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School of Biological Sciences (Z.A., F.R.A.C., J.A.S., I.D.M., A.S.I.L.), University of Manchester, Manchester, United Kingdom M13 9PT; AstraZeneca CTL (A.N.B.), Cheshire, United Kingdom SK10 4TJ; School of Biomedical Sciences (F.J.P.E.), University of Nottingham, United Kingdom NG7 2UH; Fachbereich Biologie/Zoologie (M.K.), Philipps Universtat Marburg, D-35043 Marburg, Germany
Address all correspondence and requests for reprints to: Dr. Andrew S. I. Loudon, School of Biological Sciences, 3.614 Stopford Building, Oxford Road, University of Manchester, Manchester, United Kingdom M13 9PT. E-mail: andrew.loudon{at}man.ac.uk
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Leptin, the product of the adipose tissue-derived ob gene, has been strongly implicated as one of the major peripheral signals controlling body fat reserves and appetite in mammals (4). The central nervous system, in particular the hypothalamus, is known to be a major site of leptin action, and it is here that the active form of the leptin receptor colocalizes to peptidergic circuits intimately involved in energy balance (5). It is now recognized that leptin may also play an important role in the regulation of reproductive function. Mutations of this gene result in primary obesity and reproductive dysfunction in man and mice (6, 7), both of which are reversed after treatment with recombinant murine leptin (7, 8, 9). In the Siberian hamster, expression of the leptin gene in both white and brown adipose tissue is powerfully influenced by photoperiod, with a 6-fold reduction in expression in short days (10). These observations raise important questions as to what role seasonal changes in the leptin signaling pathway may play in regulation of the annual cycle of metabolism and reproduction.
The experimental approach used here was to infuse short day-exposed hamsters with recombinant murine leptin for 2 weeks at a level designed to mimic circulating concentrations observed naturally on long photoperiods. Specifically, we aimed to test the hypothesis that seasonal changes in reproduction are mediated via photoperiodic changes in endogenous leptin concentrations. We studied the reproductive response at the gonadal level in males (testicular size change and testosterone response) and at the pituitary level in males and ovariectomized estrogen-implanted females (pituitary LH concentrations) to circumvent the confounding effects of changing sex steroid feedback. In both sexes, leptin infusion did not overcome SD-induced reproductive suppression. In contrast, SD-treated animals exhibited significant weight and fat loss in response to leptin, but without an altered pattern of food intake. LD animals did not exhibit a significant food intake or weight loss response to leptin. These data demonstrate that 1) the response to leptin may be gated by photoperiod; 2) leptin effects on energy metabolism and food intake can be dissociated from one another; and 3) despite profound natural seasonal changes in leptin, this hormone does not appear to play a central role in activating reproduction in this species.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Leptin infusion protocols
Recombinant murine leptin (supplied by Amgen, Inc.,
Thousand Oaks, CA) was dissolved in 0.01 M PBS and
administered via an osmotic minipump (100-µl capacity; Alzet model
1007D, Charles River Laboratories UK Ltd., Kent, UK) to
deliver a concentration of 15 µg/day for a 7-day period. Control
animals received PBS vehicle alone. Pumps were implanted sc in the
scapular region by sterile surgical procedure under halothane
(Fluothane, AstraZeneca Ltd., Cheshire, UK) anesthesia.
Experimental protocols
Exp 1: effects of leptin infusion on metabolism and reproduction
in male hamsters in LD and SD. Twenty-six weight-matched male
Siberian hamsters (16 weeks of age) previously reared in LD conditions
were individually housed and maintained under either LD or SD
photoperiods. Once weekly measurements of body weight and food intake
(by measurement of weighed refusals) were undertaken. In addition, left
testicular diameter was determined under light halothane anesthesia.
Changes in pelage type were recorded on a four-point scale from full
agouti type (summer, stage1) to white (winter, stage 4) coat type
(12). Two animals on SD were nonresponsive to the SD
photoperiod, as judged from persistent stable body weight, agouti coat
type, and nonregressed testes. This nonresponsive phenotype has
previously been described for this species (13), and these
animals were excluded from subsequent experimental manipulations. After
8 weeks, animals were implanted with osmotic pumps containing
recombinant leptin or PBS (n = 6/treatment/photoperiod). Pumps
were replaced on day 7 for an additional 7-day period. During this
14-day treatment period, daily changes in body weight and food intake
were recorded. On day 14, hamsters were anesthetized, and blood samples
were taken by cardiac puncture for serum testosterone and leptin
determinations. Animals were then killed by cervical dislocation, and
the pituitary was rapidly dissected, frozen in dry ice, and stored at
-80 C before LH RIA. Serum was left overnight at 4 C before
collection. Retroperitoneal and epididymal fat depots and paired testes
were dissected and weighed.
Exp 2: establishment of a steroid-clamp model in ovariectomized female hamsters. Fourteen-week-old female hamsters bred under LD conditions were ovariectomized (OVX) and 2 weeks later were implanted sc in the scapular region with an estradiol (E2)-containing implant. Manufacture of E2 implants has been described previously (14). Briefly, implants were made by mixing a range of estrogen doses (1,3,5[10]-estratriene-3,17ß-diol; Sigma-Aldrich Corp. Ltd., Dorset, UK) with SILASTIC brand elastomer and a curing agent (Merck Ltd., Dorset, UK) to polymerize the elastomer. After curing, implants were cut to 4 x 4-mm squares and contained estimated estrogen doses of 0, 31, 62, 125, 250, and 500 µg/implant. A total of six animals per dose were employed and compared with a group of six ovary-intact controls. Three weeks after implantation, animals were killed by cervical dislocation, and paired fat-free uteri were weighed.
To define the photoperiodic drive on LH secretion in the castrate, steroid-implanted model, a further cohort of 16-week-old females was divided into three groups. These were ovariectomized and treated with an empty implant (OVX), ovariectomized and implanted with the lowest (31 µg) dose of E2 (OVX+E2), or left intact and treated with an empty implant (INT). All animals were individually housed under either a SD or LD photoperiod (six per treatment per photoperiod) 2 weeks after surgery, and over the next 12 weeks weekly measurements of body weight, food intake, and pelage score were undertaken to validate a SD photoperiod response. At the end of week 12, animals were killed, and the pituitary was rapidly dissected, frozen in dry ice, and stored at -80 C before LH assay. Paired uteri and retroperitoneal fat depots were dissected and weighed. The 31-µg implants described above were used in all subsequent experiments.
Exp 3: leptin infusion in steroid-clamped female hamsters in LD and SD. Twenty-four weight-matched 16-week-old OVX steroid-implanted hamsters previously reared in LD were individually housed and exposed to LD or SD conditions for an 8-week period. Weekly measurements of body weight, food intake, and pelage score were undertaken over weeks 0–8. At weeks 9–11, each animal received an osmotic pump containing either leptin or PBS as described above (six animals per group per treatment). Pumps were replaced after 1 week for a further 1-week period. From weeks 9–11, daily changes in food intake and body weight were recorded. On day 14, hamsters were anesthetized, and blood samples were taken by cardiac puncture for serum leptin determination. Animals were killed by cervical dislocation, and the pituitary was rapidly removed, frozen in dry ice, and stored at -80 C before LH assay. The retroperitoneal fat depots and uteri were dissected and weighed.
Pituitary homogenization and hormone assays
Processing of pituitaries. Each pituitary was homogenized
for 2 min in a 50-mM sodium carbonate solution (pH 7.4)
containing 1% Triton-X 100 and then left to stand for 30 min. A
50-µl aliquot was removed for determination of pituitary protein by
Bradford assay (15). The remaining homogenate was
centrifuged at 10,000 x g for 30 min, and the
supernatant was collected for determining LH concentration.
LH. A double antibody RIA was used to determine pituitary LH concentration, as previously described for use in hamsters (16). RIA reagents were supplied by the National Hormone and Pituitary Program (NIDDK, Bethesda, MD) and employed rabbit antirat LH antibody S-11 and rat LH RP-3 reference preparation. The mean minimally detected concentration of LH in the pituitary homogenate was 0.156 ng/ml, and the intra- and interassay coefficients of variation were 4% and 17% for pools of homogenates at 2.8 and 1.4 ng/ml, respectively. Pituitary dilutions over a 16-fold (1:8–1:128) range exhibited clear parallelism (data not shown). The LH concentration was converted to nanograms of LH per µg pituitary protein concentration. We did not undertake serum LH assays because we were constrained by the serum volume required for leptin assay.
Testosterone. Serum testosterone levels were determined by enzyme-linked immunosorbent assay as described for use in this species (17). All samples were included in a single assay. Extraction efficiency was 81%, and the limit of detection was 0.05 ng/ml. The intraassay coefficient of variation based on replicates of serum pool was 12.9%.
Leptin. Serum leptin concentrations were determined by a solid phase sandwich enzyme immunoassay using affinity-purified rabbit antirecombinant murine leptin immobilized in microtiter wells (18). Bound leptin was detected with affinity-purified antimurine polyclonal antibody conjugated to horseradish peroxidase and quantified with a chromogenic substance. Leptin concentrations were calculated from standard curves generated for each microtiter plate using recombinant murine leptin. The limit of detection for the assay was 0.15 ng/ml, and the intra- and interassay coefficients of variation were 4.5% and 8%, respectively, determined from internal murine leptin controls. Due to the heterologous nature of the leptin standards, the measured serum leptin concentrations are relative and not necessarily absolute. Serum samples were always assayed at three dilutions in duplicate and with two dilutions normally falling into the range of the standard curve. The comparison of calculated concentrations of the two dilutions from each hamster demonstrated that values varied from each other by no more than 13%.
Data analysis
Parametric data were analyzed by ANOVA followed by a
post-hoc Student-Newman-Keuls test. Nonparametric data were
analyzed by Kruskal-Wallis test followed by post-hoc
Tukey’s test. Time-course responses were analyzed by repeated measures
ANOVA. All analyses were undertaken using a statistical package
(SigmaStat, SPSS, Chicago, IL). Results are presented as
the mean ± SEM. Differences were considered
statistically significant at the P < 0.05 level.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). In a subsequent
study using the 31-µg dose, pituitary LH concentrations were
significantly modulated by photoperiod (P = 0.018, by
two-way ANOVA). In OVX animals exposed to LD, there was a significant
(P < 0.05) 2-fold increase in LH concentration
compared with that in SD hamsters, and this was further augmented
(P < 0.001 compared with SD) to a 5-fold difference in
the OVX+E2 animals. There was no significant
effect of photoperiod on pituitary LH concentration in females with
intact ovaries (Fig. 2). All groups of SD
animals exhibited a robust photoperiodic response of weight loss
(P < 0.01) and decreased appetite (P
< 0.01; Fig. 3. There was a significant
effect of both photoperiod and estrogen treatment on body weight
(photoperiod, P = 0.003; estrogen, P <
0.001; by two-way repeated measures ANOVA) and food intake
(photoperiod, P = 0.001; treatment, P =
0.023; by two-way repeated measures ANOVA) over the 12-week period.
Ovariectomized females on SD exhibited a consistent weight loss over
the 12-week period, whereas estrogen-clamped females initially
exhibited an increase in body weight over the first 3 weeks of SD
exposure before undergoing a reduction in body weight. In all animals
kept in LD body weight remained stable during the 12-week period.
Pelage changes were observed from weeks 3–4 in all SD-exposed animals,
and by week 12 all animals were at stage 3 on the four-point scale
(data not shown), with no significant effect of ovariectomy or estrogen
clamp on the rate of pelage change.
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). Infusion of leptin over a 2-week
period resulted in significant (P < 0.05) elevation of
circulating leptin concentrations in both males and females on SD and
in males on LD. This increase in leptin concentrations in SD-treated
males resulted in concentrations similar to those observed in LD
vehicle-treated controls. In females, leptin concentrations were
significantly greater (P < 0.05) in SD-treated animals
than in either of the LD groups.
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, a and b). In SD females,
there was an initial increase in body weight over the first 2 weeks,
similar in magnitude to that observed in the previous experiment (see
Fig. 3
). Animals on SD also consumed significantly less
(P < 0.05) food over this period (data not shown). In
both sexes, exposure to SD for 8 weeks caused the development of a
white winter pelage, such that by the end of the study all animals were
between stages 2 and 3 (data not shown).
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). Overall, leptin had no
significant effect (males, P = 0.837; females,
P = 0.06; by two-way ANOVA) on daily food intake on
either photoperiod. For both sexes on day 2 (the first full day
postsurgery) there was a transient 1-day decrease in food intake in
SD-housed leptin vs. that in SD PBS-treated animals (males,
0.336 ± 0.2 vs. 1.288 ± 0.34 g; females,
1.057 ± 0.23 vs. 2.29 ± 0.18 g for leptin
and PBS treatments, respectively). There was no significant transient
effect of leptin on day 2 for LD-housed animals. Over the 14-day leptin
treatment period, there was a significant photoperiodic effect (males,
P < 0.001; females, P < 0.001; by
two-way repeated measures ANOVA) on daily changes in body weight (Fig. 6b). There was also a significant interaction of leptin treatment and
photoperiod on body weight (P < 0.001, by two-way
repeated measures ANOVA) for both sexes over the 14-day infusion
period, with a significant weight loss in SD-housed leptin-treated
animals (P < 0.001, by two-way repeated measures
ANOVA). There was a significant interaction of leptin treatment and
photoperiod on the mass of retroperitoneal fat depot in both sexes
(P < 0.001, by Kruskal-Wallis one-way ANOVA; Fig. 6c).
In SD-housed animals (both sexes), leptin caused a significant
(P < 0.05) reduction in fat depot. There was no
significant effect of leptin in LD-housed animals. In males, SD
treatment was also associated with a significant (P <
0.05) reduction in epididymal fat depot (data not shown), with no
significant effect for LD-housed animals.
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, a and b), but no effect of leptin
treatment (testicular mass, P = 0.174; serum
testosterone, P = 0.362; by two-way ANOVA) on either of
these parameters. In both sexes, there was a highly significant effect
of photoperiod on pituitary LH concentrations (P <
0.001, by two-way ANOVA) with a 3-fold reduction in pituitary
concentrations on SD for both sexes (Fig. 8, a and b). There was no significant
effect of leptin treatment (males, P = 0.091; females
P = 0.095; by two-way ANOVA) on pituitary LH.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Previous studies of the Siberian hamster have shown that short daylengths are associated with a significant reduction in leptin gene expression in both brown and white adipose tissue (10) and with reduced serum concentrations of leptin (18). In the closely related Djungarian hamster (Phodopus campbelli), food restriction also causes marked down-regulation of leptin gene expression in adipose tissue (19). Our studies employed a heterologous assay system and may therefore underestimate concentrations of native leptin peptide in circulation. Nonetheless, it is clear that at the doses of leptin used, we were able to produce clear physiological effects, but only on short photoperiods. Leptin action was characterized by an almost complete loss of measurable fat reserves in both sexes on SD over a 14-day period, but with no corresponding alteration in food intake, suggesting an altered pattern of metabolism and thermogenesis independent of appetite. A similar dissociation of these effects of leptin has been shown in suckling rat pups and food- restricted rats and mice, in which leptin causes fat loss by altering the circadian pattern of energy expenditure rather than food intake (20, 21). Interestingly, in our studies, these dissociated effects of leptin were observed in ad libitum-fed animals. In the ob/ob mouse, leptin has been shown to act directly on energy expenditure (22, 23) as well as increase sympathetic outflow to brown adipose tissue (24). Further, in laboratory rats leptin up-regulates mitochondrial uncoupling protein messenger RNA levels in brown adipose tissue and increases oxygen consumption (25). We have recently suggested that leptin action may be mediated by interleukin-1, with action on thermogenic pathways dependent upon cyclooxygenase products (26). As these aspects of leptin action on metabolism and thermogenesis are also observed in marsupials (27), they may indicate a generalized feature of mammalian physiology.
Our data describing leptin action on SD-housed animals contrast with two recently published studies that report acute inhibitory effects on food intake of either a single daily ip injection of leptin (5 mg/kg) to SD- or LD-housed hamsters (28) or a 10-day regimen of twice daily ip injection (6.5 mg/kg) of leptin (18). In both of these studies, acute leptin treatment caused reductions in food intake in both SD- and LD-housed animals. The 10-day regimen of leptin treatment also caused fat loss on both photoperiods, but there was a significantly greater fat loss in SD-housed animals (18). In the study reported here, there was a transient effect of leptin infusion on day 2 food intake (the first full 24-h period after surgery) in both sexes, but this was only observed on SD. The absence of a significant effect of leptin on food intake on either photoperiod over the 14-day period may therefore be attributable to differences between chronic and acute treatment regimens and in the dosages employed. In our study the serum leptin concentrations were within a physiological range. Intriguingly, the acute ip leptin treatment reported by Reddy et al. (28) was without effect on hypothalamic orexin, neuropeptide Y, or POMC expression despite a reduced food intake over the 6-h posttreatment period. This result suggests that although acute homeostatic mechanisms operate in both LD and SD conditions in this species (i.e. appetite response to leptin and neuropeptide Y expression change), long-term seasonal homeostatic regulation may be regulated by hitherto unknown central mechanisms that alter the set-point around which homeostasis occurs, perhaps independently of leptin feedback (18). Such a set-point change may explain the seemingly paradoxical observations in Siberian hamsters, in which fat depot mobilization, reduced appetite, declines in leptin gene expression and serum concentrations, and an apparently increased drive on the anabolic melanocortin pathway are associated with short photoperiods (1, 29). Long-term regulation of seasonal weight cycles in this species may reside beyond the immediate region of the mediobasal hypothalamus, as destruction of this area neonatally by monosodium glutamate treatment does not prevent expression of a robust photoperiodic response (30).
A number of studies have reported actions of leptin on reproduction. Mutations have been described in both muroid rodents and man in which the leptin gene or the hypothalamic receptors are nonfunctional, and in all cases the reproductive phenotype is infertile (31). Reproductive failure does not appear to be a secondary consequence of obesity, as ob/ob mice pair-fed with wild-type animals lose weight but do not become fertile (32). In the infertile ob/ob mouse, exogenous recombinant leptin is effective in restoring fertility in both sexes (7, 9), whereas in man, consanguineous leptin gene defects and severe obesity have been described (6). Here, exogenous leptin treatment results in weight loss and establishment of LH pulsatility (6). These studies clearly indicate that leptin plays an important permissive role in the onset of puberty. The precise role in pubertal timing is less clear. Leptin is reported to be capable of advancing sexual maturation in normal female mice (33, 34), but in rats it is only capable of partially reversing the delay in sexual maturation in food-restricted prepubertal rats, with little effect on pubertal timing in ad libitum-fed animals (35). In postpubertal animals, exogenous leptin has been shown to override the suppressive effects of undernutrition on LH secretion in rats (36, 37), mice (38), and monkeys (39), whereas administration of leptin antiserum in rats reduces pulsatile secretion of LH (40). Taken together, the above studies suggest that functional leptin secretion is an essential prerequisite for puberty. Furthermore, leptin is clearly a key component in the signaling pathway in undernourished animals exhibiting suppressed reproductive function, perhaps by acting indirectly on the reproductive system by increasing metabolic substrate oxidation (41).
Our data show that leptin does not act on the photoperiodically inhibited gonadotropin pathways of either sex, as measured by changes in the pituitary LH concentration. Using steroid-clamped OVX females, we have generated a clear steroid-modulated photoperiodic drive on gonadotropin secretion, with 3-fold differences in LH concentrations. In our model, LH is not sensitive to leptin infusion. Furthermore, there is no indication that leptin is able to modulate go-nadotrophin or gonadal steroid secretion in intact male hamsters, as assessed by the absence of effect on both LH and testosterone concentrations. Thus, our data demonstrate that physiological actions of leptin can be dissociated, with a significant seasonal modulation of metabolic responses, but no reproductive response at either the pituitary or gonadal level. In a recent study using ovariectomized ewes, Henry et al. (42) reported an absence of reproductive response (LH) to intracerebroventricular leptin infusion administered during the period of seasonal anestrus. Our own results suggest that despite substantial seasonal fluctuation in fatness and serum leptin concentrations in the Siberian hamster, seasonal infertility is not amenable to leptin provocation. It is not yet known whether the failure of LD-housed animals to exhibit a metabolic response to chronic leptin infusion is a consequence of seasonal differences in body fat reserves and endogenous serum leptin concentrations, perhaps mediated via the saturation of hypothalamic leptin receptor populations, or whether these differences are a primary consequence of photoperiodic action on postreceptor pathways activated by leptin.
In summary, our data demonstrate clear photoperiodic differences in metabolic responsiveness of Siberian hamsters to leptin infusion that are independent of suppression in food intake, implying a direct action of this hormone on thermogenesis and energy expenditure. The failure of this hormone to reactivate the photo-inhibited reproductive axis strongly suggests that the pathways involved in the seasonal suppression of reproduction via the melatonin signal are different from those implicated in proximal responses to short-term nutrient supply and leptin feedback.
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Acknowledgments |
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Footnotes |
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2 The first two authors contributed equally to this study.
Received May 5, 2000.
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) or
SD (
) photoperiods. Values are the mean ±
SEM. *, P < 0.05; **,
P < 0.001 (compared with the SD photoperiod).
) or short day (•) photoperiods for 8 weeks. Values are the
mean ± SEM. *, P < 0.05; **,
P < 0.01 (compared with LD photoperiod).
