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Endocrinology Vol. 145, No. 2 686-691
Copyright © 2004 by The Endocrine Society

The Evolutionarily Conserved Gonadotropin-Releasing Hormone II Modifies Food Intake

Alexander S. Kauffman and Emilie F. Rissman

Department of Biochemistry and Molecular Genetics and the Center for Research in Reproduction, University of Virginia, Charlottesville, Virginia 22908

Address all correspondence and requests for reprints to: Alexander S. Kauffman, University of Virginia Medical School, P.O. Box 800733, Jordan Hall, Room 1229, 1300 Jefferson Park Ave, Charlottesville, Virginia 22908. E-mail: ask5j{at}virginia.edu.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
GnRH is an evolutionarily conserved peptide of which there are multiple structural variants. One form, GnRH II, is the most widespread in vertebrates, but its primary function remains unclear. In female musk shrews, administration of GnRH II, but not GnRH I, reinstates mating behavior previously inhibited by food restriction. Because this finding suggests that the function of GnRH II may be linked to energetic status, we tested whether GnRH II directly affects food intake. Adult female musk shrews were maintained on ad libitum feeding or food restricted for 48 h, after which they were infused centrally with GnRH I (1 µg), GnRH II (1 µg), or saline. Food intake was recorded 90 min, and 3, 6, 24, and 48 h after infusion. GnRH II administration, but not saline or GnRH I, reduced 24-h food intake in ad libitum animals. Short-term food intake (90 min and 3 h) of both ad libitum and underfed shrews receiving GnRH II was also reduced by as much as 33%, relative to the food intake of saline-infused controls. GnRH I infusion did not affect short-term food intake differently than saline infusion in shrews fed ad libitum. In underfed females, GnRH I had an effect on short-term food intake that was intermediate to saline and GnRH II. We conclude that, in addition to its permissive role in regulating reproduction, GnRH II may also modulate food intake in mammals. Because GnRH II is present in primate brain, it may also serve a similar function in humans.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
GnRH IS AN evolutionarily conserved decapeptide that plays a crucial role in the regulation of reproduction. The form of GnRH first discovered in mammal brain (GnRH I) controls LH and FSH release from the pituitary (1). GnRH I also plays a direct role in stimulating mammalian reproductive behavior (2, 3, 4, 5, 6).

In addition to GnRH I, there are at least 15 other structural forms of GnRH present in animals (7, 8). Most vertebrates have multiple forms of GnRH present in brain (9, 10, 11, 12, 13). In almost every vertebrate species examined, one form is the variant originally isolated in chicken brains (chicken GnRH II or GnRH II) (7, 14). Within mammals, GnRH II is present in the brains of musk and tree shrews (15, 16), moles (17), rodents (18, 19, 20), nonhuman primates (21, 22), and humans (13). The omnipresence of GnRH II across vertebrate species indicates that this variant is highly conserved evolutionarily and likely to have an important biological function (7, 8). However, at present, its primary function remains uncertain.

GnRH II has been hypothesized to preferentially activate FSH (an FSH-releasing peptide), but to date, there is scant evidence for this (23, 24). Although several studies have determined that GnRH II can promote LH secretion, it does so with a much lower potency than GnRH I (~2% as effective) (25, 26). Furthermore, GnRH II stimulation of gonadotropins is completely blocked with the GnRH I receptor antagonist Antide (27, 28). In mammals, the vast majority of GnRH II cell bodies are localized to the midbrain, with a few present in hypothalamic and extrahypothalamic regions (13, 15, 16). In addition, only a minority of the fiber projections from neurons containing GnRH II project to the median eminence or pituitary regions that regulate LH/FSH release; in the musk shrew, the majority of GnRH II-containing neurons project to the medial habenula (29). Finally, GnRH II plays a neuromodulatory role in amphibian neurons by regulating currents through K+ and Ca2+ channels (30, 31). Collectively, these findings suggest that the primary role of GnRH II is not to stimulate gonadotropin hormones but rather to act as a neurotransmitter (32).

Temple et al. (8) proposed that GnRH II acting as a neurotransmitter regulates reproduction according to a female’s energetic status. Female musk shrews that are food restricted for 48 h exhibit a significant decline in mating behaviors. However, central administration of GnRH II, but not GnRH I, significantly reversed the inhibitory effects of food restriction on female sexual behavior (8). In contrast, GnRH II did not further increase female reproductive behavior in ad libitum-fed animals (33), implying that this peptide’s function in reproduction may be permissive and not merely stimulatory. In addition, food restriction resulted in significantly more GnRH II immunoreactive cell bodies in the midbrain of female shrews, as well as greater densities of GnRH II-containing fibers in the forebrain, indicating increased storage in underfed animals (8). Therefore, GnRH II may be a neurotransmitter that signals the energetic state of a female, permitting mating only if sufficient energy is available; under this hypothesis, when animals are energetically challenged, less GnRH II is released, thereby inhibiting reproductive behavior.

As a corollary hypothesis, we speculated that, in addition to its role as a regulator of sexual behavior, GnRH II might also act as a modulator of feeding. GnRH II fibers innervate forebrain regions implicated in feeding regulation, and several of these sites contain receptors for GnRH II (7, 8). Specifically, we conjectured that if food is not plentiful and a female is in negative energy balance, low GnRH II release might be a signal to increase food intake while inhibiting reproduction. Conversely, if abundant food is available, the resulting higher levels of GnRH II release might be a signal to eat less (or at a baseline level) while concurrently permitting mating to occur. Thus, under either energetic state, a bolus infusion of GnRH II should depress food consumption. Such feeding regulation by GnRH II would complement Temple et al.’s (8) proposed role for this peptide in regulating sex behavior according to food availability. In the present study, we centrally administered GnRH I or II to ad libitum-fed and food-restricted female musk shrews and determined its effects on short- and long-term food intake.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Subjects
All studies used adult (38–58 d of age), sexually naïve, female musk shrews (Suncus murinus) weighing between 18 and 26 g. All animals were born in our breeding colony at the University of Virginia (Charlottesville, VA). Upon weaning, at 21 d of age, shrews were housed individually with food (Purina Cat Chow; Nestlé Purina PetCare, St. Louis, MO) and water available ad libitum (unless noted differently in specific experiments). The room was maintained on a 14-h light, 10-h dark photoperiod (lights off at 1900 h) at a temperature of 23 ± 2 C and contained only females. All experiments were performed in compliance with regulations of the Animal Care and Use Committee of University of Virginia.

Stereotaxic implantation of cannula
To implant cannulas, females were anesthetized with sodium pentobarbital (4.5 mg/kg; 0.1 ml/10 g body weight). A midline incision was made along the top of the head, and 1% lidocane (0.1 ml) was injected into the muscles above the skull. The muscle was then cleared from the skull, and the animal was fitted into a modified mouse stereotaxic apparatus (Kopf Instruments, Tujunga, CA.). Guide cannulas (26 gauge; Plastics One, Roanoke, VA) containing an internal dummy cannula were centered on bregma and positioned -4.5 rostral-caudal and -1.0 medial-lateral. A hole was then drilled in the skull, and the cannula was lowered to a depth of 2.2 mm, aimed at the lateral ventricle. The cannula was fixed to the skull with glue and dental acrylic, after which the skin was sutured, and the animal was allowed to recover on a heating pad for several hours.

Hormone infusions
For intracerebroventricular infusions, females were briefly anesthetized with halothane and infused with 10 µl of either saline (0.09%), GnRH I (1 µg; Sigma, St. Louis, MO), or GnRH II (1 µg; Bachem, Torrence, CA). The 1-µg doses of GnRH peptides were based on previously published reports showing that this dose is sufficient to stimulate ovulation in female musk shrews; lower doses of either peptide were less effective (8, 33). The 1-µg dose of GnRH II was also previously shown to stimulate female mating behavior in underfed musk shrews (8). All infusions were made using an internal cannula (33 gauge) with a 0.1-mm projection attached to a syringe and delivered slowly by hand over the course of 10–30 sec. The internal cannula was left in place for at least 10 sec after infusion to allow the liquid to spread in the ventricle. After infusion, the dummy cannula was replaced, and the female was returned to her home cage. Females aroused from anesthesia within 1–2 min after the infusion. At the end of the study, we confirmed cannula placement; females were overdosed with sodium pentobarbital, and 0.01 ml India ink was injected into the cannula. The brains were then removed, frozen, and sectioned on a cryostat. Cannulas were considered placed correctly if the ventricles were filled with ink and/or the cannula tract was visibly intersecting the ventricle.

Food restriction and food intake measurements
Food intake was measured for 4 consecutive days at approximately the same time each day. Female musk shrews are induced ovulators and do not have ovarian or behavioral estrous cycles; thus, daily food intake is not influenced by variations in ovarian hormone secretion from day to day. Shrews received preweighed food at the outset; the remaining food was weighed each day, and the difference was used to calculate 24-h food intake values. The average daily food intake over the 4 d was determined for each animal; animals undergoing food restriction then received 60% of their daily average intake for 2 consecutive days. Control animals remained on ad libitum food intake during this same 48-h period. These methods have been described previously (34).

Methods
In experiment 1, the food intake of 10 adult female shrews was measured throughout the day to determine the circadian feeding pattern of this species. Food intake was calculated for the following five time intervals that spanned the 24-h circadian cycle: 0500–1000 h, 1000–1400 h, 1400–1900 h, 1900–2400 h, and 2400–0500 h. (Lights in the room came on at 0500 h and went off at 1900 h.)

In experiment 2, 36 female shrews were implanted with a cannula aimed at the lateral ventricle. Several days later, baseline 24-h food intake was measured for 4 consecutive days (measurements taken at 1800 h). On the fifth day, females were briefly anesthetized and infused 1 h before lights were turned off with 10 µl of either saline (0.09%; n = 12), GnRH I (1 µg; n = 12), or GnRH II (1 µg; n = 13). After infusion, the females were returned to their cages, and food intake was recorded at the following intervals: 3, 6, 24, and 48 h. Body weights were recorded on the day of drug infusion and the day after treatment.

In experiment 3, the daily food intake of 30 cannulated females from experiment 2 was measured for 4 consecutive days beginning 5–10 d after the conclusion of experiment 2. On the fifth day, all females were food restricted (60% of baseline 24-h ad libitum intake) for 48 h. After the 48-h food restriction, females were infused (at 1800 h, 1 h before lights were turned off) with 10 µl saline (0.09%; n = 10), GnRH I (1 µg; n = 10), or GnRH I (1 µg; n = 10). Females were then immediately returned to ad libitum feeding, and their food intake was recorded 3, 6, 24, and 48 h later, as was done in experiment 2. Additionally, food intake was also measured 90 min after infusion to more extensively study the short-term effects of peptide administration. Body weights were recorded before food restriction, at the time of drug treatment, and the day after infusion.

Statistical analyses
Group differences in short-term food intake during specific time periods after drug infusion (first 3 h, second 3 h, etc.) were analyzed using a one-way ANOVA. Repeated-measures ANOVAs were used to compare changes in 24-h food intake between groups over time and to compare differences in food intake at different time periods throughout the day (experiment 1). For ANOVA, all post hoc comparisons were made using a Fisher’s protected least significant difference test, with a significance level set at P < 0.05. All data are presented as means ± SEM.


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Experiment 1. Timing of musk shrew feeding behavior
The 24-h food intake of adult female shrews ranged from 3.3–4.6 g, with an average daily intake of 3.8 g/d. The shrews displayed a nocturnal pattern of eating, consuming 75% of their daily food during the lights-off portion of their 24-h light-dark cycle. The most food was eaten during the first 5 h of lights off, and the least was eaten during the first 5 h of lights on (P < 0.05; Fig. 1Go).



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  		FIG. 1. Timing of musk shrew feeding over the course of the 24-h light-dark cycle. Lights in the room turned on at 0500 h and turned off at 1900 h, as indicated by the white and black horizontal bar at the top of the figure. *, Significantly different from all other points; **, significantly different from 1400–1900 h, 1900–2400 h, and 2400–0500 h.

 
Experiment 2. Effects of GnRH II infusion on ad libitum feeding
Short-term food intake was significantly decreased in ad libitum-fed female shrews infused with GnRH II. GnRH II-treated shrews consumed approximately 28% less food relative to saline-infused controls during the first 3 h after infusion (Fig. 2Go, P < 0.02). In contrast, GnRH I infusion in ad libitum shrews did not result in significant suppression of short-term food intake relative to saline infusion (Fig. 2Go). The inhibitory effects of GnRH II on feeding in ad libitum females waned 3 h after infusion; although slightly lower, the food intake of GnRH II-treated shrews was not significantly less than that of the other groups during h 3–6 (P > 0.10, Fig. 2Go).



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  		FIG. 2. Effects of GnRH I and II infusion (1 µg) on short-term food intake in ad libitum-fed female musk shrews. *, Significantly different from saline group.

 
GnRH II also depressed 24-h food intake in ad libitum-fed animals (P < 0.05, Fig 3Go). The daily food intake of all groups was the same during the baseline period before infusion, but it decreased by approximately 10% in animals subsequently treated with GnRH II (P < 0.05, Fig. 3Go). In contrast, a single infusion of GnRH I or saline had no effect on 24-h food intake (Fig. 3Go). The inhibitory effects of GnRH II on daily food intake were transient; all the groups ate the same amount on the second day after infusion (Fig. 3Go). Body weights were unaffected by drug treatment; body weights did not change over time for any of the groups, and none of the groups differed in body weight before or after infusion (Table 1Go).



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  		FIG. 3. Effects of drug infusion (1 µg) on 24-h food intake in ad libitum-fed female musk shrews. GnRH I and II were both given in a dose of 1 µg. Preinfusion average was calculated from 24-h intake of 4 d before infusion. All food intake was recorded 1 h before lights were turned off (1800 h). *, Significantly different from saline and GnRH I groups.

 

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  		TABLE 1. Body weights in grams of ad libitum and underfed shrews before and after treatment

 
Experiment 3. Effects of GnRH II infusion on food intake after food restriction
Short-term food intake was significantly reduced by GnRH II in food-restricted females that were returned to ad libitum feeding after infusion. Relative to saline, GnRH II infusions in underfed females decreased short-term food intake by 33% during the first 90 min after return to ad libitum feeding (P < 0.001, Fig. 4Go). Infusion of GnRH I also resulted in a significant decrease in food intake during the first 90 min after infusion but to a lesser degree than GnRH II (14% vs. 33%, respectively; P < 0.05; Fig. 4Go). Decreases in short-term feeding were still present during the second 90-min interval after infusion in underfed animals that received GnRH II but not GnRH I (P < 0.001, Fig. 4Go). Similar to experiment 2, the inhibitory effects of GnRH II were gone 3–6 h after infusion, and food intake did not differ between groups during this period (data not shown).



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  		FIG. 4. Effects of GnRH I and II infusion (1 µg) on short-term food intake in food-restricted musk shrews that were returned to ad libitum feeding after drug administration. *, Significantly different from saline group during same time period; **, significantly different from both the GnRH I and saline groups during same time period.

 
Long-term (24-h) food intake of underfed females significantly increased in all groups after return to ad libitum feeding (P < 0.01) but was unaffected by drug treatment. Both saline- and GnRH I-infused underfed shrews ate approximately 21% more during the first 24 h after return to ad libitum feeding than they did per day during the baseline period (P < 0.001, Fig. 5Go). Compared with the other groups, food-restricted shrews infused with GnRH II had a dampened increase in 24-h feeding after being refed (~11% increase), but this pattern was not statistically different from the other groups (Fig. 5Go).



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  		FIG. 5. Twenty-four-hour food intake of female musk shrews that were food restricted for 48 h and then returned to ad libitum feeding after infusion of either GnRH I, GnRH II, or saline. GnRH I and II were given in doses of 1 µg. Preinfusion average was calculated from 24 h intake of 4 d before infusion. All food intake was recorded 1 h before lights were turned off (1800 h). None of the groups differed from each other before or after drug infusion.

 
All underfed groups showed the same pattern of body weight change over time, and none of the groups differed in body weight during any period. Body weights decreased by approximately 5% in all groups after 48-h food restriction (P < 0.001, Table 1Go) and increased again after return to ad libitum feeding (P < 0.001, Table 1Go).


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
GnRH was first isolated in the mammalian hypothalamus and identified as a peptide hormone (GnRH I) that regulates the reproductive system by stimulating the release of pituitary gonadotropins (1). However, it is now apparent that GnRH I is only one of at least 15 structural variants that have evolved from a more ancient form (32). The most ubiquitous and evolutionarily conserved variant is GnRH II, and yet the primary biological function of this peptide is unclear. Neuroanatomical evidence suggests that GnRH II may have a neuromodulatory function (32). Behavioral studies support this conjecture because GnRH II infusion stimulates sexual behavior in underfed female musk shrews (8). In this article, we report a novel and previously unsuspected function of GnRH II: to modulate and coordinate short-term food intake. We propose that this peptide may have evolved to coordinate reproductive and feeding behaviors based on an animal’s energetic status and current environmental conditions. The primary function of GnRH II may, therefore, be as a neurochemical mediator between exogenous conditions (availability of energy resources) and endogenous physiological processes (neural activation of behavior).

A single GnRH II infusion significantly decreased short-term food consumption in both ad libitum-fed musk shrews and food-restricted females that were returned to ad libitum feeding. The decreased food intake was greatest during the first several hours after GnRH II infusion (28–33% of control levels) and, in all cases, waned 3 h after administration. Twenty-four-hour food intake was moderately reduced by a single GnRH II infusion in ad libitum-fed shrews but not strongly affected by GnRH II in underfed animals returned to ad libitum feeding. The 10% decrease in overall 24-h food intake in ad libitum-fed females was entirely due to the inhibitory effects of GnRH II during the first several hours after infusion. After the first 3 h, GnRH II-treated animals did not eat less than saline-infused controls for the remainder of the day. These findings indicate that GnRH II can rapidly and significantly regulate short-term food intake in female mammals and that its effects on feeding are short in duration, lasting several hours at most.

It is unlikely that the reduced food intake during the first several hours after infusion were due to GnRH II inducing sickness. Musk shrews have a strong and well-documented emetic reflex, and this species responds to a wide range of central chemical treatments with vomiting (35). We did not observe any emetic reflexes after infusion, suggesting the animals were not sick. Furthermore, female shrews mate within 15 min of GnRH II infusion (8, 33), indicating that the females’ health status after infusion is sufficient to engage in both the aggressive fighting ritual before mating, as well as mating itself. Although we did not observe any obvious impairment in locomotion after infusion, direct measures of locomotor activity or water intake were not recorded; it is possible that GnRH II’s inhibitory effects on feeding were related to changes in either of these behavioral variables. Future studies could address these possibilities with the use of infrared activity monitors or open-field tests.

Two GnRH receptors, type I and type II, have been identified in vertebrates (7, 36). Although GnRH II can bind both receptors, it has a 24-fold higher affinity for the type II compared with the type I GnRH receptor (36). It is likely that the effects of GnRH II on feeding are mediated through the type II GnRH receptor because GnRH I had no effect on feeding in ad libitum females and only minor short-term effects in underfed animals. Because GnRH I can bind the type II GnRH receptor, albeit with a lower affinity than it binds the type I GnRH receptor, it is possible that GnRH I may have been acting through type II receptors to achieve its mild inhibition in underfed shrews. It is unclear why GnRH I only had an effect in underfed animals; one possible explanation is that food restriction up-regulates type II GnRH receptors, thereby facilitating some binding of GnRH I and, consequently, a moderate reduction in food intake. The effects of GnRH II on short-term feeding were slightly greater in underfed animals compared with ad libitum-fed animals (33 vs. 28%, respectively), suggesting that such up-regulation of type II receptors may indeed occur. Future studies invoking type I GnRH receptor antagonists in combination with GnRH I or II will better elucidate which receptors these peptides are binding to achieve their effects on food intake. Overall, GnRH I had little to no effect on short- and long-term food intake in musk shrews; the principal GnRH peptide that affects food intake in this species appears to be GnRH II.

The GnRH II system is well suited to play a role in regulating feeding and reproduction. First, previous studies have shown that immunoreactivity for GnRH II in the brain can change rapidly in response to food availability (8). Second, the type II GnRH receptor, in contrast to the type I GnRH receptor, possesses a cytoplasmic C-terminal tail that allows for fast desensitization and down-regulation (36, 37, 38, 39); such rapid down-regulation of type II receptors may be an additional mechanism by which the GnRH II system quickly responds to rapid fluctuations in environmental energy availability. Whether or not changes in food availability modify type II receptor number and distribution still requires testing. Last, because the effects of GnRH II are primarily short term, it allows for more precise control of behaviors, with an ability to constantly update the degree of regulation in light of changing energetic conditions.

It is currently unknown which neural target sites of GnRH II mediate its effects on feeding. GnRH II-containing fibers are widespread in their neural projections and innervate numerous brain regions. Furthermore, type II GnRH receptors are located throughout the brain (7, 8, 36); intracerebroventricular infusion of GnRH II could potentially activate many of these regions. However, the best candidate sites are those containing type II GnRH receptors that have previously been implicated in the regulation of mammalian feeding; such sites include the ventromedial hypothalamus, arcuate nucleus, and amygdala (7, 8). Current studies are underway in our lab to determine which neural sites are specifically activated by GnRH II. In addition, there are numerous neurotransmitters that play a role in the regulation of feeding in mammals (40, 41), and GnRH II is certainly not the sole modulator of this behavior. Future research should examine the interactions of the GnRH II system with other neurotransmitters and hormones known to regulate feeding (neuropeptide Y, galanin-like peptide, agouti-related protein, leptin, etc.).

Temple et al. (8) first proposed a behavioral function of GnRH II in mammals in permitting female reproduction based on energetic status. Our findings posit a related function of GnRH II, which is to modulate energy intake; such feeding regulation complements the permissive role of GnRH II in regulating mating according to energy availability. Thus, if abundant food is available, the resulting high level of GnRH II secretion is a signal to eat less (or at a baseline level) while diverting energy resources and motivation toward seeking a mating opportunity. Whether or not GnRH II plays the same role(s) in other vertebrate species remains to be tested. GnRH II was shown to promote female mating behavior in two bird species, although it is unclear whether the birds were in negative energy balance at the time of GnRH II administration (32, 42); food intake of GnRH II-infused birds was not reported. Other mammals, including humans, possess both GnRH II peptide and type II GnRH receptors in the brain (7); it is intriguing to speculate that this peptide might have similar regulatory actions on feeding in humans as well.

Musk shrews in our study ate the majority of their food during the dark phase of the light-dark cycle, indicating a nocturnal pattern of feeding behavior. Only a few other studies have examined the circadian timing of musk shrew behavior and physiology. Balakrishnan and Alexander (43) also reported a nocturnal feeding rhythm in musk shrews, with peak food intake occurring during the latter half of the dark phase. A nocturnal rhythm in drinking and locomotor behavior has also been described, with intermittent activity occurring throughout the light phase (44, 45). Our data on the pattern of musk shrew food intake confirm and extend these previous findings and support a primarily nocturnal pattern of physiology and behavior in this species.

In summary, GnRH II treatment decreased short-term food intake for several hours in female musk shrews. The ability to quickly and acutely modulate food intake indicates that the GnRH II system may have evolved to respond to rapidly fluctuating changes in environmental energy availability. To precisely adjust to external changes, an animal’s physiology and behavior requires the potential to be constantly updated and quickly changed if needed, and the GnRH II system meets this requirement. Musk shrews inhabit dense vegetation regions near the equator (46, 47) where it is likely that environmental food availability rapidly fluctuates day to day and even hour to hour. Because of their high metabolism (~80% higher than other small tropical mammals) and reliance on mobile prey, musk shrews must take in considerable energy each day for mammals of their size (48, 49). Females have apparently evolved to reproduce only when environmental conditions are most favorable to successfully promote pregnancy and lactation (8, 50, 51, 52). Thus, female musk shrews require a precise, yet rapid, coordination between energetic status and activation of reproduction. GnRH II may have evolved in early mammalian species to help coordinate the interaction between food intake, energy balance, and reproduction.


   Acknowledgments
 
We thank Aileen Wills for expert animal care, and Drs. Jennifer Temple and Elka Scordalakes for surgical and experimental assistance.


   Footnotes
 
This work was supported by National Science Foundation Grant IBN-0097885 and NIH Grant T32-HD07382.

Received September 3, 2003.

Accepted for publication October 14, 2003.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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