help button home button Endocrine Society Endocrinology
HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints, Permissions and Rights
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hill, J. W.
Right arrow Articles by Levine, J. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hill, J. W.
Right arrow Articles by Levine, J. E.
Endocrinology Vol. 144, No. 5 1780-1786
Copyright © 2003 by The Endocrine Society

Abnormal Response of the Neuropeptide Y-Deficient Mouse Reproductive Axis to Food Deprivation But Not Lactation

Jennifer W. Hill and Jon E. Levine

Department of Neurobiology and Physiology, Northwestern University, Evanston, Illinois 60208

Address all correspondence and requests for reprints to: Jon E. Levine, Ph.D., Department of Neurobiology and Physiology, Northwestern University, 2205 Tech Drive, Evanston, Illinois 60208. E-mail: jlevine{at}northwestern.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Neuropeptide Y (NPY) plays a key role in both food intake and GnRH secretion. Food deprivation elevates hypothalamic NPY activity and suppresses LH and gonadal steroid secretion. Similarly, lactation up-regulates NPY expression as food consumption increases and estrous cycles cease. These observations suggest that NPY coordinates reproductive suppression in response to energy deficiency; if so, the reproductive axis of NPY knockout (KO) mice should be impervious to lactation and food deprivation. We monitored food consumption, body weight, and estrous cyclicity during lactation in NPY KO mice with large and small litters. NPY KO mice with either litter size resembled wild types (WTs) in weight regulation and food consumption. Large-litter mothers had longer anestrous periods and smaller pups at weaning, but NPY KOs and WTs did not differ in either respect. We also examined the LH response of NPY KO mice to 48 h without food. Basal levels of LH in ovariectomized NPY KO animals decreased in response to fasting, but LH levels in intact and estrogen-treated ovariectomized NPY KO animals did not. In contrast, WTs consistently showed fasting-induced suppression of LH. Our findings suggest that other systems can sustain the hyperphagia of lactation and NPY alone is not responsible for suppressing cyclicity during lactation. Nevertheless, the suppression of basal LH release that accompanies food deprivation in normal female mice appears to require the steroid-dependent actions of NPY.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
CIRCUMSTANCES THAT TAX an animal’s energy resources strongly affect the reproductive axis. Because lactation demands that the mother expend a great amount of energy on the production of milk, being pregnant during lactation endangers the mother’s reproductive success (1, 2, 3). In most mammalian species, lactation is accompanied by a cessation of ovarian cycles and profound hyperphagia. Although rodents exhibit a postpartum ovulation following parturition, the implantation of any resulting embryo is delayed to ensure that peak energy demands of pregnancy and lactation do not coincide (2, 3). In addition, this ovulation is followed by an infertile period that lasts until weaning. Because blockade of milk production in the latter half of the lactational period increases LH secretion even while pups persist in suckling (4), some have theorized that the increased caloric demand of producing milk for young suppresses the reproductive axis (4, 5).

Energy reserves can also be threatened by scarce food or increased demands from thermoregulation or exercise. Inadequate food intake causes most species to divert energy away from sexual maturation, maintenance of pregnancies, and secretion of reproductive hormones. In the female laboratory mouse, a 20% loss of body weight causes ovulation to cease (6). GnRH release, as reflected by LH secretory patterns, is extremely sensitive to food deprivation; pulsatile secretion is inhibited during fasting and returns within 1–2 h after food is reintroduced (7).

Hypothalamic neuropeptide Y (NPY) influences both energy homeostasis and the release of reproductive hormones; thus, it has been suggested, may coordinate the reproductive response to energy deficiency (reviewed in8). In the mouse, chronic central infusion of NPY markedly enhances food intake and suppresses LH, leading to obesity and hypogonadism (9). In addition, food restriction increases NPY levels in the arcuate (ARC), paraventricular, and ventromedial nuclei of the hypothalamus (10) and NPY gene expression in the ARC (11). Similarly, lactating mice show elevated ARC levels of NPY as well as a dramatic increase in NPY in the median eminence that disappears rapidly after pup removal (12, 13). Nevertheless, the role of NPY in lactation or fasting-induced infertility remains controversial.

Attempts to demonstrate an inhibitory effect of NPY on the reproductive axis of lactating animals have yielded mixed results. Chronic exogenous NPY administration to lactating rats fed ad libitum resulted in a profound decline in milk production and smaller pup size, accompanied by a significantly shorter period of lactational diestrus (14), possibly because of NPY suppression of prolactin (PRL) secretion (13, 15). On the other hand, NPY Y5 receptor stimulation in lactating animals lengthens the period of acylicity (16). Furthermore, lactating rats restricted to 50% of ad libitum food levels for the first 2 wk postpartum show a significant increase in the length of lactational diestrus associated with high levels of hypothalamic NPY (17).

NPY mediation of the suppression of reproduction during fasting has been challenged by results from NPY-deficient animals. Erickson et al. (18), in their initial characterization of the NPY knockout (KO) mouse, food-restricted male wild-type (WT) and NPY KO mice and analyzed the degree to which testosterone levels were altered in the two genotypes. A 48-h fast was found to inhibit testosterone levels to the same degree in WT and KO animals, suggesting inhibition of LH secretion. They also examined the effect of 48 h of food deprivation on the vaginal cytology of female mice. Recovery of cyclicity following refeeding required an equal amount of time for both genotypes.

Using female NPY null-mutant mice, we tested the hypothesis that NPY mediates lactation and fasting-induced suppression of LH release. Specifically, we examined the impact of NPY deficiency on food consumption, body weight regulation, and estrous stage throughout the lactational period in mothers with small or large litters. In addition, we investigated the effect of a 48-h fast on basal LH release in the NPY KO animals. Because the influence of both fasting (19, 20) and NPY (21, 22) on LH release can be modified by steroid hormones, we went on to examine the impact of ovariectomy and steroid replacement on these animals.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Animals
All animal and surgical experimental procedures were conducted with the explicit approval of the Northwestern University’s Animal Care and Use Committee. NPY KO mice were generously provided by Dr. Richard Palmiter from the University of Washington (Seattle, WA). The NPY-deficient mice were previously generated using homologous recombination techniques and maintained on a C56BL x 129SV background (23). The NPY -/- mice were bred in the Center for Experimental Animal Resources at Northwestern University under standard conditions. Mice of strain 129/SVIMJ were purchased from The Jackson Laboratory (Bar Harbor, ME) and used as WT controls in experiments. Animals were housed singly in a humidity- and temperature-controlled room, with Purina rodent chow and water available ad libitum. Lighting was maintained on a 14-h light, 10-h dark cycle, with lights on at 0500 h and off at 1900 h.

Reagents
17ß-Estradiol (E2) was purchased from Sigma (St. Louis, MO). Silicon tubing (0.04-in. internal diameter, 0.085-in. outer diameter) was obtained from Helix Medical (Carpinteria, CA), and silicon type A medical adhesive was supplied by Dow Corning Corp. (Midland, MI).

Experimental design
Experiment 1.
Adult female KO and WT mice less than 6 months old were used in the lactation studies. All animals were fed standard (not high-fat) rodent chow. The date of parturition was recorded as d 1. On d 3, the number of pups for each of the experimental mothers was normalized to three for the small litters and 6–11 for the large litters using age- and genotype-matched surrogate pups when necessary. Weights of male and female pups were recorded on d 22.

In a subset of each group (small litters: n = 7 WT, n = 6 KO; large litters: n = 3 WT, KO), vaginal cytology and the weight of the mother were measured starting on d 3, thus avoiding the normal postpartum ovulation that occurs on the morning of d 2 or 3. Measurements continued until weaning and the resumption of cyclicity. Because the initial weights of the mothers varied by up to 8 g, maternal weights are reported as deviation from the mean of weights recorded over the lactational period for each individual animal, thus emphasizing changes during this period. Maternal food consumption was calculated in the small-litter group by recording the mass of food given each morning and then subtracting what food remained in the food receptacle or bedding the following day. Because food consumed mirrored maternal weight change but exhibited higher variability, this measure was omitted for the large litters. Estrous cyclicity was monitored by daily inspection of vaginal cytology according to the guidelines of Bingel and Schwartz (24).

Experiment 2.
The fasting experiments consisted of placing the mouse in a clean cage with no food (water was freely available) for 48 h beginning at 1000 h. In intact animals, fasting began on diestrus I. These animals had previously exhibited a consistent 5-d cycle so that they were killed on the morning of presumptive proestrus. A control group was sham fasted by placing the animal into a new cage with food and water at 1000 h, again on diestrus I for intact animals. Bilateral ovariectomy (OVX) was performed on groups of WT and control animals 6 or 20 d before the fast. Because length of OVX did not affect the results, data were later pooled. Mice were anesthetized with an 80-mg/kg ip injection of ketamine (Ketaset, Fort Dodge Laboratories, Fort Dodge, IA) and 5 mg/kg (ip) xylazine (Gemini SA, Burns Veterinary Supply, Inc., Rockville Center, NY).

SILASTIC (Dow Corning Corp.) capsules containing E2 (Sigma) were made using SILASTIC silicone type A (Dow Corning Corp.) and medical silicone tubing (0.04-in. inner diameter, 0.085-in. outer diameter, Helix). Capsules were prepared by evenly mixing a measured amount of E2 in a fixed volume of sterile adhesive and then fitting the adhesive mixture immediately into the silicon tubing and allowing the filled capsules to cure overnight. Tubing was then cut into pieces 1 cm in length, with each containing a total of 1.25 mg E2. The capsules were stored at 4 C. Capsules were soaked in PBS for 24 h before use. They were implanted sc in the appropriate group of mice during OVX.

For blood collection, animals were anesthetized by halothane inhalation (Halocarbon Laboratories, River Edge, NJ), and blood samples were obtained via terminal cardiac puncture. Serum samples were derived by centrifugation and stored at -70 C until used for RIA.

Hormone assays
Serum LH was measured by RIA. The LH RIA used reagents provided by the NIDDK, including the LH RP-3 reference preparation. The intraassay coefficient of variation was 3.00%, and the interassay coefficient of variation was 16.6%.

Statistical analysis
Linear regression for litter size and pup weight was performed using GraphPad Software, Inc. Prism software (GraphPad Software, Inc., San Diego, CA). A two-way ANOVA was used to compare the weight and food consumption of the mothers over the lactational period. To assess differences in hormone levels between genotypes, mean and SE values for a given hormone were calculated for each of the two genotypes and compared by means of t tests. Hormone responses to OVX were analyzed by one-way ANOVA followed by post hoc comparisons using the Newman-Keuls test. For all statistical tests, differences were considered significant with P < 0.05.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Feeding and body weight regulation of mothers during lactation
Figure 1Go depicts the inverse relationship that was observed between litter size and pup weights at weaning. This relationship was observed in both WT and KO animals. At litter sizes of 9 or 10 pups, the average pup weight (for both male and female pups) decreased by 2.10 ± 0.47 g (P = 0.0021) in comparison with three pup litters, likely reflecting the inability of the mother to produce sufficient milk to maintain pup weights at the higher level. One null-mutant litter is recorded as having 11 pups, despite the fact that a pup died on d 18, its small size suggestive of malnutrition. All other litter sizes remained unchanged through weaning.



View larger version (16K):
[in this window]
[in a new window]
  		Figure 1. Inverse correlation between litter size and pup weight. (linear regression, r2 = 0.6987, P < 0.0001.) {blacksquare}, WT male pups; {blacktriangleup}, WT female pups; {square}, NPY KO male pups; {triangleup}, NPYKO female pups; {bullet}, WT pups, gender unspecified; {circ}, NPY KO pups, gender unspecified.

 
Previous studies have shown that body weights of lactating mice increase up to peak lactation around d 15 postpartum (4) and subsequently decrease until weaning (generally d 19 or 20). After peak lactation, the pups start to eat solid food in addition to milk (25). The maternal weights and food intake in this study followed a similar trend, although food consumption exhibited greater variability. As depicted in Fig. 2Go, the minimal lactational demands of a three-pup litter resulted in no significant effect of day postpartum on maternal weight or food intake. Additionally, the NPY-deficient mice showed no difference in their regulation of body weight or food intake, compared with the WT mothers of small litters. In contrast, females with large litters showed a pronounced variation in weight over the course of the lactational period. Despite the considerable lactational demands, the weight regulation of KO and WT animals was similar (Fig. 3Go).



View larger version (34K):
[in this window]
[in a new window]
  		Figure 2. a, Weights of NPY KO and WT mothers with small litters expressed as deviation from mean during lactational period. Litters consisted of three pups. Day postpartum did not affect maternal weight significantly. No differences in body weights were observed between the groups (WT, n = 7; NPYKO, n = 6). 2b, Food consumed by NPY KO and WT mothers with small litters during lactational period. Day postpartum did not influence maternal food intake significantly. No differences in food consumption were observed between the groups (WT, n = 7, NPYKO, n = 6).

 


View larger version (21K):
[in this window]
[in a new window]
  		Figure 3. Weight of NPY KO and WT mothers with large litters expressed as deviation from mean during lactational period. Litters consisted of 6–11 pups. Day postpartum had a highly significant effect on maternal weight (P < 0.0001). No differences in body weights were observed between the groups (WT, NPYKO, n = 3).

 
Length of lactational anestrus of NPY KO vs. WT mice
Figure 4Go shows the average length of anestrus during the lactational period. Analysis revealed a significantly longer period of anestrus in the large litters than the small litters in the NPY KO animals and a similar trend in the WTs. Nevertheless, no significant difference in length of cycle cessation was seen when comparing NPY KO and WT mothers of either litter size.



View larger version (31K):
[in this window]
[in a new window]
  		Figure 4. Day of first postlactational estrus. Small litters consisted of three pups, n = 6; large litters consisted of 6–10 pups, n = 3. No significant difference in day of estrus cycle resumption existed between WT and NPYKO animals. NPYKO large litter day of first estrus was significantly later than NPYKO small litter first estrus day (P = 0.036). *, P < 0.05.

 
LH response to fasting in intact animals
WT and KO animals were tested for their hormonal response to a 48-h fast. Basal levels of LH measured in blood serum at 1000 h were suppressed in WT animals (Fig. 5Go). In contrast, NPY-deficient animals showed no reduction in LH levels following the fast. Neither WT nor NPY KO mice showed an effect of fasting on FSH or progesterone levels (data not shown).



View larger version (14K):
[in this window]
[in a new window]
  		Figure 5. LH levels of intact NPYKO and WT mice after a 48-h fast. Fast or sham fast began on diestrus I at 1000 h. WT fasted levels were significantly less than levels in animals fed ad libitum (P < 0.01, n = 7–8, all groups). **, P < 0.01.

 
Effects of estrogen on LH response to fasting in ovariectomized (OVXed) animals
Because removal of steroid-negative feedback by OVX causes a substantial increase in GnRH and LH release, we expected the response of NPY KO OVXed mice to resemble that of the intact animals on a larger scale. Contrary to expectations, however, although WT and KO animals did exhibit this increase in basal LH levels, both OVXed KO and WT animals showed a decrease in LH when subjected to food deprivation (Fig. 6Go). Despite this decrease, OVX prevented full suppression of gonadotropin levels; the fasting levels of LH in OVXed animals did not approach the levels seen in intact fasted mice.



View larger version (13K):
[in this window]
[in a new window]
  		Figure 6. LH levels of OVX NPYKO and WT mice after a 48-h fast. Fasting significantly suppressed LH levels of WT and NPYKO animals (P < 0.001 and P < 0.001, respectively; n = 10–12, all groups). **, P < 0.01; ***, P < 0.001.

 
The removal of ovarian factors by OVX clearly altered the responsiveness of the reproductive axis to fasting, so we investigated the effect of E2 replacement. When OVXed animals were treated with E2 capsules, LH levels in animals of both genotypes fed ad libitum fell to a range similar to that of intact animals, although levels in fed NPY-deficient mice were significantly lower than their WT counterparts. Just as seen in intact animals, fasting caused a significant suppression of LH levels in the WT animals, but LH secretion in NPY KO proved resistant to the effects of food deprivation (Fig. 7Go).



View larger version (12K):
[in this window]
[in a new window]
  		Figure 7. LH levels of OVX and estradiol-treated NPYKO and WT mice after a 48-h fast. LH levels in WT mice fed ad libitum were significantly greater than all other groups. LH levels were not different between fasted vs. fed ovariectomized, estrogen-treated NPYKO mice (P < 0.05, n = 5, all groups). *, P < 0.05.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
The blockade of ovulation in lactating mothers arises from suppression of the basal pulsatile LH secretion necessary for follicular development (26, 27). However, controversy exists concerning the means by which lactation exerts this suppression. In rhesus monkeys, projections to the hypothalamus carrying input from the suckling stimulus alone can often maintain lactational anestrus, yet in some monkeys, elevated levels of PRL are required to suppress cyclicity (28). In fact, PRL has been shown to directly suppress neuronal GnRH release (29, 30, 31). Others have suggested a third mechanism, namely that the caloric expenditure of lactation suppresses estrous cycles through mechanisms similar to those engaged during food deprivation (4, 5). The relative importance of these mechanisms in the rodent may depend on the stage of lactation, with PRL levels and/or metabolic factors becoming more important than the suckling stimulus in late lactation (32, 33, 34).

Given its involvement in the hypothalamic control of energy intake and GnRH release, NPY may convey information about the metabolic status of an animal to the reproductive axis. To investigate the role of NPY in postpartum anestrus, we measured food consumption, body weight regulation, and timing of the resumption of cyclicity in the NPY KO mouse. Our data suggest that the suppression of estrous cycles during lactation and the reestablishment of cyclicity after weaning can occur independently of the actions of NPY. The absence of NPY in the KO mothers did not impair cessation of their estrous cycles over the course of the lactational period. These results suggest that nonmetabolic mechanisms such as direct actions by PRL or the suckling stimulus may play a dominant role in the suppression of cyclicity during lactation, at least in mice. As is the case with all null-mutant animals, alternative signaling pathways may have compensated for any role played by NPY. One might speculate that ghrelin-expressing (35), melanin-concentrating hormone-expressing (5, 36, 37), or orexin-expressing (5, 38, 39) neurons could also link energy regulation and control of gonadotropin secretion.

Our findings also revealed no evidence of a contribution of NPY to maintenance of metabolic balance during lactation, even with high-energy expenditure caused by large litter sizes. These data recall previous studies showing no effect of the NPY KO genotype on fasting weight loss and refeeding (23, 40). Redundant pathways may well take over the metabolic functions of NPY in the KO animals. The high degree of colocalization of agouti-related peptide (AGRP) and NPY suggest that they could be coordinately regulated during lactation. Indeed, AGRP gene expression is significantly elevated in a subset of the AGRP neurons in the ARC during lactation (41). Proopiomelanocortin neurons may also help maintain weight regulation during lactation because proopiomelanocortin gene expression changes across pregnancy and lactation (42).

NPY activity has been proposed to mediate the neuroendocrine response to starvation, including the suppression of the reproductive axis. In contrast to previous studies using NPY-deficient male mice, we have shown that a 48-h fast causes a near-complete suppression of basal LH levels in the WT females but producing no effect on LH in the NPY KO animals. Thus, NPY appears play a key role in the fasting-induced suppression of reproductive hormone secretions in females but possibly playing less of a requisite role in the male. This type of selective alteration in the reproductive axis of NPY KO mice has been seen before, e.g. in the size of the preovulatory LH surge (43). Our results also suggest that NPY plays a more integral role in the reproductive responsiveness to fasting than to lactation.

Both the effects of E2 replacement on fasted females and the apparent contrast with NPY KO males (18) point to an important role for sex steroids in the actions of NPY during fasting. Studies by Cagampang et al. (19, 20) found that rats possess both a steroid-dependent and steroid-independent component to fasting-induced suppression of LH release. Administration of an opioid antagonist reversed the steroid-independent suppression seen in OVXed animals (44). Our WT mice exhibited a similar dual response to fasting in that LH levels fell lower in the intact and estrogen-treated conditions than in the OVXed animals. The KO animals may retain a steroid-independent mechanism for LH suppression but lacking a steroid-dependent mechanism that involves NPY. In addition, a sexually dimorphic mechanism may be at work. The female reproductive axis is more sensitive to food restriction during pubertal development than that of the male (45), and food restriction decreases estrogen receptor immunoreactivity in hypothalamic areas of female but not male mice (46). Our results demonstrate that neither ovarian hormones nor the actions of NPY are required for restraint of LH release; nevertheless, in the presence of estrogen, NPY may serve to suppress the hypothalamic-pituitary-gonadal axis fully during fasting. Additional studies are needed to elucidate the precise actions of steroid hormones in the mouse fasting response.

These studies show that NPY KO animals retain their ability to respond to the negative feedback effects of estrogen. When the steroid is removed, LH levels increase as they do in WT animals, and E2 replacement returns LH levels to the normal range. In fact, the NPY KO animals may be more sensitive to this negative feedback effect of estrogen because OVXed, E2-replaced KO mice display lower levels of basal LH than their WT counterparts. This result is unexpected because NPY administration in the presence of low E2 levels generally reduces LH secretion (47, 48). It should be noted, however, that a general trend toward lower LH levels in the KO animals was seen in the intact and OVXed animals as well. It is conceivable that the absence of NPY mildly impairs LH secretion under any circumstance.

The results of these studies suggest that non-NPY systems can sustain the hyperphagia of lactation and NPY alone does not mediate the lactational suppression of cyclicity. Our findings also illustrate that NPY is required for the suppression of basal LH release that normally accompanies food deprivation in female mice. NPY suppression of GnRH-induced basal LH release may occur through one or more NPY receptor subtypes (16, 49, 50, 51, 52, 53, 54). Sainsbury et al. (54) found that deletion of the Y4 receptor restores fertility to 50% of female ob/ob mice. In addition, Pralong et al. (55) found that starvation has fewer reproductive consequences in male mice lacking Y1 or Y5 receptors, with the Y1 null-mutant mice showing the least severe phenotype. Thus, NPY may act through Y1, Y4,or Y5 receptors to signal fasting-induced alterations in energy balance, triggering LH suppression. The specific population of receptors involved in such a role and the relative contribution of these subtypes remain to be identified and fully characterized.


   Acknowledgments
 
We thank Dr. Richard Palmiter for providing the NPY KO mice and Brigitte Mann for her expert technical assistance with hormone measurements.


   Footnotes
 
This work was supported by NIH Grants RO1-HD-20677 and PO1-HD-21921.

Abbreviations: AGRP, Agouti-related peptide; ARC, arcuate; E2, 17ß-estradiol; KO, knockout; NPY, neuropeptide Y; OVX, ovariectomy; OVXed, ovariectomized; PRL, prolactin; WT, wild-type.

Received October 25, 2002.

Accepted for publication January 15, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Koiter TR, Moes H, Valkhof N, Wijkstra S 1999 Interaction of late pregnancy and lactation in rats. J Reprod Fertil 115:341–347[Abstract/Free Full Text]
  2. Johnson MS, Thomson SC, Speakman JR 2001 Limits to sustained energy intake. III. Effects of concurrent pregnancy and lactation in Mus musculus. J Exp Biol 204:1947–1956[Abstract/Free Full Text]
  3. Oswald C, McClure PA 1987 Energy allocation during concurrent pregnancy and lactation in Norway rats with delayed and undelayed implantation. J Exp Zool 241:343–357[CrossRef][Medline]
  4. Tsukamura H, Maeda K 2001 Non-metabolic and metabolic factors causing lactational anestrus: rat models uncovering the neuroendocrine mechanism underlying the suckling-induced changes in the mother. Prog Brain Res 133:187–205[Medline]
  5. Smith MS, Grove KL 2002 Integration of the regulation of reproductive function and energy balance: lactation as a model. Front Neuroendocrinol 23:225–256[CrossRef][Medline]
  6. Heideman PD, Bronson FH 1992 A pseudoseasonal reproductive strategy in a tropical rodent, Peromyscus nudipes. J Reprod Fertil 95:57–67[Abstract/Free Full Text]
  7. Foster DL, Ebling FJ, Micka AF, Vannerson LA, Bucholtz DC, Wood RI, Suttie JM, Fenner DE 1989 Metabolic interfaces between growth and reproduction. I. Nutritional modulation of gonadotropin, prolactin, and growth hormone secretion in the growth-limited female lamb. Endocrinology 125:342–350[Abstract/Free Full Text]
  8. Hill J, Xu M, Levine J 2002 Revisiting the reproductive functions of neuropeptide Y. Curr Opin Endocrinol Diabetes 9:203–214
  9. Raposinho PD, Pierroz DD, Broqua P, White RB, Pedrazzini T, Aubert ML 2001 Chronic administration of neuropeptide Y into the lateral ventricle of C57BL/6J male mice produces an obesity syndrome including hyperphagia, hyperleptinemia, insulin resistance, and hypogonadism. Mol Cell Endocrinol 185:195–204[CrossRef][Medline]
  10. Jang M, Romsos DR 1998 Neuropeptide Y and corticotropin-releasing hormone concentrations within specific hypothalamic regions of lean but not ob/ob mice respond to food-deprivation and refeeding. J Nutr 128:2520–2525[Abstract/Free Full Text]
  11. Schwartz MW, Erickson JC, Baskin DG, Palmiter RD 1998 Effect of fasting and leptin deficiency on hypothalamic neuropeptide Y gene transcription in vivo revealed by expression of a lacZ reporter gene. Endocrinology 139:2629–2635[Abstract/Free Full Text]
  12. Ciofi P, Fallon JH, Croix D, Polak JM, Tramu G 1991 Expression of neuropeptide Y precursor-immunoreactivity in the hypothalamic dopaminergic tubero-infundibular system during lactation in rodents. Endocrinology 128:823–834[Abstract/Free Full Text]
  13. Ciofi P, Crowley WR, Pillez A, Schmued LL, Tramu G, Mazzuca M 1993 Plasticity in expression of immunoreactivity for neuropeptide Y, enkephalins and neurotensin in the hypothalamic tubero-infundibular dopaminergic system during lactation in mice. J Neuroendocrinol 5:599–602[CrossRef][Medline]
  14. Toufexis DJ, Yorozu S, Woodside B 2002 Y1 receptor activation is involved in the effect of exogenous neuropeptide Y on pup growth and the early termination of lactational diestrus in the postpartum rat. J Neuroendocrinol 14:354–360[CrossRef][Medline]
  15. Hsueh YC, Cheng SM, Pan JT 2002 Fasting stimulates tuberoinfundibular dopaminergic neuronal activity and inhibits prolactin secretion in oestrogen-primed ovariectomized rats: involvement of orexin A and neuropeptide Y. J Neuroendocrinol 14:745–752[CrossRef][Medline]
  16. Toufexis DJ, Kyriazis D, Woodside B 2002 Chronic neuropeptide Y Y5 receptor stimulation suppresses reproduction in virgin female and lactating rats. J Neuroendocrinol 14:492–497[CrossRef][Medline]
  17. Woodside B 1991 Effects of food restriction on the length of lactational diestrus in rats. Horm Behav 25:70–83[CrossRef][Medline]
  18. Erickson JC, Ahima RS, Hollopeter G, Flier JS, Palmiter RD 1997 Endocrine function of neuropeptide Y knockout mice. Regul Pept 70:199–202[CrossRef][Medline]
  19. Cagampang FR, Maeda K, Yokoyama A, Ota K 1990 Effect of food deprivation on the pulsatile LH release in the cycling and ovariectomized female rat. Horm Metab Res 22:269–272[Medline]
  20. Cagampang FR, Maeda KI, Tsukamura H, Ohkura S, Ota K 1991 Involvement of ovarian steroids and endogenous opioids in the fasting-induced suppression of pulsatile LH release in ovariectomized rats. J Endocrinol 129:321–328[Abstract/Free Full Text]
  21. Kalra SP, Crowley WR 1984 Norepinephrine-like effects of neuropeptide Y on LH release in the rat. Life Sci 35:1173–1176[CrossRef][Medline]
  22. Bauer-Dantoin AC, McDonald JK, Levine JE 1992 Neuropeptide Y potentiates luteinizing hormone (LH)-releasing hormone-induced LH secretion only under conditions leading to preovulatory LH surges. Endocrinology 131:2946–2952[Abstract/Free Full Text]
  23. Erickson JC, Clegg KE, Palmiter RD 1996 Sensitivity to leptin and susceptibility to seizures of mice lacking neuropeptide Y. Nature 381:415–421[CrossRef][Medline]
  24. Bingel AS, Schwartz NB 1969 Pituitary LH content and reproductive tract changes during the mouse oestrous cycle. J Reprod Fertil 19:215–222[Abstract/Free Full Text]
  25. Rauw WM, Knap PW, Verstegen MW, Luiting P 2002 Food resource allocation patterns in lactating females in a long-term selection experiment for litter size in mice. Genet Sel Evol 34:83–104[CrossRef][Medline]
  26. Hammons JA, Velasco M, Rothchild I 1973 Effect of the sudden withdrawal or increase of suckling on serum LH levels in ovariectomized postparturient rats. Endocrinology 92:206–211[Abstract/Free Full Text]
  27. Taya K, Sasamoto S 1991 Mechanisms responsible for suppression of FSH and LH during lactation in the rat. J Endocrinol 129:119–130[Abstract/Free Full Text]
  28. Ordog T, Chen MD, O’Byrne KT, Goldsmith JR, Connaughton MA, Hotchkiss J, Knobil E 1998 On the mechanism of lactational anovulation in the rhesus monkey. Am J Physiol 274:E665–E676
  29. Sauder SE, Frager M, Case GD, Kelch RP, Marshall JC 1984 Abnormal patterns of pulsatile luteinizing hormone secretion in women with hyperprolactinemia and amenorrhea: responses to bromocriptine. J Clin Endocrinol Metab 59:941–948[Abstract/Free Full Text]
  30. Koike K, Miyake A, Aono T, Sakumoto T, Ohmichi M, Yamaguchi M, Tanizawa O 1991 Effect of prolactin on the secretion of hypothalamic GnRH and pituitary gonadotropins. Horm Res 35(Suppl 1):5–12
  31. Milenkovic L, D’Angelo G, Kelly PA, Weiner RI 1994 Inhibition of gonadotropin hormone-releasing hormone release by prolactin from GT1 neuronal cell lines through prolactin receptors. Proc Natl Acad Sci USA 91:1244–1247[Abstract/Free Full Text]
  32. Smith MS 1978 The relative contribution of suckling and prolactin to the inhibition of gonadotropin secretion during lactation in the rat. Biol Reprod 19:77–83[Abstract]
  33. Hansen S, Sodersten P, Eneroth P 1983 Mechanisms regulating hormone release and the duration of dioestrus in the lactating rat. J Endocrinol 99:173–180[Abstract/Free Full Text]
  34. Maeda K, Uchida E, Tsukamura H, Ohkura N, Ohkura S, Yokoyama A 1990 Prolactin does not mediate the suppressive effect of the suckling stimulus on luteinizing hormone secretion in ovariectomized lactating rats. Endocrinol Jpn 37:405–411[Medline]
  35. Furuta M, Funabashi T, Kimura F 2001 Intracerebroventricular administration of ghrelin rapidly suppresses pulsatile luteinizing hormone secretion in ovariectomized rats. Biochem Biophys Res Commun 288:780–785[CrossRef][Medline]
  36. Murray JF, Mercer JG, Adan RA, Datta JJ, Aldairy C, Moar KM, Baker BI, Stock MJ, Wilson CA 2000 The effect of leptin on luteinizing hormone release is exerted in the zona incerta and mediated by melanin-concentrating hormone. J Neuroendocrinol 12:1133–1139[CrossRef][Medline]
  37. Tsukamura H, Thompson RC, Tsukahara S, Ohkura S, Maekawa F, Moriyama R, Niwa Y, Foster DL, Maeda K 2000 Intracerebroventricular administration of melanin-concentrating hormone suppresses pulsatile luteinizing hormone release in the female rat. J Neuroendocrinol 12:529–534[CrossRef][Medline]
  38. Pu S, Jain MR, Kalra PS, Kalra SP 1998 Orexins, a novel family of hypothalamic neuropeptides, modulate pituitary luteinizing hormone secretion in an ovarian steroid-dependent manner. Regul Pept 78:133–136[CrossRef][Medline]
  39. Tamura T, Irahara M, Tezuka M, Kiyokawa M, Aono T 1999 Orexins, orexigenic hypothalamic neuropeptides, suppress the pulsatile secretion of luteinizing hormone in ovariectomized female rats. Biochem Biophys Res Commun 264:759–762[CrossRef][Medline]
  40. Qian S, Chen H, Weingarth D, Trumbauer ME, Novi DE, Guan X, Yu H, Shen Z, Feng Y, Frazier E, Chen A, Camacho RE, Shearman LP, Gopal-Truter S, MacNeil DJ, Van der Ploeg LH, Marsh DJ 2002 Neither agouti-related protein nor neuropeptide Y is critically required for the regulation of energy homeostasis in mice. Mol Cell Biol 22:5027–5035[Abstract/Free Full Text]
  41. Chen P, Li C, Haskell-Luevano C, Cone RD, Smith MS 1999 Altered expression of agouti-related protein and its colocalization with neuropeptide Y in the arcuate nucleus of the hypothalamus during lactation. Endocrinology 140:2645–2650[Abstract/Free Full Text]
  42. Mann PE, Rubin BS, Bridges RS 1997 Differential proopiomelanocortin gene expression in the medial basal hypothalamus of rats during pregnancy and lactation. Brain Res Mol Brain Res 46:9–16[Medline]
  43. Xu M, Hill JW, Levine JE 2000 Attenuation of luteinizing hormone surges in neuropeptide Y knockout mice. Neuroendocrinology 72:263–271[CrossRef][Medline]
  44. Dyer RG, Mansfield S, Dean AD 1984 Relative effectiveness of naloxone and MR2266 in potentiating oestrogen-stimulated luteinizing hormone surges in ovariectomized female rats. Neurosci Lett 49:111–115[CrossRef][Medline]
  45. Hamilton GD, Bronson FH 1986 Food restriction and reproductive development: male and female mice and male rats. Am J Physiol 250:R370–R376
  46. Roemmich JN, Li X, Rogol AD, Rissman EF 1997 Food availability affects neural estrogen receptor immunoreactivity in prepubertal mice. Endocrinology 138:5366–5373[Abstract/Free Full Text]
  47. Khorram O, Pau KY, Spies HG 1987 Bimodal effects of neuropeptide Y on hypothalamic release of gonadotropin-releasing hormone in conscious rabbits. Neuroendocrinology 45:290–297[Medline]
  48. McDonald JK, Lumpkin MD, DePaolo LV 1989 Neuropeptide-Y suppresses pulsatile secretion of luteinizing hormone in ovariectomized rats: possible site of action. Endocrinology 125:186–191[Abstract/Free Full Text]
  49. Gerald C, Walker MW, Criscione L, Gustafson EL, Batzl-Hartmann C, Smith KE, Vaysse P, Durkin MM, Laz TM, Linemeyer DL, Schaffhauser AO, Whitebread S, Hofbauer KG, Taber RI, Branchek TA, Weinshank RL 1996 A receptor subtype involved in neuropeptide-Y-induced food intake. Nature 382:168–171[CrossRef][Medline]
  50. Kanatani A, Ishihara A, Asahi S, Tanaka T, Ozaki S, Ihara M 1996 Potent neuropeptide Y Y1 receptor antagonist, 1229U91: blockade of neuropeptide Y-induced and physiological food intake. Endocrinology 137:3177–3182[Abstract]
  51. Leupen SM, Besecke LM, Levine JE 1997 Neuropeptide Y Y1-receptor stimulation is required for physiological amplification of preovulatory luteinizing hormone surges. Endocrinology 138:2735–2739[Abstract/Free Full Text]
  52. Schaffhauser AO, Stricker-Krongrad A, Brunner L, Cumin F, Gerald C, Whitebread S, Criscione L, Hofbauer KG 1997 Inhibition of food intake by neuropeptide Y Y5 receptor antisense oligodeoxynucleotides. Diabetes 46:1792–1798[Abstract]
  53. Li C, Chen P, Smith MS 1999 Morphological evidence for direct interaction between arcuate nucleus neuropeptide Y (NPY) neurons and gonadotropin-releasing hormone neurons and the possible involvement of NPY Y1 receptors. Endocrinology 140:5382–5390[Abstract/Free Full Text]
  54. Sainsbury A, Schwarzer C, Couzens M, Jenkins A, Oakes SR, Ormandy CJ, Herzog H 2002 Y4 receptor knockout rescues fertility in ob/ob mice. Genes Dev 16:1077–1088[Abstract/Free Full Text]
  55. Pralong FP, Gonzales C, Voirol MJ, Palmiter RD, Brunner HR, Gaillard RC, Seydoux J, Pedrazzini T 2002 The neuropeptide Y Y1 receptor regulates leptin-mediated control of energy homeostasis and reproductive functions. FASEB J 16:712–714[Free Full Text]



This article has been cited by other articles:


Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
W. Huang, M. Acosta-Martinez, T. H. Horton, and J. E. Levine
Fasting-induced suppression of LH secretion does not require activation of ATP-sensitive potassium channels
Am J Physiol Endocrinol Metab, December 1, 2008; 295(6): E1439 - E1446.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
D. Titolo, C. M. Mayer, S. S. Dhillon, F. Cai, and D. D. Belsham
Estrogen Facilitates both Phosphatidylinositol 3-Kinase/Akt and ERK1/2 Mitogen-Activated Protein Kinase Membrane Signaling Required for Long-Term Neuropeptide Y Transcriptional Regulation in Clonal, Immortalized Neurons
J. Neurosci., June 18, 2008; 28(25): 6473 - 6482.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Endocrinol. Metab.Home page
J. W. Hill, J. K. Elmquist, and C. F. Elias
Hypothalamic pathways linking energy balance and reproduction
Am J Physiol Endocrinol Metab, May 1, 2008; 294(5): E827 - E832.
[Abstract] [Full Text] [PDF]

Home page
 EndocrinologyHome page
C. T. Phillips and R. D. Palmiter
Role of Agouti-Related Protein-Expressing Neurons in Lactation
Endocrinology, February 1, 2008; 149(2): 544 - 550.
[Abstract] [Full Text] [PDF]

Home page
 Hum Reprod UpdateHome page
G. G. Gosman, H. I. Katcher, and R. S. Legro
Obesity and the role of gut and adipose hormones in female reproduction
Hum. Reprod. Update, September 1, 2006; 12(5): 585 - 601.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
P. L. Seymour, S. L. Dettloff, J. E. Jones, and G. N. Wade
Corticotropin-releasing factor receptor subtypes mediating nutritional suppression of estrous behavior in Syrian hamsters
Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2005; 289(2): R418 - R423.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Physiol. Regul. Integr. Comp. Physiol.Home page
G. N. Wade and J. E. Jones
Neuroendocrinology of nutritional infertility
Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2004; 287(6): R1277 - R1296.
[Abstract] [Full Text] [PDF]

Home page
 J. Neurosci.Home page
P. Chen, S. M. Williams, K. L. Grove, and M. S. Smith
Melanocortin 4 Receptor-Mediated Hyperphagia and Activation of Neuropeptide Y Expression in the Dorsomedial Hypothalamus during Lactation
J. Neurosci., June 2, 2004; 24(22): 5091 - 5100.
[Abstract] [Full Text] [PDF]

Home page
 J. Clin. Endocrinol. Metab.Home page
M. J. Cunningham, M. Shahab, K. L. Grove, J. M. Scarlett, T. M. Plant, J. L. Cameron, M. S. Smith, D. K. Clifton, and R. A. Steiner
Galanin-Like Peptide as a Possible Link between Metabolism and Reproduction in the Macaque
J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1760 - 1766.
[Abstract] [Full Text] [PDF]

This Article
Right arrow Abstract Freely available
Right arrow Full Text (PDF)
Right arrow Submit a related Letter to the Editor
Right arrow Alert me when this article is cited
Right arrow Alert me when eLetters are posted
Right arrow Alert me if a correction is posted
Right arrow Citation Map
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Reprints, Permissions and Rights
Citing Articles
Right arrow Citing Articles via HighWire
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Hill, J. W.
Right arrow Articles by Levine, J. E.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Hill, J. W.
Right arrow Articles by Levine, J. E.

HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS
Endocrinology Endocrine Reviews J. Clin. End. & Metab.
Molecular Endocrinology Recent Prog. Horm. Res. All Endocrine Journals