and when the pups received chronic leptin treatment during PND3–9 (L/L vs. L/S) (Fig. 8). There was no significant effect of acute leptin on CRFR-2 expression in the VMH (V/S vs. V/L; 30 min, P = 0.784; 120 min, P = 0.812) and no residual effect seen 24 h after the last injection (V/S vs. L/S; 30 min, P = 0.170; and 120 min, P = 0.490). Consistent with the chronic effect of leptin on CRFR-2 expression demonstrated in adults (20), our results show that CRFR-2 expression is only transiently increased by leptin and that the acute effects of leptin on CRFR-2 expression are only revealed after chronic neonatal treatment with leptin.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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During the neonatal period, the elevated circulating levels of leptin (39) acting as a catabolic and anorexigenic hormone in adults might appear to be paradoxical at a time of rapid growth and development. Other studies and our present results however failed to demonstrate a decrease in food intake in pups treated with leptin (6, 26, 40, 41) suggesting either 1) that leptin signaling is not functional in the neonatal brain, or 2) that anorexigenic or orexigenic circuits are modulated differently compared with adults.
Using the production of SOCS-3 as a marker of functional activation of leptin receptor and intracellular signaling (29), we showed that an acute injection of leptin on PND10 increased the expression of SOCS-3 in the ARC. This effect disappeared 24 h after leptin administration in pups chronically injected with leptin between PND3–9. Interestingly, leptin retained its ability to activate intracellular signaling after chronic daily administration and despite the down-regulation of leptin receptors that we observed in the ARC. This result demonstrates that leptin receptors, and in particular Ob-Rb, can mediate the activation of SOCS-3 in the ARC and that leptin signal is functional in the hypothalamus of developing rats.
One of our salient observations is that POMC mRNA expression in PND10 pups was stimulated by acute leptin administration (V/L), although only in the rostral part of the ARC as demonstrated in adults (10). The acute effects of leptin on POMC mRNA were not observed in neonates treated daily with leptin, suggesting that POMC expression had reached a ceiling and could not be increased further in this group (L/L). The acute effects of leptin on POMC neurons could have been mediated directly through the binding of leptin to Ob-Rb expressed on these neurons or indirectly via the modulation of other neuropeptides such as NPY. Indeed, in addition to both being under the control of leptin, NPY, and POMC neurons regulate each other through reciprocal interactions (42) involving NPY Y1 receptors (43, 44) and/or GABA release (45). A recent study demonstrated that GABA and NPY are colocalized in axon terminals of the ARC that establish inhibitory synapses on POMC neurons. Leptin may directly depolarize POMC neurons and simultaneously hyperpolarize the somata of NPY/GABA neurons, thus removing the GABA inhibitory tone exerted on POMC neurons (45).
Because the product of POMC processing, -MSH, is considered to be the predominant pathway regulating food intake in adults (42), it is surprising to observe leptin-induced increase in POMC expression, whereas we failed to observe any significant effect on food intake in neonates. This might point out to immaturity of POMC projections to target nuclei expressing melanocortin-4 receptors in the early postnatal period or suggest that POMC is not the primary regulator of food intake during development. Other systems like those stimulating food intake may rather be predominant at this time.
Similarly to POMC, NPY neurons appear to be already responsive to leptin treatment on PND10 as we found a decrease in NPY expression in various levels of the ARC after acute or chronic leptin injection. In the acute treatment, leptin reduced NPY expression in the more rostral part of the ARC but increased it in a more caudal level. These effects were transient because they were not present 120 min after acute leptin injection. If NPY is a primary regulator of food intake in neonates, the transient nature of the leptin effect on NPY expression might explain why we did not measure any significant difference in food intake between leptin and vehicle-injected groups 3 h after an acute treatment. The inhibition of NPY mRNA expression induced by an acute injection of leptin was more consistent and prolonged in animals chronically treated with leptin during the first 10 d of life. Again, it is remarkable that changes in NPY expression occurred despite leptin receptor down-regulation in the ARC. In contrast with the acute leptin injection, in the chronic condition all levels of the ARC, but the more rostral showed reduced NPY expression. It is possible that populations of NPY neurons along the ARC are differentially sensitive to acute and/or chronic leptin treatment due to the pattern of distribution of Ob-Rb or to the differential distribution of neuronal inputs to NPY neurons. An interesting parallel can be drawn between our results showing reduced NPY expression by increasing circulating leptin levels and other studies reporting increased NPY expression after maternal separation and food deprivation during neonatal development (16, 46).
Our results are in contrast with those reported by Ahima et al. (17) who failed to observe any difference in POMC or NPY mRNA content in the ARC of 17-d-old pups receiving a chronic leptin treatment. Methodological differences could account for the discrepancies because Ahima and Hileman (17) used RT-PCR to determine hypothalamic content of neuropeptides expression and we used in situ hybridization, which offers a better spatial resolution than RT-PCR. Moreover, we subdivided the ARC nucleus into four different levels allowing for a more refined level of analysis. Indeed, Smith and colleagues (46, 47) previously showed that failure to distinguish the different levels of the ARC does not permit the detection of region-restricted changes in NPY expression.
As an index of modifications in energy balance, we reported a tendency for leptin to lower body weight and a significant decrease in fat pads weight in pups receiving chronic leptin administration compared with vehicle-treated pups, even though we did not detect significant changes in food intake following an acute injection of leptin. Rather than being a consequence of reduced food intake, the effect of leptin on body and fat pads weight could be due to an increase in sympathetic activity as demonstrated in 2-wk-old neonates (40). In adult rodents, leptin activates sympathetic outflow via stimulation of hypothalamic POMC neurons and inhibition of the NPYergic system (8, 48). In our study, the observed changes in NPY and POMC expression induced by leptin might be more closely related to changes in sympathetic activation in neonates than to processes regulating food intake per se.
Consistent with adult experiments (49), chronic leptin administration in neonates down-regulated all types of leptin receptors, including probably the most abundant and functional form in the brain, Ob-Rb. Conversely, conditions reducing circulating leptin levels, such as fasting, have been reported to up-regulate Ob-Rb in the ARC and the VMH of adult rats (49). Although Ob-Rb are localized on NPY and POMC-producing neurons in the ARC of adults, the phenotype of neurons expressing leptin receptors in neonates is still unknown. Given the enhancement of leptin effect on NPY expression with chronic treatment and the lack of further effect of leptin on POMC in the same condition, it is tempting to speculate that leptin receptor down-regulation might have affected POMC neurons predominantly over those expressing NPY. Confirmation of this awaits further investigation.
Expression of CRF and its receptors, in particular CRFR-2, represents another important system regulating food intake (50, 51). Okamoto et al. (52) recently demonstrated that some of the anorexigenic effect of leptin are mediated through CRF, but not urocortin in adult rats. In neonates, acute leptin injection up-regulated the expression of CRFR-2 in the VMH, but only in pups chronically treated with leptin from PND3–9. This suggests that transient leptin’s effects on CRFR-2 expression are only revealed when superimposed on chronic elevation of leptin levels and possibly reduced CRF release. When leptin levels are dramatically reduced in neonates, such as after 24 h of maternal separation and food deprivation (Walker, C.-D., and M. Oates, unpublished), a strong down-regulation of CRFR-2 mRNA expression in the VMH was reported (24). What remains unclear is how leptin exerts its action on CRFR-2 expression in the VMH, whether it is directly via Ob-Rb present on VMH neurons harboring CRFR-2 (53) or indirectly through the regulation of CRF release (20). In the present study, we observed no SOCS-3 mRNA labeling in the VMH, suggesting rather an indirect action of leptin. Although some controversy remains as to the effects of leptin on CRF, it is generally accepted that leptin is inhibitory to CRF production in the PVN (54) and to HPA axis activity in neonates (25, 39). We previously showed that stimulated but not basal CRF mRNA levels were reduced by leptin in 10-d-old pups (25). Thus, the observed elevation in CRFR-2 mRNA expression could represent a compensatory mechanism induced after the reduction of CRF expression.
In summary, our results demonstrate that the expression of NPY, POMC, and Ob-Rall in the arcuate nucleus, and CRFR-2 in the VMH is differentially sensitive to acute and/or chronic leptin treatment in developing rats. Because leptin did not reduce food consumption in the same period, we conclude that the neuropeptides studied in these experiments are not predominant to determine food intake during early development. In particular, because adequate feeding is essential for survival in the early stages of life, neonatal hypothalamic regulation protects the organism against threat to this behavior by establishing several compensatory mechanisms aimed at maintaining energy homeostasis. Orexigenic circuits other than or in addition to the ones that we have studied here might have provided stronger signals to maintain food intake in leptin-treated pups. For example, agouti-related peptide, orexins, and ghrelin are all very potent neuropeptides that have been shown to strongly stimulate appetite in adulthood. Future experiments are designed to investigate the regulation of these neuropeptides by leptin during development.
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Acknowledgments |
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Footnotes |
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Abbreviations: ARC, Arcuate nucleus; BW, body weight; CRF, corticotropin-releasing factor; CRFR2, CRF receptor type 2; HPA, hypothalamo-pituitary-adrenal; L, leptin; NPY, neuropeptide Y; Ob-Rall, all subtypes of leptin receptors; Ob-Rb, long form of leptin receptor; PND, postnatal day; POMC, proopiomelanocortin; PVN, paraventricular portion of the hypothalamus; S, saline; SOCS, suppressor of cytokine signaling; TEA, trietholamine; V, vehicle; VMH, ventromedial hypothalamus.
Received June 6, 2002.
Accepted for publication August 1, 2002.
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 M. Acosta-Martinez and J. E. Levine Regulation of KATP channel subunit gene expression by hyperglycemia in the mediobasal hypothalamus of female rats Am J Physiol Endocrinol Metab, June 1, 2007; 292(6): E1801 - E1807. [Abstract] [Full Text] [PDF]
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 M. Desai, D. Gayle, G. Han, and M. G. Ross Programmed Hyperphagia Due to Reduced Anorexigenic Mechanisms in Intrauterine Growth-Restricted Offspring Reproductive Sciences, May 1, 2007; 14(4): 329 - 337. [Abstract] [PDF]
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C.-S. J. Wu, D. R. Greenwood, J. M. Cooney, D. J. Jensen, M. A. Tatnell, G. J. S. Cooper, and K. G. Mountjoy Peripherally administered desacetyl {alpha}-MSH and {alpha}-MSH both influence postnatal rat growth and associated rat hypothalamic protein expression Am J Physiol Endocrinol Metab, December 1, 2006; 291(6): E1372 - E1380. [Abstract] [Full Text] [PDF]
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 B. E Levin Metabolic imprinting: critical impact of the perinatal environment on the regulation of energy homeostasis Phil Trans R Soc B, July 29, 2006; 361(1471): 1107 - 1121. [Abstract] [Full Text] [PDF]
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 I. C. Mcmillen and J. S. Robinson Developmental Origins of the Metabolic Syndrome: Prediction, Plasticity, and Programming Physiol Rev, April 1, 2005; 85(2): 571 - 633. [Abstract] [Full Text] [PDF]
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M. G. Ross and M. Desai Gestational programming: population survival effects of drought and famine during pregnancy Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2005; 288(1): R25 - R33. [Abstract] [Full Text] [PDF]
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A. Varma, J. He, B.-C. Shin, L. A. Weissfeld, and S. U. Devaskar Postnatal intracerebroventricular exposure to leptin causes an altered adult female phenotype Am J Physiol Endocrinol Metab, December 1, 2004; 287(6): E1132 - E1141. [Abstract] [Full Text] [PDF]
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S. G. Bouret and R. B. Simerly Minireview: Leptin and Development of Hypothalamic Feeding Circuits Endocrinology, June 1, 2004; 145(6): 2621 - 2626. [Abstract] [Full Text] [PDF]
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 S. G. Bouret, S. J. Draper, and R. B. Simerly Formation of Projection Pathways from the Arcuate Nucleus of the Hypothalamus to Hypothalamic Regions Implicated in the Neural Control of Feeding Behavior in Mice J. Neurosci., March 17, 2004; 24(11): 2797 - 2805. [Abstract] [Full Text] [PDF]
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