Melatonin-based photoperiod time-measurement and circannual rhythm generation are long-term time-keeping systems used to regulate seasonal cycles in physiology and behaviour in a wide range of mammals including man. We summarise recent evidence that temporal, melatonin-controlled expression of clock genes in specific calendar cells may provide a molecular mechanism for long-term timing. The agranular secretory cells of the pars tuberalis (PT) of the pituitary gland provide a model cell-type because they express a high density of melatonin (mt1) receptors and are implicated in photoperiod/circannual regulation of prolactin secretion and the associated seasonal biological responses. Studies of seasonal breeding hamsters and sheep indicate that circadian clock gene expression in the PT is modulated by photoperiod via the melatonin signal. In the Syrian and Siberian hamster PT, the high amplitude Per1 rhythm associated with dawn is suppressed under short photoperiods, an effect that is mimicked by melatonin treatment. More extensive studies in sheep show that many clock genes (e.g. Bmal1, Clock, Per1, Per2, Cry1 and Cry2) are expressed in the PT, and their expression oscillates through the 24-h light/darkness cycle in a temporal sequence distinct from that in the hypothalamic suprachiasmatic nucleus (central circadian pacemaker). Activation of Per1 occurs in the early light phase (dawn), while activation of Cry1 occurs in the dark phase (dusk), thus photoperiod-induced changes in the relative phase of Per and Cry gene expression acting through PER/CRY protein/protein interaction provide a potential mechanism for decoding the melatonin signal and generating a long-term photoperiodic response. The current challenge is to identify other calendar cells in the central nervous system regulating long-term cycles in reproduction, body weight and other seasonal characteristics and to establish whether clock genes provide a conserved molecular mechanism for long-term timekeeping.
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GA Lincoln, H Andersson, and A Loudon
J. D. Curlewis and A. S. I. Loudon
Experiments were conducted to investigate whether prolactin suppresses the corpus luteum during lactational quiescence in the Bennett's wallaby. In the first experiment, pouch young were removed from lactating wallabies (day 0) which were then treated daily for 7 days with either saline, or 8 mg domperidone or 2 mg ovine prolactin. In the saline-injected animals there was a transient peak in progesterone concentrations on day 4 and birth on day 28. The transient progesterone peak and births were significantly (P <0·01) delayed by 5 and 8 days in animals treated with domperidone and ovine prolactin respectively. In the second experiment, four groups of lactating wallabies were treated on day 0 with either 60 mg bromocriptine (groups C and D) or the vehicle (groups A and B). On days 0–6, groups B and D were injected daily with 2 mg ovine prolactin while groups A and C received the vehicle. In group C, three pouch young died 14–29 days after administration of bromocriptine, and there was a transient rise in progesterone on day 4 in all animals, indicating that bromocriptine resulted in immediate reactivation of the quiescent corpus luteum. New births occurred in two animals on day 28. In group D, which received bromocriptine followed by ovine prolactin for 7 days, all the original pouch young remained alive at the end of the experiment. Four of the animals from this group showed a transient progesterone peak on day 11, with births in two animals on days 35 and 36 indicating that the effects of bromocriptine were prevented whilst ovine prolactin was being administered. In one animal given ovine prolactin alone (group B), there was a transient progesterone peak and birth on days 12 and 35 respectively, suggesting that removal of exogenous prolactin may also act to terminate reproductive quiescence in some animals. In summary, these results support the hypothesis that prolactin suppresses the corpus luteum during lactational quiescence, and that the effects of bromocriptine are due to suppression of endogenous prolactin.
J. Endocr. (1988) 119, 405–411
B. R. Brinklow and A. S. I. Loudon
Two experiments were performed to investigate whether prolactin blocks the reactivation of the corpus luteum during seasonal reproductive quiescence in the Bennett's wallaby. In the first experiment three groups of non-lactating females (groups (A–C) were subjected in mid-April to photoperiods corresponding to those of the summer solstice from day 0 to day 13 of the experiment. Between days 14 and 52, photoperiods were reduced to correspond to those of the winter solstice (groups B and C). Animals in group A were maintained on the long photoperiods. Two milligrams ovine prolactin (groups A and C) or vehicle (group B) were administered on the mornings of days 14–22. In group A, no animal showed evidence of an active corpus luteum based on increased plasma progesterone levels. All animals in groups B and C exhibited reactivation of the corpus luteum. In group C, reactivation was significantly (P < 0·01) delayed by a mean of 6·3 days.
In the second experiment, two groups of non-lactating female wallabies in 'seasonal quiescence' were injected daily for 7 days with either 60 mg of the dopamine agonist bromocriptine or vehicle. The corpora lutea did not reactivate in either group. We conclude that exogenous prolactin is able to block the effect of short photoperiods in reactivating the quiescent corpus luteum during seasonal quiescence. However, the absence of an effect of bromocriptine suggests that if prolactin is the endogenous hormone responsible for maintaining seasonal quiescence it may not be under dopaminergic control at this time of year.
Journal of Endocrinology (1989) 120, 189–193
J. D. Curlewis, A. S. I. Loudon, J. A. Milne, and A. S. McNeilly
Seventeen red deer hinds were housed in individual pens and from 28 February until 11 November were injected each week with vehicle (group A; n = 6) or 5 (group B; n = 6) or 12·5 mg (group C; n = 5) of a long-acting formulation of bromocriptine. Liveweight and voluntary food intake (VFI) were recorded for each hind, and blood was collected for determination of progesterone, prolactin, tri-iodothyronine (T3) and cortisol concentrations by radioimmunoassay. Treatment with the high dose of bromocriptine was associated with a significant (P <0·05) reduction in VFI, with the effect being greatest between March and July. There was no treatment effect on liveweight, but there was a significant (P <0·01) interaction between time and treatment due to the faster rate of weight gain in control animals at the beginning of the experiment. Changes in liveweight could be explained by changes in VFI rather than by changes in the efficiency of utilization of intake. Termination of the breeding season was significantly (P <0·01) delayed by 54 days in group C hinds. Growth of the summer coat and subsequent winter coats was delayed by 1 and 3 months respectively in group C hinds, and in groups B and C the duration that animals were in summer coat was increased by about 1 month. The seasonal increase in prolactin concentrations was seen in all groups, but levels were significantly (P <0·05) lower in group C hinds. Concentrations of T3 and cortisol were not affected by bromocriptine.
J. Endocr. (1988) 119, 413–420
A. S. I. Loudon, J. A. Milne, J. D. Curlewis, and A. S. McNeilly
Non-domesticated seasonally breeding ungulates exhibit marked seasonal changes in metabolic rate, voluntary food intake (VFI), pelage growth and moult and hormone secretion. It is not known whether these seasonal rhythms are regulated by the same central processes which control the onset and termination of the breeding season. Here we compare two closely related deer species which have significantly different mating and calving seasons. Seasonal changes in VFI, liveweight, coat growth, plasma prolactin and tri-iodothyronine (T3), and the timing of the breeding season were examined over a 15-month period in six adult post-pubertal red and Père David's deer from January to April the following year. The timing of the seasonal changes in prolactin, T3, VFI and coat growth were all significantly advanced by 56, 23, 60 and 54 days respectively in the Père David's deer. The times of onset and termination of the breeding season of Père David's deer were also significantly advanced by 90 days, but in both species, the breeding season was of similar duration (160 ± 5 (s.e.m.) days). Changes in liveweight of adult red deer could be explained by changes in VFI rather than efficiency of utilization. This was not the case in Père David's deer and may indicate seasonal changes in the efficiency of energy utilization. In order to establish whether these species differences develop with age, we undertook a second study in which seasonal changes in VFI, growth, plasma prolactin concentrations and the timing of the onset of the breeding season were recorded for ten red deer and six Père David's deer from 6 to 18 months of age. Both species exhibited a similar decline in VFI in the first autumn of life. Subsequently, the Père David's deer exhibited an advance in the timing of the seasonal peak in VFI and prolactin (21 and 66 days respectively); puberty occurred 3 months earlier than in red deer. The earlier breeding season of the Père David's deer was associated with a significant advance in a range of seasonal endocrine and physiological parameters. These species differences may develop with age. Our data indicate that seasonal patterns of metabolism and growth may be closely linked to those mechanisms which also regulate the onset and termination of the breeding season.
Journal of Endocrinology (1989) 122, 733–745
J. D. Curlewis, A. S. White, A. S. I. Loudon, and A. S. McNeilly
Prolactin concentration was measured in plasma collected each week for 13 months from lactating and non-lactating Bennett's wallabies (Macropus rufogriseus rufogriseus). In non-lactating animals, prolactin concentrations decreased towards the end of the study but such changes did not appear to fit a seasonal pattern. Prolactin concentrations were low during early lactation and at a similar level to non-lactating animals, increased significantly during late pouch life (February–May), and then returned to non-lactating levels at a time coincident with permanent exit of the joey from the pouch. Temporary removal of joeys from their mothers in April was followed by a rapid decline in prolactin concentrations which remained low for 24 h until the joey was returned to its mother, whereupon prolactin concentrations increased significantly within 2 h.
The effect of a single injection of bromocriptine (5 mg/kg) on lactation, embryonic diapause and plasma prolactin concentrations was examined at two stages of lactation. In November (lactational diapause), bromocriptine had no effect on prolactin concentrations but two out of four suckling joeys died on days 13 and 14 after treatment, and three out of four females gave birth on days 27, 27 and 28. Bromocriptine treatment in April (seasonal diapause) was followed by a significant reduction in prolactin concentrations and reduced growth rate of joeys belonging to treated females. New births were not observed.
In view of the effect of bromocriptine on plasma prolactin concentrations in late lactation and the demonstration that domperidone (a dopamine antagonist) significantly increases plasma prolactin concentrations, it would seem that dopamine can act as a prolactin inhibitory hormone in this as in other mammalian species.
J. Endocr. (1986) 110, 59–66
L A Clarke, M Edery, A S I Loudon, V A Randall, M-C Postel-Vinay, P A Kelly, and H N Jabbour
The red deer is a seasonally breeding mammal with a circannual cycle of prolactin secretion which reaches its peak during the non-breeding season. This study investigated expression of the prolactin receptor gene in red deer tissues collected in the breeding and non-breeding seasons. A 562 bp fragment of the extracellular domain of the red deer prolactin receptor cDNA was amplified from red deer liver poly(A)+ RNA by reverse transcriptase-polymerase chain reaction (RT-PCR) using primers designed from the human sequence. Northern blots were prepared using 10–20 μg poly(A)+ RNA. The blots were hybridized to the 562 bp cDNA labelled by random priming with α32P-dCTP. A main transcript of 3·5 kb was expressed in liver, heart, kidney and testis throughout the year and in epididymis during the breeding season only. In the testis an additional major transcript of 1·7 kb was present during the breeding and non-breeding seasons. Competitive binding assays using 125I-ovine prolactin (125I-oPRL) were performed on microsomal membrane fractions prepared from liver. Scatchard analyses confirmed the presence of a single class of lactogen-binding receptor with a mean Ka of 0·87 ± 0·12 × 109 m −1 and a Bmax of 73·6 ± 9·8 fmol/mg protein (n=5). Cross-linking of 125I-oPRL to liver microsomes with 0·5 mm disuccinimidyl suberate followed by SDS-PAGE revealed a major band of molecular mass 56 kDa which was displaced by ovine prolactin, suggesting a specific lactogen-binding entity of 33 kDa. This study confirms the expression of the red deer prolactin receptor gene throughout the year, characterizes the prevalent form of receptor in the liver and demonstrates the expression of a separate, short form in the testis.
Journal of Endocrinology (1995) 146, 313–321
J. A. Milne, A. S. I. Loudon, A. M. Sibbald, J. D. Curlewis, and A. S. McNeilly
Three experiments were conducted in the period between July and November with non-lactating red deer hinds to describe the effects of treatment with melatonin during this period on voluntary food intake (VFI), the onset of the breeding season, coat changes and plasma concentrations of prolactin and tri-iodothyronine (T3), and to examine whether prolactin mediated the observed effects.
In experiment 1, eight animals were treated orally each day with either 10 mg melatonin at 16.00 h or 10 mg melatonin at 16.00 h plus 10 mg domperidone (a dopamine antagonist) given twice daily for 120 days from July; eight animals were maintained as controls. In experiment 2, the same numbers of animals per treatment were used to compare treatments in which 10 mg melatonin or 20 mg bromocriptine (a dopamine agonist) were given orally each day at 16.00 h for 119 days from late June and compared with an untreated control group. In experiment 3, six animals were treated daily for 105 days from mid August with 5 mg domperidone given i.m. and compared with six control animals.
In experiments 1 and 2, the VFI of control animals reached a peak in late August and thereafter declined. Melatonin-treated animals showed a similar pattern but the peak in VFI was significantly (P<0·05) advanced by 2 weeks compared with controls, although the VFIs of both groups were similar in November. The mean date of onset of the breeding season of the melatonin-treated animals was advanced significantly (P < 0·05) by 23 days in both experiments and the coats of these animals had less undercoat and were pale coloured and patchy compared with the controls. The changes in VFI, coat and the onset of the breeding season were associated with the rapid decline in plasma prolactin concentration after the start of the melatonin treatment and significantly (P<0·01) lower plasma T3 concentrations than those of control animals.
In experiments 1 and 3, plasma prolactin concentrations in animals treated with domperidone were higher than those of controls for periods of 2–3 weeks. These short-term increases in plasma prolactin concentration were not associated with changes in VFI, coat or onset of the breeding season compared with controls.
In experiment 2, the pattern of decline in plasma prolactin concentrations was the same in bromocriptine-treated animals as in the melatonin-treated animals; plasma T3 concentrations were also similar in the two groups. The pattern of change in VFI over time in bromocriptine-treated animals was significantly (P<0·05) different from that of melatonin-treated animals and there was also a reduced amount and length of winter coat in the bromocriptine-treated animals. The mean date of onset of the breeding season in bromocriptine-treated animals was not significantly different from that of controls. It was concluded that a reduction in plasma prolactin concentration induced by bromocriptine produced different effects from that induced by melatonin treatment and that the effects of melatonin are unlikely to be induced through changes in contemporary plasma prolactin concentrations.
Journal of Endocrinology (1990) 125, 241–249
K Rousseau, Z Atcha, J Denton, F R A Cagampang, A R Ennos, A J Freemont, and A S I Loudon
Recent studies have suggested that the adipocyte-derived hormone, leptin, plays a role in the regulation of metabolism. Here, we tested this hypothesis in the seasonally breeding Siberian hamster, as this species exhibits profound seasonal changes in adiposity and circulating leptin concentrations driven by the annual photoperiodic cycle. Male hamsters were kept in either long (LD) or short (SD) photoperiods. Following exposure to short photoperiods for 8 weeks animals exhibited a significant weight-loss and a 16-fold reduction of serum leptin concentrations. At Week 9, animals in both photoperiods were infused with leptin or PBS via osmotic mini-pump for 14 days. Chronic leptin infusion mimicked LD-like concentrations in SD-housed animals and caused a further decline in body weight and adipose tissue. In LD-housed animals, leptin infusion resulted in a significant elevation of serum concentrations above natural LD-like levels, but had no discernable effect on body weight or overall adiposity. Both bending and compression characteristics and histomorphometric measurements of trabecular bone mass were unaltered by leptin treatment or photoperiod. Our data therefore show that despite a high natural amplitude cycle of leptin, this hormone has no apparent role in the regulation of bone metabolism, and therefore do not support recent propositions that this hormone is an important component in the metabolism of bone tissue.
A McMaster, T Chambers, Q-J Meng, S Grundy, A S I Loudon, R Donn, and D W Ray
There is increasing evidence that temporal factors are important in allowing cells to gain additional information from external factors, such as hormones and cytokines. We sought to discover how cell responses to glucocorticoids develop over time, and how the response kinetics vary according to ligand structure and concentration, and hence have developed a continuous gene transcription measurement system, based on an interleukin-6 (IL-6) luciferase reporter gene. We measured the time to maximal response, maximal response and integrated response, and have compared these results with a conventional, end point glucocorticoid bioassay. We studied natural glucocorticoids (corticosterone and cortisol), synthetic glucocorticoids (dexamethasone) and glucocorticoid precursors with weak, or absent bioactivity. We found a close correlation between half maximal effective concentration (EC50) for maximal response, and for integrated response, but with consistently higher EC50 for the latter. There was no relation between the concentration of ligand and the time to maximal response. A comparison between conventional end point assays and real-time measurement showed similar effects for dexamethasone and hydrocortisone, with a less effective inhibition of IL-6 seen with corticosterone. We profiled the activity of precursor steroids, and found pregnenolone, progesterone, 21-hydroxyprogesterone and 17-hydroxyprogesterone all to be ineffective in the real-time assay, but in contrast, progesterone and 21-hydroxyprogesterone showed an IL-6 inhibitory activity in the end point assay. Taken together, our data show how ligand concentration can alter the amplitude of glucocorticoid response, and also that a comparison between real-time and end point assays reveals an unexpected diversity of the function of glucocorticoid precursor steroids, with implications for human disorders associated with their overproduction.