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David G Hazlerigg

Publications and source records attributed to David G Hazlerigg.

9 recordsLinked to original sources
PubMed2006

Characterizing a mammalian circannual pacemaker.

Many species express endogenous cycles in physiology and behavior that allow anticipation of the seasons. The anatomical and cellular bases of these circannual rhythms have not been defined. Here, we provide strong evidence using an in vivo Soay sheep model that the circannual regulation of prolactin secretion, and its associated biology, derive from a pituitary-based timing mechanism. Circannual rhythm generation is seen as the product of the interaction between melatonin-regulated timer cells and adjacent prolactin-secreting cells, which together function as an intrapituitary "pacemaker-slave" timer system. These new insights open the way for a molecular analysis of long-term timing mechanisms.

Animals↗
PubMed2006

Ontogenic loss of brown adipose tissue sensitivity to beta-adrenergic stimulation in the ovine.

In ruminants and other large animals, expression of uncoupling protein-1 (UCP1) in brown adipose tissue (BAT) is confined to the perinatal period when it plays a key role in nonshivering thermogenesis. This study determined whether loss of expression of the BAT phenotype was due to reduced response to a beta-agonist, isoprenaline, and expression of the peroxisome proliferator-activated receptor (PPAR) family [PPARalpha, PPARgamma, PPAR coactivator 1alpha (PGC-1alpha)], which regulates UCP1 gene expression. Perirenal adipose tissue (PAT) was sampled from ovine fetuses, newborn lambs, and lambs on d 1, 5, 7, and 21 of life. UCP1 mRNA and protein in PAT increased from d 123 of fetal life to reach a maximum at birth followed by a rapid decrease over the first 5 d of life. Expression of the coactivator, PGC-1alpha and PPAR alpha, peaked between fetal day 123 and birth, and then declined to undetectable levels in the first days of life. In vivo administration of isoprenaline was able to induce expression of UCP1, PGC-1alpha, and PPARalpha in BAT up to 5 d of age but thereafter was ineffective. In vitro addition of beta-receptor, PPARalpha, and PPARgamma agonists were unable to overcome the suppression of UCP1, PPARalpha, and PPARgamma expression observed in differentiated adipocytes prepared from 30-d-old compared with 1-d-old lambs. These data are consistent with a model in which postnatal loss of UCP1 expression and beta-adrenergic induction of the brown adipocyte phenotype is due to loss of expression of PGC-1alpha and PPARalpha.

Adipocytes↗
PubMed2006

Seasonal photoperiodism in vertebrates: from coincidence to amplitude.

In vertebrates living in regions that range from tropical to polar zones, the day length (photoperiod) is a powerful synchronizer of seasonal changes in endocrine and metabolic physiology. This seasonal photoperiodism depends on the responses of internal circadian clocks to changing patterns of light-dark exposure, which can be conceptualized in the form of "coincidence-timing" models. The structural basis for this timing function is formed by a specialized "photoperiodic axis" that links light reception to the neuroendocrine system. In this review we describe the essential elements of this axis in mammals and birds, and discuss recent progress in understanding the cellular and molecular mechanisms through which this axis transduces photoperiodic change into altered endocrine output.

Animals↗
PubMed2005

Multiple effects of melatonin on rhythmic clock gene expression in the mammalian pars tuberalis.

In mammals, changing day length modulates endocrine rhythms via nocturnal melatonin secretion. Studies of the pituitary pars tuberalis (PT) suggest that melatonin-regulated clock gene expression is critical to this process. Here, we considered whether clock gene rhythms continue in the PT in the absence of melatonin and whether the effects of melatonin on the expression of these genes are temporally gated. Soay sheep acclimated to long photoperiod (LP) were transferred to constant light for 24 h, suppressing endogenous melatonin secretion. Animals were infused with melatonin at 4-h intervals across the final 24 h, and killed 3 h after infusion. The expression of five clock genes (Per1, Per2, Cry1, Rev-erbalpha, and Bmal1) was measured by in situ hybridization. In sham-treated animals, PT expression of Per1, Per2, and Rev-erbalpha showed pronounced temporal variation despite the absence of melatonin, with peak times occurring earlier than predicted under LP. The time of peak Bmal1 expression remained LP-like, whereas Cry1 expression was continually low. Melatonin infusion induced Cry1 expression at all times and suppressed other genes, but only when they showed high expression in sham-treated animals. Hence, 3 h after melatonin treatment, clock gene profiles were driven to a similar state, irrespective of infusion time. In contrast to the PT, melatonin infusions had no clear effect on clock gene expression in the suprachiasmatic nuclei. Our results provide the first example of acute sensitivity of multiple clock genes to one endocrine stimulus and suggest that rising melatonin levels may reset circadian rhythms in the PT, independently of previous phase.

Analysis of Variance↗
PubMed2005

Photorefractoriness in mammals: dissociating a seasonal timer from the circadian-based photoperiod response.

In seasonal animals, prolonged exposure to constant photoperiod induces photorefractoriness, causing spontaneous reversion in physiology to that of the previous photoperiodic state. This study tested the hypothesis that the onset of photorefractoriness is correlated with a change in circadian expression of clock genes in the suprachiasmatic nucleus (circadian pacemaker) and the pars tuberalis (PT, a melatonin target tissue). Soay sheep were exposed to summer photoperiod (16-h light) for either 6 or 30 wk to produce a photostimulated and photorefractory physiology, and seasonal changes were tracked by measuring the long-term prolactin cycles. Animals were killed at 4-h intervals throughout 24 h. Contrary to the hypothesis, the 24-h rhythmic expression of clock genes (Rev-erbalpha, Per1, Per2, Bmal1, Cry1) in the suprachiasmatic nucleus and PT reflected the ambient photoperiod/melatonin signal and not the changing physiology. Contrastingly, the PT expression of alpha-glycoprotein hormone subunit (alphaGSU) and betaTSH declined in photorefractory animals toward a short day-like endocrinology. We conclude that the generation of long-term endocrine cycles depends on the interaction between a circadian-based, melatonin-dependent timer that drives the initial photoperiodic response and a non-circadian-based timer that drives circannual rhythmicity in long-lived species. Under constant photoperiod the two timers can dissociate, leading to the apparent refractory state.

ARNTL Transcription Factors↗
PubMed2005

Photoperiod regulates multiple gene expression in the suprachiasmatic nuclei and pars tuberalis of the Siberian hamster (Phodopus sungorus).

Photoperiod regulates the seasonal physiology of many mammals living in temperate latitudes. Photoperiodic information is decoded by the master circadian clock in the suprachiasmatic nuclei (SCN) of the hypothalamus and then transduced via pineal melatonin secretion. This neurochemical signal is interpreted by tissues expressing melatonin receptors (e.g. the pituitary pars tuberalis, PT) to drive physiological changes. In this study we analysed the photoperiodic regulation of the circadian clockwork in the SCN and PT of the Siberian hamster. Female hamsters were exposed to either long or short photoperiod for 8 weeks and sampled at 2-h intervals across the 24-h cycle. In the SCN, rhythmic expression of the clock genes Per1, Per2, Cry1, Rev-erbalpha, and the clock-controlled genes arginine vasopressin (AVP) and d-element binding protein (DBP) was modulated by photoperiod. All of these E-box-containing genes tracked dawn, with earlier peak mRNA expression in long, compared to short, photoperiod. This response occurred irrespective of the presence of additional regulatory cis-elements, suggesting photoperiodic regulation of SCN gene expression through a common E-box-related mechanism. In long photoperiod, expression of Cry1 and Per1 in the PT tracked the onset and offset of melatonin secretion, respectively. However, whereas Cry1 tracked melatonin onset in short period, Per1 expression was not detectably rhythmic. We therefore propose that, in the SCN, photoperiodic regulation of clock gene expression primarily occurs via E-boxes, whereas melatonin-driven signal transduction drives the phasing of a subset of clock genes in the PT, independently of the E-box.

Animals↗
PubMed2004

Molecular characterization of the long-day response in the Soay sheep, a seasonal mammal.

In mammals, seasonal timekeeping depends on the generation of a nocturnal melatonin signal that reflects nightlength/daylength. To understand the mechanisms by which the melatonin signal is decoded, we studied the photoperiodic control of prolactin secretion in Soay sheep, which is mediated via melatonin responsive cells in the pars tuberalis of the pituitary. We demonstrate that the phases of peak expression of the clock genes Cryptochrome1 (Cry1), Period1 (Per1), and RevErbalpha respond acutely to altered melatonin secretion after a switch from short to long days. Cry1 is activated by melatonin onset, forming the dusk component of the molecular decoder, while Per1 expression at dawn reflects the offset of melatonin secretion. The Cry1-Per1 interval immediately adjusts to the melatonin signal on the first long day, and this is followed within 24 hr by an increase in prolactin secretion. The timing of peak RevErbalpha expression also responds to a switch to long days due to altered melatonin secretion but does not immediately reset to an entrained long-day state. These data suggest that effects of melatonin on clock gene expression are pivotal events in the neuroendocrine response and that pars tuberalis cells can act as molecular calendars, carrying a form of "photoperiodic memory."

Animals↗
PubMed2003

Gonadotrophin-releasing hormone drives melatonin receptor down-regulation in the developing pituitary gland.

Melatonin is produced nocturnally by the pineal gland and is a neurochemical representation of time. It regulates neuroendocrine target tissues through G-protein-coupled receptors, of which MT(1) is the predominant subtype. These receptors are transiently expressed in several fetal and neonatal tissues, suggesting distinct roles for melatonin in development and that specific developmental cues define time windows for melatonin sensitivity. We have investigated MT(1) gene expression in the rat pituitary gland. MT(1) mRNA is confined to the pars tuberalis region of the adult pituitary, but in neonates extends into the ventral pars distalis and colocalizes with luteinizing hormone beta-subunit (LH beta) expression. This accounts for the well documented transient sensitivity of rat gonadotrophs to melatonin in the neonatal period. Analysis of an upstream fragment of the rat MT(1) gene revealed multiple putative response elements for the transcription factor pituitary homeobox-1 (Pitx-1), which is expressed in the anterior pituitary from Rathke's pouch formation. A Pitx-1 expression vector potently stimulated expression of both MT(1)-luciferase and LH beta-luciferase reporter constructs in COS-7 cells. Interestingly, transcription factors that synergize with Pitx-1 to trans-activate gonadotroph-associated genes did not potentiate Pitx-1-induced MT(1)-luciferase activity. Moreover, the transcription factor, early growth response factor-1, which is induced by gonadotrophin-releasing hormone (GnRH) and trans-activates LH beta expression, attenuated Pitx-1-induced MT(1)-luciferase activity. Finally, pituitary MT(1) gene expression was 4-fold higher in hypogonadal (hpg) mice, which do not synthesize GnRH, than in their wild-type littermates. These data suggest that establishment of a mature hypothalamic GnRH input drives the postnatal decline in pituitary MT(1) gene expression.

Animals↗