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Reproductive Sciences Program (S.N., D.L.F.), Departments of Medicine (Y.Z., C.A.J.), Obstetrics and Gynecology (D.L.F.), and Biology (D.L.F.), University of Michigan, Ann Arbor, Michigan 48109; Ann Arbor Veterans Affairs Medical Center (C.A.J.), Ann Arbor, Michigan 48105; and Department of Animal Sciences, University of Missouri (D.K.), Columbia, Missouri 65211
Address all correspondence and requests for reprints to: Dr. Craig A. Jaffe, Division of Endocrinology and Metabolism, 3920 Taubman Center, Box 0354, University of Michigan Medical Center, Ann Arbor, Michigan 48109-0354. E-mail: cjaffe{at}umich.edu
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Introduction |
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In ruminants, however, the effect of leptin on LH and GH secretion is less clear. In well fed sheep, intracerebroventricular (icv) infusion of leptin was reported to depress appetite, but had no apparent influence on the neuroendocrine control of pituitary function (25). In a preliminary communication, Morrison and colleagues reported that GH secretion in sheep was increased, but LH secretion was unaltered by feed restriction (26). In that study, central leptin treatment further augmented GH release, but did not affect the secretion of LH.
The present investigation reevaluated whether leptin plays a role in pituitary regulation during food deprivation in sheep. Our approach was to establish a model in which acute food deprivation altered pulsatile LH and GH secretion in sheep. We then determined whether systemic leptin administration prevented these fasting-induced changes in neuroendocrine function.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Exp 1: establishment of a fasting-mediated, hypogonadotropic
model
To develop an animal model in which acute fasting inhibits
pulsatile LH secretion, we compared the effect of estrogen on the
secretion of LH during food deprivation. In rats, estrogen has been
found either to be required for (29, 30) or to potentiate
(18) fasting-mediated inhibition of LH. In sheep, the role
of estrogen is unclear, and several studies in castrated male sheep
failed to show an affect of food restriction on LH secretion (26, 31). In contrast to these sheep data, Beckett and colleagues
found an estradiol-dependent suppression of LH in chronically
undernourished wethers that did not occur in better nourished animals
(32).
During the initial development of a model, we studied LH secretion in agonadal, yearling female sheep (40 weeks of age, 55–60 kg BW, November). LH secretory profiles in the fed animals were obtained by sampling every 15 min for 4 h beginning at 0800 h on day 0. The second frequent blood collection using the same protocol began at 0800 h on day 3 during the final 4 h of the 78-h fast. We determined that in these females, a 78-h fast produced no significant change in mean circulating LH concentrations (13.3 ± 1.2 vs. 14.9 ± 2.0 ng/ml; fed vs. fasting), LH pulse frequency (6.8 ± 0.5 vs. 7.5 ± 0.4 pulses/6 h), or LH amplitude (3.7 ± 0.6 vs. 5.5 ± 1.9 ng/ml).
We then studied six similarly aged males treated with low dose estrogen using the same fasting protocol. In contrast to our results in estrogen-deficient females, there was unequivocal LH suppression in the estrogen-treated males. Because of the clear effect of fasting on LH secretion in the presence of steroids, this identical experimental design was used in the same six males, in addition to nine others, for Exp 2.
Exp 2: effects of leptin on hormone secretion
Castrated males bearing estradiol implants (n = 15) were
fed ad libitum for 14 days before the start of the protocol.
At 0800 h on day 0, jugular blood was collected at 15-min
intervals for 6 h to obtain estimates of the frequency and
amplitude of LH and GH pulses before fasting. The animals were then
stratified by weight into two groups, leptin treated (n = 8) and
control (n = 7), and begun on a 78-h fast as in Exp 1. The
leptin-treated animals received recombinant human met-leptin
(rhmet-leptin; Amgen, Inc., Thousand Oaks, CA; 50 µg/kg,
sc, every 8 h) from 2400 h on day 0 until 2400 h on day
2 for a total of sevem doses. This dose was based on the hypothesis
that the low systemic GH level found in obese humans (33)
was the result of high circulating concentrations of leptin and on
published data for peripheral leptin concentrations in obese men and
women (34, 35, 36). Control animals received the same volume
of PBS sc every 8 h. In a preliminary experiment (n = 2), we
determined that 1.5 h after a sc leptin injection of 30 µg/kg,
the peak leptin concentrations was 34 ng/ml, and that the exogenous
leptin had an estimated circulating half-life of 4 h. Peripheral
(jugular) blood samples were obtained every 8 h, just before each
leptin injection. Beginning at 0800 h on day 3, a second frequent
blood sampling (15-min intervals for 6 h) was performed to assess
the influence of exogenous leptin on LH and GH secretion.
Upon completion of blood sample collections, the effect of leptin on feeding was assessed. The penned sheep were allowed free access to preweighed pelleted food, with two sheep per pen. The sum of weight of food consumed by the two sheep during the next 45 min was measured.
Hormone and metabolite assays
Plasma samples were stored at -20 C until assayed. Plasma LH
concentrations were determined in duplicate by a double antibody RIA
and were expressed in terms of NIH LH-S12 as previously described
(37). Assay sensitivity, defined as 2 SD from
the zero standard, averaged 0.4 ng/ml for 50 µl plasma. The mean
intra- and interassay coefficients of variation were 8% and 14%,
respectively, at a bound/free ratio (B/Bo) of 75%. Plasma GH was
measured in duplicate in a double antibody RIA with National Hormone
and Pituitary Program reagents using GH standard GH-2 as previously
described (38). The mean GH intraassay coefficient of
variation (CV) was 5% at a B/Bo of 30% and 4% at a B/Bo of 70%.
Assay sensitivity was 0.4 ng/ml using 100 µl plasma. Cortisol was
measured in pooled plasma and basal samples by RIA (Diagnostic Products, Los Angeles, CA). The pools were made by combining
equal aliquots of hourly samples obtained during the frequent sampling
periods. The cortisol assay sensitivity was 3.8 ng/ml, and the
intraassay CV was 3%. All LH, GH, and cortisol determinations for an
individual sheep were run in the same assay. Plasma insulin was
measured in the pooled plasma by RIA (ICN Pharmaceuticals, Inc., Costa Mesa, CA). The sensitivity of the insulin RIA was
0.21 IU/ml, and the intra- and interassay CVs were 5% and 17%,
respectively.
Plasma leptin was measured in the pooled plasma and basal tubes by two
different methods. The first method used a recently developed RIA for
ovine leptin (39). The oleptin standard curve and data
from a serial dilution of a sheep plasma sample are shown in Fig. 1
. The detection limit of the assay,
using 100 µl plasma/tube, was 0.06 ng/ml. The cross-reactivity
between the antioleptin antibody and rhmet-leptin was less than 0.5%
compared with the oleptin standard. Sheep plasma spiked with
rhmet-leptin did not dilute with the zero standard in a parallel
fashion to the oleptin standard. All samples were run in a single
assay, and the intraassay CV was 8% at a B/Bo of 85%. For the second
method, leptin was measured in 100-µl aliquots of the basal and
pooled plasma samples using a multispecies leptin RIA kit (Linco Research, Inc., St. Charles, MO). The assay sensitivity for the
multispecies RIA averaged 0.29 ng/ml. The intra- and interassay
coefficients of variation were 3% and 13%, respectively, at a B/Bo of
70%. In contrast to the specific oleptin RIA, there was 100%
cross-reactivity of rhmet-leptin with the assay standard, and fed
endogenous leptin immunoreactivity was near the detection limit of the
multispecies RIA. Thus, this assay was used to quantify the exogenous
hormone. Plasma insulin-like growth factor I (IGF-I) and nonesterified
fatty acids (NEFA) were measured in the fed and fasting pools and in
the basal sample collected after 24 h of fasting. Plasma IGF-I was
measured by immunoradiometric assay after extraction (Diagnostics Systems Laboratories, Inc., Webster, TX), and NEFA were measured
by a calorimetric method (Wako Chemicals, Inc., Richmond, VA). Glucose
was measured in single 5-µl aliquot of the pooled plasma using an
enzymatic method (Glucose Trinder kit, Sigma).
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The effects of fasting and treatment on hormonal parameters, metabolites, feed intake, and weight were determined by repeated measures ANOVA using treatment group and time (duration of fasting) as the between- and within-group factors, respectively. Pooled samples from the two frequent sampling time periods as well as intermediate time points were included in the analyses. When the primary analysis demonstrated a significant (P < 0.05) treatment x time interaction, subsequent repeated measures ANOVAs were performed on the data from control and leptin-treated animals individually. Contrasts comparing fasting values to the fed baseline or comparing between-treatment groups were performed as appropriate when significant main effects or interactions were identified by ANOVA. Data were log transformed before analysis when appropriate.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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provides patterns of LH
secretion for estrogen-treated males during the fed and fasted states.
All animals exhibited rapid LH pulse frequency during the fed period,
but during fasting few LH pulses occurred (3.5 ± 0.6
vs. 0.8 ± 0.3 pulses/4 h; fed vs. fasting,
P = 0.02). There was a trend to lower mean LH
concentrations during fasting (19.1 ± 3.0 vs.
11.8 ± 2.8 ng/ml; P = 0.11). LH pulse amplitudes
were similar between the two studies (24.5 ± 5.6 vs.
40.9 ± 14.0 ng/ml; P = 0.26).
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shows the effect of fasting
on ovine plasma leptin concentrations. Plasma leptin measurements using
the specific ovine leptin RIA are presented for samples collected
before leptin administration or from control sheep (no leptin
treatment). As rhmet-leptin partially cross-reacted in the ovine leptin
assay, only the fed baseline and 16 h fasting data, which were
obtained before rhmet-leptin administration, were included in the
initial ANOVA. A repeated measures ANOVA using these two time points
demonstrated a strong time effect (P < 0.001), but no
treatment x time interaction (P = 0.9),
indicating a parallel fall in oleptin during fasting in the two
treatment groups. Equivalency in baseline oleptin concentrations in the
two groups was further supported by a two-sample t test
(1.49 ± 0.16 vs. 1.79 ± 0.25 ng/ml; control
vs. leptin, P = 0.35). During fasting,
plasma leptin fell approximately 30% within the first 16 h
(1.06 ± 0.09 ng/ml; P = 0.0005 vs.
0800 h on day 0). A repeated measures ANOVA using the fasting time
points demonstrated that ovine leptin concentrations in control animals
remained stable throughout the remainder of the experiment.
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Figure 4 presents the effect of fasting
on glucose and insulin in vehicle or leptin-treated sheep, and Fig. 5 shows the effects of fasting on NEFA
and IGF-I. There were no treatment effects (P > 0.3),
and there were highly significant time effects (P <
0.0001) for each of these metabolic parameters. There were no treatment
group x time interactions for plasma glucose (P =
0.9), insulin (P = 0.6), NEFA (P =
0.6), or IGF-I (P = 0.7). Therefore, there was no
effect of treatment group on either baseline or fasting measurements.
Plasma glucose reached a nadir 32 h into the fast. Plasma insulin
concentrations mirrored the decline in glucose, falling from 23.9
± 1.2 µU/ml at baseline to 8.47 ± 0.33 µU/ml at 72 h
(P < 0.0001). NEFA increased from 0.20 ± 0.01
mEq/liter at baseline to 0.88 ± 0.05 mEq/liter at 24 h
(P < 0.0001) and was even higher at 72 h
(1.56 ± 0.08 mEq/liter; P < 0.0001). There was a
small decline in plasma IGF-I after 24 h of fasting (208 ±
14 vs. 180 ± 20 ng/ml; P = 0.01), and
after 72 h of fasting, plasma IGF-I had decreased further (70
± 13 ng/ml; P < 0.0001 vs. fed and 24
h).
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illustrates plasma cortisol
concentrations in the vehicle- and leptin-treated sheep during the fed
and fasting periods. There was no treatment effect (P =
0.4). There was, however, a time effect (P = 0.01) and
a treatment x time interaction (P = 0.005),
indicating that the changes in cortisol between the two groups were not
parallel. The treatment x time interaction was driven by
significant differences in plasma cortisol late in the fast, with
higher plasma cortisol (P < 0.05) after 64 h of
fasting in the control group. Repeated measures ANOVA performed on the
control data found a time effect (P = 0.02), and
post-hoc contrasts demonstrated that plasma cortisol
increased over the baseline fed value late in the fast. A similar
analysis of cortisol concentrations during leptin administration also
demonstrated a time effect (P = 0.01); however, plasma
cortisol levels at all time points, except for 32 h, were similar
to the fed baseline level.
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. Plasma LH
concentrations in vehicle- and leptin-treated sheep during the fed and
fasting periods are shown in Fig. 7
(mean ± SE) and Fig. 8
(individual LH profiles). Repeated measures ANOVA for LH concentration
demonstrated a treatment effect (P = 0.03), a strong
time effect (P < 0.0001), and a strong treatment
group x time interaction (P < 0.0001) for LH
concentration. During the fed period, mean concentrations of LH were
similar for the two groups (P = 0.5). As shown in Fig. 7, within 32 h of fasting, plasma LH in the control animals fell
below the mean baseline concentration (P = 0.0005). In
contrast, fasting LH concentrations in the leptin group were unchanged
or increased slightly above the fed control level.
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ANOVA for LH pulse amplitude showed a very significant time effect
(P < 0.001), but no treatment effect and no
interaction. LH pulse amplitudes were similar in the two groups during
the fed period (P = 0.54). There was a marginal
increase in LH pulse amplitude in the vehicle-treated sheep during
fasting (P = 0.04). This increase was a result of
infrequent, large amplitude LH pulses in the fasted control sheep (Fig. 8
). Moreover, three control animals had no LH pulses during the fasting
period. Therefore, definite conclusions relative to the LH pulse
amplitude data in the control animals cannot be made. LH pulse
amplitudes in the leptin-treated sheep were marginally above amplitudes
during the fed period (P = 0.04).
Parameters characterizing pulsatile GH secretion in control and
leptin-treated sheep are presented in Table 2. Individual GH profiles for each sheep
are shown in Fig. 9. By repeated measures
ANOVA, there was a marginally insignificant effect of treatment group
on mean GH (P = 0.06), but a very strong time effect
(P < 0.0001) and treatment x time interaction
(P = 0.001). The mean GH concentration
(P = 0.8), mean GH pulse amplitudes (P
= 0.7), and pulse frequency (P = 0.9) during the fed
baseline were similar in the two groups. The equivalency of the
baseline values and the strong interaction between treatment and time
indicated that the effects of fasting on mean GH and GH pulse amplitude
were different between the vehicle- and leptin-treated animals. In the
control animals, there was a modest increase in both mean GH
concentration (P = 0.03) and GH pulse amplitude
(P = 0.04) during fasting. In contrast, in the
leptin-treated animals there was a more than 3-fold increase in both
mean GH concentration (P = 0.0001) and pulse amplitude
(P = 0.007) over the fed baseline measurements. GH
pulse frequency did not change with either fasting or leptin
treatment.
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, there was a
weak trend for less food intake in the leptin-treated sheep
(P = 0.14). Of interest, three of eight sheep treated
with leptin attempted to mount other males around the time of the last
leptin injection, and two of eight exhibited mounting behavior during
the second frequent blood collection. None of control animals
demonstrated this type of sexual behavior.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Whether food deprivation alters pulsatile LH secretion in sheep has been unclear. Long-term feed restriction suppresses LH pulse frequency (6, 7, 8, 9, 10, 11, 32). However, virtually no reports have documented that acute fasting inhibits sheep reproductive neuroendocrine function. In our preliminary acute experiments with gonadectomized females without estradiol replacement, we also found no effect of fasting on LH secretion. In contrast, fasting clearly suppressed LH in gonadectomized males administered physiological doses of estradiol. Whether this difference in LH response to fasting reflects a sex difference rather than a difference in steroid status cannot be determined from our study because the appropriate comparisons were not made.
These results, however, are consistent with other data demonstrating interactions between estrogen and nutritional status in the control of LH secretion. Several studies suggest that estrogen could alter the set-point for gonadotropin suppression during caloric restriction. Indeed, a role for estrogen in the modulation of LH secretion during caloric restriction in rats (42) and sheep (32) has been previously proposed. We recently demonstrated a decrease in LH secretion during fasting in ovariectomized rats and that sex steroid replacement enhanced this gonadotropin suppression (18). We further determined that this modulatory effect of estrogen in rats involves sex steroid feedback to brain areas exhibiting fasting-mediated increases in estrogen receptors (30, 43). Similar observations have been made in sheep. In orchidectomized sheep without gonadal steroid replacement, feed restriction did not suppress pulsatile LH secretion (32). Systemic estrogen infusion inhibited LH secretion in these feed-restricted animals, but not in more liberally fed ones (32). Of interest, feed restriction in lambs reduced LH secretion and up-regulated the number of estrogen receptor-positive cells in the preoptic area (44), which is a site for estrogen negative feedback on LH secretion in sheep (45). Therefore, enhancement of estrogen’s negative feedback on GnRH secretion is a likely mechanism for fasting-induced LH suppression in sheep and other species.
The estrogen dependency for suppression of pulsatile LH secretion in acutely fasted sheep might be an important mechanism that increases survival. During periods of starvation, fertility is not desirable, and metabolic signals to the brain would tend to suppress LH secretion. When estrogen is absent, the brain would sense that the reproductive axis is "off." In contrast, the presence of systemic estrogen would inform the central mechanisms controlling the hypothalamic-pituitary-gonadal axis that the axis is "on." As fertility during periods of food scarcity would be detrimental to survival, neuroendocrine mechanisms that actively turn off LH secretion would be beneficial to survival. This teleological argument fits well with observations from this and other (30, 32, 42, 43) studies demonstrating that caloric restriction enhances estrogen negative feedback.
If leptin serves as a metabolic hormone that connects the level of nutrition with reproductive hormone secretion, it probably has a permissive role. Although it was reported that icv leptin administration increased LH pulse amplitude in nonfasted, well fed rats (46), most studies have found an effect of leptin on gonadotropin secretion only in fasting animals. For example, we recently demonstrated that leptin administration to fed rats did not affect LH pulses (47). Similarly, an icv leptin infusion did not further increase pulsatile LH secretion in fed sheep (25). Our finding that exogenous leptin prevents fasting-induced suppression of pulsatile LH secretion in sheep is consistent with previous reports using ovariectomized, fasted rats (18) and gonad-intact, fasted male monkeys (19). Overall, these data indicate that the effect of leptin on pulsatile LH secretion is only manifest in hypogonadotropic animals with low plasma leptin concentrations. Artificially increasing leptin concentrations further would fail to increase LH secretion in the nonhypogonadotropic individual. This agrees with the ideas that high levels of leptin provide a signal about energy balance and that once an appropriate energy balance is achieved, greater concentrations of circulating leptin do not provide any additional information to the reproductive neuroendocrine axis.
The neuroendocrine mechanism(s) through which leptin regulates GnRH neuronal activity is uncertain. One potential mechanism is activation of the hypothalamic-pituitary-adrenal (HPA) axis by the stress of fasting (48). Arguments supporting this possibility include an association between hypogonadotropism and elevated plasma corticosterone in the fasting rat (16) and restoration of the fasting-induced LH suppression by icv injection of a CRH antagonist (49). In addition, leptin treatment of fasting ob/ob mice ameliorates both hypercortisolemia (50) and infertility (51, 52, 53). Similarly, leptin treatment of wild-type mice prevents fasting-induced increases in corticosterone and suppression of estrous cyclicity (16). Other findings do not support the view that HPA activation by fasting mediates hypogonadotropism. Foot shock stress and fasting both inhibit LH secretion in the CRH knockout mouse (54).
Our data suggest that if activation of the HPA axis is involved, then it is unlikely that an increase in glucocorticoid per se is what inhibits the reproductive axis. In our leptin-treated animals, plasma cortisol concentrations remained at fed levels. In the control animals, cortisol only increased consistently above the fed state levels late in the experiment (64–72 h of fasting), whereas there was clear suppression of LH by 32 h of fasting. These data do not, however, rule out the possibility that activation of the HPA axis is important in stress-mediated hypogonadotropism. In the case of the knockout mouse, an alternative pathway to the HPA axis might develop in response to stress. In the case of our results, central activation of the HPA axis could mediate gonadotropin suppression without an increase in cortisol secretion. Studies in vivo suggest that leptin increases paraventricular nuclei CRH messenger RNA (55) and hypothalamic CRH content (56). Leptin has been reported to either increase (57) or decrease (58) CRH release from hypothalamic tissue in culture. In addition, leptin inhibits glucocorticoid release from human (59) and bovine (60) primary adrenal cultures. The degree to which central activation of the HPA axis produces the fasting-induced suppression of GnRH secretion is yet unknown.
We have also investigated the effects of leptin on the GH-IGF-I axis. In rats, fasting potently inhibits GH secretion, presumably through increasing hypothalamic somatostatin secretion (61). Recent data have shown that arcuate nucleus neuropeptide Y (NPY) neurons regulate periventricular somatostatin (62) and that NPY inhibits GH in rats (63). Fasting suppresses GH in the rat by increasing NPY, and the fasting-mediated changes in NPY, somatostatin, and GH can be reversed by treatment with exogenous leptin (20, 21, 22, 23, 24, 64, 65).
Whether these data apply to species other than rats is uncertain. In contrast to the suppression of GH that occurs in rats, mean GH increased 3-fold in humans within 24 h of the initiation of fasting (66). In sheep, the effects of nutritional deprivation on GH secretion are less well defined. During chronic feed restriction, mean GH concentrations in lambs (9) or adult ewes (7) increased. Acute fasting of sheep was reported to either increase (67) or have no effect (68) on GH secretion. In our study, 72 h of fasting modestly increased mean GH, but did not affect GH pulse frequency. Consistent with observations in rats, food restriction increased hypothalamic NPY in sheep (31). Although it was originally reported that icv NPY had no effect on GH in sheep (69), a more recent study observed that NPY might stimulate GH in this species (70).
Based on the concordant changes in NPY and the discordant changes in GH during fasting in rats and sheep, we had hypothesized that leptin infusion would prevent an increase in GH secretion in fasting sheep. The dose used, 50 µg/kg every 8 h, resulted in circulating leptin concentrations of a magnitude similar to that measured in obese humans (34, 35, 36). Contrary to our hypothesis, GH was potently stimulated by leptin administration to fasting sheep. Of interest, a single 10- to 100-µg icv injection of porcine leptin acutely stimulated GH release in pigs (71). In a preliminary experiment we similarly observed that icv infusion of rhmet-leptin (2.5 µg/kg·day) for 3 days to fasting sheep also stimulated GH secretion (Jaffe, C., unpublished data). In contrast, a continuous icv infusion of recombinant human leptin at the dose of 480 µg/day had no effect on GH in fed sheep (25). The contradictory results from fasting and underfed animals again underscore the importance of careful delineation of metabolic status when studying the effects of leptin on the neuroendocrine axes.
Whether our results were influenced by the dose of leptin used is uncertain. As noted above, a relatively large range of icv leptin doses stimulated GH secretion in sheep and swine. Limited in vitro data, however, suggest that the leptin dose, in addition to the nutritional status and the species of the animal, might be an issue. Although leptin did not influence GH secretion from primary rat pituitary cell cultures (65), high leptin concentrations increased GH release from pig pituitaries in culture, whereas lower concentrations suppressed GHRH-stimulated GH release leptin (71). Sheep pituitary cells express leptin receptor messenger RNA (72), so it is possible that leptin has a direct pituitary effect in this species. Human leptin had no acute effect on GH release in primary cultures of sheep pituitaries, but in concentrations comparable to those used in the pig study, more chronic leptin exposure inhibited the GH response to GHRH (73). This suppression of GH response to GHRH could conceivably account for the low spontaneous and GHRH-stimulated GH levels in obese humans. Further studies are needed to accurately define the interactions between GH secretion and leptin, nutritional status, and IGF-I.
As opposed to the effects of leptin on gonadotropin and GH secretion, we did not find a clear effect of leptin on food intake. This is contrary to the recent report that icv leptin infusion suppresses food intake (25). There are several potential explanations for this difference. We had anticipated that the effect of leptin on feed intake would be large, so that few animals would be required to see a significant effect on feeding. We therefore penned two animals together to avoid isolation stress. It is possible that our experimental design, in which we measured the combined feed intake of two sheep, did not give us adequate power to see a difference. It is also possible that a higher dose of leptin might have resulted in decreased feed intake. However, the fact that we obtained unequivocal effects on both LH and GH secretion suggests that the dose used (150 µg/kg·day) did have a significant central effect. Alternatively, rhmet-leptin, which is similar but not identical to ovine leptin, might be less anorexigenic than the ovine peptide in sheep. It is also conceivable that either sheep have relative leptin resistance with regard to satiety or that leptin does not play a role in feed intake in this species. The previous report that icv leptin suppressed food intake (25) could have been due to a toxic effect of administering the peptide icv. Finally, it is most likely that the model used for study accounts for the observed differences in feeding during leptin treatment. Henry et al. (25) demonstrated decreased feed intake in chronically feed-restrained sheep. Our studies were performed with sheep fasted for 78 h. This more extreme acute nutritional deprivation might have stimulated pathways that overruled any anorexigenic input from the exogenous leptin.
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Acknowledgments |
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Footnotes |
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Received February 25, 2000.
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References |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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 V. Popovic, M. Djurovic, A. Cetkovic, D. Vojvodic, S. Pekic, S. Spremovic, M. Petakov, S. Damjanovic, N. Milic, C. Dieguez, et al. Inhibin B: A Potential Marker of Gonadal Activity in Patients with Anorexia Nervosa during Weight Recovery J. Clin. Endocrinol. Metab., April 1, 2004; 89(4): 1838 - 1843. [Abstract] [Full Text] [PDF]
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H. V. Leon, J. Hernandez-Ceron, D. H. Keisler, and C. G. Gutierrez Plasma concentrations of leptin, insulin-like growth factor-I, and insulin in relation to changes in body condition score in heifers J Anim Sci, February 1, 2004; 82(2): 445 - 451. [Abstract] [Full Text] [PDF]
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M.N. Maciel, D.A. Zieba, M. Amstalden, D.H. Keisler, J.P. Neves, and G.L. Williams Leptin Prevents Fasting-Mediated Reductions in Pulsatile Secretion of Luteinizing Hormone and Enhances Its Gonadotropin-Releasing Hormone-Mediated Release in Heifers Biol Reprod, January 1, 2004; 70(1): 229 - 235. [Abstract] [Full Text] [PDF]
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M. Amstalden, D.A. Zieba, J.F. Edwards, P.G. Harms, T.H. Welsh Jr., R.L. Stanko, and G.L. Williams Leptin Acts at the Bovine Adenohypophysis to Enhance Basal and Gonadotropin-Releasing Hormone-Mediated Release of Luteinizing Hormone: Differential Effects Are Dependent upon Nutritional History Biol Reprod, November 1, 2003; 69(5): 1539 - 1544. [Abstract] [Full Text] [PDF]
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J. Bispham, G. S. Gopalakrishnan, J. Dandrea, V. Wilson, H. Budge, D. H. Keisler, F. Broughton Pipkin, T. Stephenson, and M. E. Symonds Maternal Endocrine Adaptation throughout Pregnancy to Nutritional Manipulation: Consequences for Maternal Plasma Leptin and Cortisol and the Programming of Fetal Adipose Tissue Development Endocrinology, August 1, 2003; 144(8): 3575 - 3585. [Abstract] [Full Text] [PDF]
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R. E. Campbell, K. L. Grove, and M. S. Smith Gonadotropin-Releasing Hormone Neurons Coexpress Orexin 1 Receptor Immunoreactivity and Receive Direct Contacts by Orexin Fibers Endocrinology, April 1, 2003; 144(4): 1542 - 1548. [Abstract] [Full Text] [PDF]
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 D. A. Zieba, M. Amstalden, M. N. Maciel, D. H. Keisler, N. Raver, A. Gertler, and G. L. Williams Divergent Effects of Leptin on Luteinizing Hormone and Insulin Secretion Are Dose Dependent Experimental Biology and Medicine, March 1, 2003; 228(3): 325 - 330. [Abstract] [Full Text] [PDF]
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 S. C. Liefers, R. F. Veerkamp, M. F. W. te Pas, C. Delavaud, Y. Chilliard, and T. van der Lende Leptin Concentrations in Relation to Energy Balance, Milk Yield, Intake, Live Weight, and Estrus in Dairy Cows J Dairy Sci, March 1, 2003; 86(3): 799 - 807. [Abstract] [Full Text] [PDF]
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R. P. Wettemann, C. A. Lents, N. H. Ciccioli, F. J. White, and I. Rubio Nutritional- and suckling-mediated anovulation in beef cows J Anim Sci, February 1, 2003; 81(14_suppl_2): E48 - 59. [Abstract] [Full Text] [PDF]
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M. R. Garcia, M. Amstalden, C. D. Morrison, D. H. Keisler, and G. L. Williams Age at puberty, total fat and conjugated linoleic acid content of carcass, and circulating metabolic hormones in beef heifers fed a diet high in linoleic acid beginning at four months of age J Anim Sci, January 1, 2003; 81(1): 261 - 268. [Abstract] [Full Text] [PDF]
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M. L. Barker-Gibb, A. Sahu, C. R. Pohl, and T. M. Plant Elevating Circulating Leptin in Prepubertal Male Rhesus Monkeys (Macaca mulatta) Does Not Elicit Precocious Gonadotropin-Releasing Hormone Release, Assessed Indirectly J. Clin. Endocrinol. Metab., November 1, 2002; 87(11): 4976 - 4983. [Abstract] [Full Text] [PDF]
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P. R. Buff, A. C. Dodds, C. D. Morrison, N. C. Whitley, E. L. McFadin, J. A. Daniel, J. Djiane, and D. H. Keisler Leptin in horses: Tissue localization and relationship between peripheral concentrations of leptin and body condition J Anim Sci, November 1, 2002; 80(11): 2942 - 2948. [Abstract] [Full Text] [PDF]
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 H. Watanobe and S. Habu Leptin Regulates Growth Hormone-Releasing Factor, Somatostatin, and alpha -Melanocyte-Stimulating Hormone But Not Neuropeptide Y Release in Rat Hypothalamus In Vivo: Relation with Growth Hormone Secretion J. Neurosci., July 15, 2002; 22(14): 6265 - 6271. [Abstract] [Full Text] [PDF]
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M. Amstalden, M.R. Garcia, R.L. Stanko, S.E. Nizielski, C.D. Morrison, D.H. Keisler, and G.L. Williams Central Infusion of Recombinant Ovine Leptin Normalizes Plasma Insulin and Stimulates a Novel Hypersecretion of Luteinizing Hormone after Short-Term Fasting in Mature Beef Cows Biol Reprod, May 1, 2002; 66(5): 1555 - 1561. [Abstract] [Full Text]
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K. Wallenius, K. Sjogren, X.-D. Peng, S. Park, V. Wallenius, J.-L. Liu, M. Umaerus, H. Wennbo, O. Isaksson, L. Frohman, et al. Liver-Derived IGF-I Regulates GH Secretion at the Pituitary Level in Mice Endocrinology, November 1, 2001; 142(11): 4762 - 4770. [Abstract] [Full Text] [PDF]
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P. Peyon, S. Zanuy, and M. Carrillo Action of Leptin on In Vitro Luteinizing Hormone Release in the European Sea Bass (Dicentrarchus labrax) Biol Reprod, November 1, 2001; 65(5): 1573 - 1578. [Abstract] [Full Text] [PDF]
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) gave a percent
binding curve that was parallel with the ovine standard.
