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Francis J P Ebling - One of the best experts on this subject based on the ideXlab platform.
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VGF-peptides in the Siberian Hamster
Italian journal of anatomy and embryology, 2020Co-Authors: Barbara Noli, Francis J P Ebling, Cristina Cocco, Preeti H. Jethwa, Filomena D'amato, Gian-luca FerriAbstract:vgf is one of the few genes selectively induced in the hypothalamus of Siberian Hamsters upon their typical change from an obese phenotype (long day adaptation, during summer) to a lean, catabolic phenotype (short day, or winter adaptation). In fact, the i.c.v. injection of the VGF-derived peptide TLQP-21 caused hypophagia and a decrease in body weight in long day Hamster. Hence, we studied VGF multi-peptide profiles in brain cortex and hypothalamus of (male) Siberian Hamsters, in the long day (LD) versus short day (SD) adapted state. Specific antisera were produced against short sequences at the C- or N-termini of VGF, and of several known/predicted VGF-derived products: TLQP, NERP-1, and PGH peptides, and used in immunohistochemistry (IHC) and ELISA. Hamsters were perfused with 4% paraformaldehyde (n= 4/group) for IHC or used for tissue sampling and extraction (n= 7/group). In IHC, VGF C- and N- terminus peptides were brightly labelled, as well as most abundant. They were found in both perikarya and axons, in different layers of brain cortex and in multiple hypothalamic areas, including the paraventricular (PVN), suprachiasmatic (SCN), supraoptic (SON) and arcuate nuclei, the lateral and anterior hypothalamic areas, and the median eminence (ME). TLQP peptides were largely restricted to SCN perikarya, and ME axons, while PGH and NERP-1 peptides were revealed in perikarya of the brain cortex, in ME axons, and certain perikarya of PVN and SON (NERP-1 only). Most VGF peptides studied were well represented in tissue extracts of hypothalamus and cortex, VGF C- and N- terminus peptides being again most abundant (hypothalamus: 1.8±0.3 and 10.9±0.6; cortex: 0.7±0.1 and 5±0.3 nmol/g, mean±SEM, C- and N-terminus, respectively, LD animals). A selective decrease in certain VGF peptides was revealed in SD animals, compared to LD ones, so that NERP-1 peptides were decreased in hypothalamus and cortex (61.3±12.7% and 45.8±11.1% of LD animals, respectively, mean±SEM, p
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genome sequencing and transcriptome analyses of the Siberian Hamster hypothalamus identify mechanisms for seasonal energy balance
Proceedings of the National Academy of Sciences of the United States of America, 2019Co-Authors: Kenneth G Onishi, Brian J Prendergast, Francis J P Ebling, Perry Barrett, Elisabetta Tolla, Jo E Lewis, Richard L Anderson, Tyler J StevensonAbstract:Synthesis of triiodothyronine (T3) in the hypothalamus induces marked seasonal neuromorphology changes across taxa. How species-specific responses to T3 signaling in the CNS drive annual changes in body weight and energy balance remains uncharacterized. These experiments sequenced and annotated the Siberian Hamster (Phodopus sungorus) genome, a model organism for seasonal physiology research, to facilitate the dissection of T3-dependent molecular mechanisms that govern predictable, robust, and long-term changes in body weight. Examination of the Phodopus genome, in combination with transcriptome sequencing of the Hamster diencephalon under winter and summer conditions, and in vivo-targeted expression analyses confirmed that proopiomelanocortin (pomc) is a primary genomic target for the long-term T3-dependent regulation of body weight. Further in silico analyses of pomc promoter sequences revealed that thyroid hormone receptor 1β-binding motif insertions have evolved in several genera of the Cricetidae family of rodents. Finally, experimental manipulation of food availability confirmed that hypothalamic pomc mRNA expression is dependent on longer-term photoperiod cues and is unresponsive to acute, short-term food availability. These observations suggest that species-specific responses to hypothalamic T3, driven in part by the receptor-binding motif insertions in some cricetid genomes, contribute critically to the long-term regulation of energy balance and the underlying physiological and behavioral adaptations associated with the seasonal organization of behavior.
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reduced adiposity attenuates fgf21 mediated metabolic improvements in the Siberian Hamster
Scientific Reports, 2017Co-Authors: Jo E Lewis, Ricardo J Samms, Scott Cooper, Andrew C Adams, Kostas Tsintzas, Jeni Luckett, A C Perkins, Francis J P EblingAbstract:FGF21 exerts profound metabolic effects in Siberian Hamsters exposed to long day (LD) photoperiods that increase appetite and adiposity, however these effects are attenuated in short day (SD) animals that display hypophagia and reduced adiposity. The aim of this study was to investigate whether the beneficial effects of a novel mimetic of FGF21 in the LD state are a consequence of increased adiposity or of the central photoperiodic state. This was achieved by investigating effects of FGF21 in aged Hamsters, which is associated with reduced adiposity. In LD Hamsters with increased adiposity, FGF21 lowered body weight as a result of both reduced daily food intake and increased caloric expenditure, driven by an increase in whole-body fat oxidation. However, in LD animals with reduced adiposity, the effect of FGF21 on body weight, caloric intake and fat oxidation were significantly attenuated or absent when compared to those with increased adiposity. These attenuated/absent effects were underpinned by the inability of FGF21 to increase the expression of key thermogenic genes in interscapular and visceral WAT. Our study demonstrates the efficacy of a novel FGF21 mimetic in Hamsters, but reveals attenuated effects in the animal model where adiposity is reduced naturally independent of photoperiod.
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photoperiodic regulation of fgf21 production in the Siberian Hamster
Hormones and Behavior, 2014Co-Authors: Ricardo J Samms, Maxine J Fowler, Scott Cooper, Paul J Emmerson, Tamer Coskun, Andrew C Adams, Alexei Kharitonenkov, Kostas Tsintzas, Francis J P EblingAbstract:Abstract This article is part of a Special Issue "Energy Balance". FGF21 is an endocrine member of the fibroblast growth factor superfamily that has been shown to play an important role in the physiological response to nutrient deprivation. Food restriction enhances hepatic FGF21 production, which serves to engage an integrated response to energy deficit. Specifically, elevated FGF21 levels lead to reduced gluconeogenesis and increased hepatic ketogenesis. However, circulating FGF21 concentrations also paradoxically rise in states of metabolic dysfunction such as obesity. Furthermore, multiple peripheral tissues also produce FGF21 in addition to the liver, raising questions as to its endocrine and paracrine roles in the control of energy metabolism. The objectives of this study were to measure plasma FGF21 concentrations in the Siberian Hamster, a rodent which undergoes a seasonal cycle of fattening and body weight gain in the long days (LD) of summer, followed by reduction of appetite and fat catabolism in the short days (SD) of winter. Groups of adult male Hamsters were raised in long days, and then exposed to SD for up to 12 weeks. Chronic exposure of LD animals to SD led to a significant increase in circulating FGF21 concentrations. This elevation of circulating FGF21 was preceded by an increase in liver FGF21 protein production evident as early as 4 weeks of exposure to SD. FGF21 protein abundance was also increased significantly in interscapular brown adipose tissue, with a positive correlation between plasma levels of FGF21 and BAT protein abundance throughout the experimental period. Epididymal white adipose tissue and skeletal muscle (gastrocnemius) also produced FGF21, but levels did not change in response to a change in photoperiod. In summary, a natural programmed state of fat catabolism was associated with increased FGF21 production in the liver and BAT, consistent with the view that FGF21 has a role in adapting Hamsters to the hypophagic winter state.
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conserved expression of the glutamate nmda receptor 1 subunit splice variants during the development of the Siberian Hamster suprachiasmatic nucleus
PLOS ONE, 2012Co-Authors: Giles E Duffield, Jens D Mikkelsen, Francis J P EblingAbstract:Glutamate neurotransmission and the N-methyl-D-aspartate receptor (NMDAR) are central to photic signaling to the master circadian pacemaker located in the hypothalamic suprachiasmatic nucleus (SCN). NMDARs also play important roles in brain development including visual input circuits. The functional NMDAR is comprised of multiple subunits, but each requiring the NR1 subunit for normal activity. The NR1 can be alternatively spliced to produce isoforms that confer different functional properties on the NMDAR. The SCN undergoes extensive developmental changes during postnatal life, including synaptogenesis and acquisition of photic signaling. These changes are especially important in the highly photoperiodic Siberian Hamster, in which development of sensitivity to photic cues within the SCN could impact early physiological programming. In this study we examined the expression of NR1 isoforms in the Hamster at different developmental ages. Gene expression in the forebrain was quantified by in situ hybridization using oligonucleotide probes specific to alternatively spliced regions of the NR1 heteronuclear mRNA, including examination of anterior hypothalamus, piriform cortex, caudate-putamen, thalamus and hippocampus. Gene expression analysis within the SCN revealed the absence of the N1 cassette, the presence of the C2 cassette alone and the combined absence of C1 and C2 cassettes, indicating that the dominant splice variants are NR1-2a and NR1-4a. Whilst we observe changes at different developmental ages in levels of NR1 isoform probe hybridization in various forebrain structures, we find no significant changes within the SCN. This suggests that a switch in NR1 isoform does not underlie or is not produced by developmental changes within the Hamster SCN. Consistency of the NR1 isoforms would ensure that the response of the SCN cells to photic signals remains stable throughout life, an important aspect of the function of the SCN as a responder to environmental changes in quality/quantity of light over the circadian day and annual cycle.
Perry Barrett - One of the best experts on this subject based on the ideXlab platform.
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ovarian hormones induce de novo dna methyltransferase expression in the Siberian Hamster suprachiasmatic nucleus
Journal of Neuroendocrinology, 2020Co-Authors: Chris S Coyle, Perry Barrett, Federico Caso, Elisabetta Tolla, Kenneth G Onishi, Javier A Tello, Tyler J StevensonAbstract:The present study investigated neuroanatomically localised changes in de novo DNA methyltransferase expression in the female Siberian Hamster (Phodopus sungorus). The objectives were to identify the neuroendocrine substrates that exhibit rhythmic Dnmt3a and Dnmt3b expression across the oestrous cycle and also examine the role of ovarian steroids. Hypothalamic Dnmt3a expression was observed to significantly increase during the transition from pro-oestrous to oestrous. A single bolus injection of diethylstilbestrol and progesterone was sufficient to increase Dnmt3a cell numbers and Dnmt3b immunoreactive intensity in the suprachiasmatic nucleus. In vitro analyses using an embryonic rodent cell line revealed that diethylstilbestrol was sufficient to induce Dnmt3b expression. Up-regulating DNA methylation in vitro reduced the expression of vasoactive intestinal polypeptide, Vip, and the circadian clock gene, Bmal1. Together, these data indicate that ovarian steroids drive de novo DNA methyltransferase expression in the mammalian suprachiasmatic nucleus and increased methylation may regulate genes involved in the circadian timing of oestrous: Vip and Bmal1. Overall, epigenetically mediated neuroendocrine reproductive events may reflect an evolutionarily ancient process involved in the timing of female fertility.
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genome sequencing and transcriptome analyses of the Siberian Hamster hypothalamus identify mechanisms for seasonal energy balance
Proceedings of the National Academy of Sciences of the United States of America, 2019Co-Authors: Kenneth G Onishi, Brian J Prendergast, Francis J P Ebling, Perry Barrett, Elisabetta Tolla, Jo E Lewis, Richard L Anderson, Tyler J StevensonAbstract:Synthesis of triiodothyronine (T3) in the hypothalamus induces marked seasonal neuromorphology changes across taxa. How species-specific responses to T3 signaling in the CNS drive annual changes in body weight and energy balance remains uncharacterized. These experiments sequenced and annotated the Siberian Hamster (Phodopus sungorus) genome, a model organism for seasonal physiology research, to facilitate the dissection of T3-dependent molecular mechanisms that govern predictable, robust, and long-term changes in body weight. Examination of the Phodopus genome, in combination with transcriptome sequencing of the Hamster diencephalon under winter and summer conditions, and in vivo-targeted expression analyses confirmed that proopiomelanocortin (pomc) is a primary genomic target for the long-term T3-dependent regulation of body weight. Further in silico analyses of pomc promoter sequences revealed that thyroid hormone receptor 1β-binding motif insertions have evolved in several genera of the Cricetidae family of rodents. Finally, experimental manipulation of food availability confirmed that hypothalamic pomc mRNA expression is dependent on longer-term photoperiod cues and is unresponsive to acute, short-term food availability. These observations suggest that species-specific responses to hypothalamic T3, driven in part by the receptor-binding motif insertions in some cricetid genomes, contribute critically to the long-term regulation of energy balance and the underlying physiological and behavioral adaptations associated with the seasonal organization of behavior.
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somatostatin agonist pasireotide inhibits exercise stimulated growth in the male Siberian Hamster phodopus sungorus
Journal of Neuroendocrinology, 2017Co-Authors: Rebecca Dumbell, Stephan Steinlechner, Frank Scherbarth, Victoria Diedrich, Herbert A Schmid, Ines Petri, Perry BarrettAbstract:R.Dumbell was supported by a University of Aberdeen PhD studentship and a research visit grant awarded by the British Society of Neuroendocrinology. Further support was provided by the Scottish Government Rural and Environment Science and Analytical Services Division (Barrett and the German Research Foundation (DFG; STE 331/8-1; Steinlechner lab). We are grateful for technical assistance from Dana Wilson at RINH and Siegried Hiliken at UVMH, and thank Dr Claus-Dieter Mayer of Biomathematics & Statistics Scotland for valuable advice on statistical analysis.
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somatostatin agonist pasireotide promotes a physiological state resembling short day acclimation in the photoperiodic male Siberian Hamster phodopus sungorus
Journal of Neuroendocrinology, 2015Co-Authors: Rebecca Dumbell, Stephan Steinlechner, Frank Scherbarth, Victoria Diedrich, Herbert A Schmid, Perry BarrettAbstract:: The timing of growth in seasonal mammals is inextricably linked to food availability. This is exemplified in the Siberian Hamster (Phodopus sungorus), which uses the annual cycle of photoperiod to optimally programme energy expenditure in anticipation of seasonal fluctuations in food resources. During the autumn, energy expenditure is progressively minimised by physiological adaptations, including a 30% reduction in body mass, comprising a reduction in both fat and lean tissues. However, the mechanistic basis of this adaptation is still unexplained. We hypothesised that growth hormone (GH) was a likely candidate to underpin these reversible changes in body mass. Administration of pasireotide, a long-acting somatostatin receptor agonist developed for the treatment of acromegaly, to male Hamsters under a long-day (LD) photoperiod produced a body weight loss. This comprised a reduction in lean and fat mass, including kidneys, testes and brown adipose tissue, typically found in short-day (SD) housed Hamsters. Furthermore, when administered to Hamsters switched from SD to LD, pasireotide retarded the body weight increase compared to vehicle-treated Hamsters. Pasireotide did not alter photoperiod-mediated changes in hypothalamic energy balance gene expression but altered the expression of Srif mRNA expression in the periventricular nucleus and Ghrh mRNA expression in the arcuate nucleus consistent with a reduction in GH feedback and concurrent with reduced serum insulin-like growth factor-1. Conversely, GH treatment of SD Hamsters increased body mass, which included increased mass of liver and kidneys. Together, these data indicate a role for the GH axis in the determination of seasonal body mass of the Siberian Hamster.
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photoperiod dependent regulation of carboxypeptidase e affects the selective processing of neuropeptides in the seasonal Siberian Hamster phodopus sungorus
Journal of Neuroendocrinology, 2013Co-Authors: Michael Helwig, Annika Herwig, Julian G Mercer, Gerhard Heldmaier, Perry Barrett, Martin KlingensporAbstract:: The production of bioactive peptides from biologically inactive precursors involves extensive post-translational processing, including enzymatic cleavage by proteolytic peptidases. Endoproteolytic prohormone-convertases initially cleave the precursors of many neuropeptides at specific amino acid sequences to generate intermediates with basic amino acid extensions on their C-termini. Subsequently, the related exopeptidases, carboxypeptidases D and E (CPD and CPE), are responsible for removing these amino acids before the peptides achieve biological activity. We investigated the effect of photoperiod on the processing of the neuropeptide precursor pro-opiomelanocortin (POMC) and its derived neuropeptides, α-melanocyte-stimulating hormone (MSH) and β-endorphin (END), within the hypothalamus of the seasonal Siberian Hamster (Phodopus sungorus). We thus compared hypothalamic distribution of CPD, CPE, α-MSH and β-END using immunohistochemistry and measured the enzyme activity of CPE and concentrations of C-terminally cleaved α-MSH in short-day (SD; 8 : 16 h light/dark) and long-day (LD; 16 : 8 h light/dark) acclimatised Hamsters. Increased immunoreactivity (-IR) of CPE, as well as higher CPE activity, was observed in SD. This increase was accompanied by more β-END-IR cells and substantially higher levels of C- terminally cleaved α-MSH, as determined by radioimmunoassay. Our results suggest that exoproteolytic cleavage of POMC-derived neuropeptides is tightly regulated by photoperiod in the Siberian Hamster. Higher levels of biological active α-MSH- and β-END in SD are consistent with the hypothesis that post-translational processing is a key event in the regulation of seasonal energy balance.
Peter J Morgan - One of the best experts on this subject based on the ideXlab platform.
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photoperiodic regulation of glycogen metabolism glycolysis and glutamine synthesis in tanycytes of the Siberian Hamster suggests novel roles of tanycytes in hypothalamic function
Glia, 2011Co-Authors: Annika Herwig, Peter J Morgan, Francis J P Ebling, Kanishka N Nilaweera, Matei Bolborea, Gill Campbell, Claus Mayer, Perry BarrettAbstract:The objective of this study is to investigate the impact of photoperiod on the temporal and spatial expression of genes involved in glucose metabolism in the brain of the seasonal mammal Phodopus sungorus (Siberian Hamster). In situ hybridization was performed on brain sections obtained from male Hamsters held in long photoperiod (high body weight and developed testes) or short photoperiod (reduced body weight with testicular regression). This analysis revealed upregulation in expression of genes involved in glycogen and glucose metabolism in short photoperiod and localized to the tanycyte layer of the third ventricle. On the basis of these data and a previously identified photoperiod-dependent increase in activity of neighboring hypothalamic neurons, we hypothesized that the observed expression changes may reflect alteration in either metabolic fuel or precursor neurotransmitter supply to surrounding neurons. Gene expression analysis was performed for genes involved in lactate and glutamate transport. This analysis showed that the gene for the lactate transporter MCT2 and glutamate transporter GLAST was decreased in the tanycyte layer in short photoperiod. Expression of mRNA for glutamine synthetase, the final enzyme in the synthesis of the neuronal neurotransmitter precursor, glutamine, was also decreased in short photoperiod. These data suggest a role for tanycytes in modulating glutamate concentrations and neurotransmitter supply in the hypothalamic environment.
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short photoperiod induced decrease of histamine h3 receptors facilitates activation of hypothalamic neurons in the Siberian Hamster
Endocrinology, 2009Co-Authors: Perry Barrett, Peter J Morgan, Julian G Mercer, Timothy J Bartness, David Wilson, C K Song, David SpanswickAbstract:Nonhibernating seasonal mammals have adapted to temporal changes in food availability through behavioral and physiological mechanisms to store food and energy during times of predictable plenty and conserve energy during predicted shortage. Little is known, however, of the hypothalamic neuronal events that lead to a change in behavior or physiology. Here we show for the first time that a shift from long summer-like to short inter-like photoperiod, which induces physiological adaptation to winter in the Siberian Hamster, including a body weight decrease of up to 30%, increases neuronal activity in the dorsomedial region of the arcuate nucleus (dmpARC) assessed by electro physiological patch-clamping recording. Increased neuronal activity in short days is dependent on a photoperiod-driven down-regulation of H3 receptor expression and can be mimicked in long-day dmpARC neurons by the application of the H3 receptor antagonist, clobenproprit. Short-day activation of dmpARC neurons results in increased c-Fos expression. Tract tracing with the trans-synaptic retrograde tracer, pseudorabies virus, delivered into adipose tissue reveals a multisynaptic neuronal sympathetic outflow from dmpARC to white adipose tissue. These data strongly suggest that increased activity of dmpARC neurons, as a consequence of down-regulation of the histamine H3 receptor, contributes to the physiological adaptation of body weight regulation in seasonal photoperiod.
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photoperiod and acute energy deficits interact on components of the thyroid hormone system in hypothalamic tanycytes of the Siberian Hamster
American Journal of Physiology-regulatory Integrative and Comparative Physiology, 2009Co-Authors: Annika Herwig, Tracy Logie, Peter J Morgan, Dana Wilson, Anita Boelen, Julian F B Mercer, Perry BarrettAbstract:In the Siberian Hamster, seasonal weight loss occurs gradually over many weeks during autumn and winter. This is driven by a regulatory mechanism that is able to integrate duration of exposure to short days (SDs) with the size of body energy reserves. After food restriction in SDs, followed by ad libitum refeeding, body weight of the Hamster does not return to its former level; rather, it increases to a level defined by the length of time spent in SDs. In this report, we show that components of the thyroid hormone system that are involved in seasonal weight loss change expression in response to 48 h of starvation. Eight weeks in an SD photoperiod induced weight loss in the Siberian Hamster. In the hypothalamus of these Hamsters, type II deiodinase expression was decreased and type III deiodinase expression was induced, but there was no change in hypothalamic neuropeptide Y or thyrotropin-releasing hormone gene expression. For the first time, we show that the thyroid hormone transporter monocarboxylate transporter 8 is expressed in tanycytes and is increased in response to an SD photoperiod. Food restriction (48 h of starvation) reversed the direction of gene expression change for type II and III deiodinase and monocarboxylate transporter 8 induced by SD photoperiods. Furthermore, fasting increased neuropeptide Y expression and decreased thyrotropin-releasing hormone expression. VGF, a gene upregulated in SDs in the dorsal region of the medial posterior area of the arcuate nucleus, was not changed by starvation. These data point to a mechanism whereby energy deprivation can interact with an SD photoperiod on hypothalamic tanycytes to regulate components of the thyroid hormone system involved in photoperiodic regulation of seasonal physiology.
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photoperiod regulates genes encoding melanocortin 3 and serotonin receptors and secretogranins in the dorsomedial posterior arcuate of the Siberian Hamster
Journal of Neuroendocrinology, 2009Co-Authors: Alexander W Ross, Julian G Mercer, Francis J P Ebling, Zoë A. Archer, Kanishka N Nilaweera, Gillian Patricia Campbell, Clausdieter Mayer, A Balik, Peter J MorganAbstract:: The mechanism(s) involved in the regulation of the seasonal-appropriate body weight of the Siberian Hamster are currently unknown. We have identified photoperiodically regulated genes including VGF in a sub-region of the arcuate nucleus termed the dorsomedial posterior arcuate (dmpARC). Gene expression changes in this nucleus so far account for a significant number of those reported as photoperiodically regulated and are therefore likely to contribute to seasonal physiological responses of the Hamsters. The present study aimed to identify additional genes expressed in the dmpARC regulated by photoperiod that could be involved in regulating the activity of this nucleus with respect to seasonal physiology of the Siberian Hamster. Using laser capture microdissection coupled with a microarray analysis and a candidate gene approach, we have identified several photoperiodically regulated genes in the dmpARC that are known to have roles in secretory and intracellular signalling pathways. These include secretogranin (sg) III and SgVI (secretory pathway), melanocortin 3 receptor (MC3-R) and serotonin (5-HT) receptors 2A and 7 (signalling pathway), all of which increase in expression under a short photoperiod. The spatial relationship between receptor signalling and potential secretory pathways was investigated by dual in situ hybridisation, which revealed that 5-HT2A and 5-HT7 receptors are expressed in neurones expressing VGF mRNA and that a sub-population (approximately 40%) of these neurones express MC3-R. These gene expression changes in dmpARC neurones may reflect the functional requirement of these neurones for seasonal physiological responses of the Hamster.
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the thyrotropin releasing hormone secretory system in the hypothalamus of the Siberian Hamster in long and short photoperiods
Journal of Neuroendocrinology, 2008Co-Authors: Francis J P Ebling, Peter J Morgan, Julian G Mercer, Dana Wilson, J Wood, D Hughes, Perry BarrettAbstract:Thyrotropin-releasing hormone (TRH) is not only essential for the regulation of the pituitary-thyroid axis, but also exerts complementary effects on energy metabolism within the brain. We hypothesised that increased activity of the TRH secretory system may contribute to seasonal adaptations in the Siberian Hamster whereby food intake is decreased in winter, and catabolism of fat stores is increased to support thermogenesis. We determined the distribution of TRH producing neurones and TRH-R1 receptor expressing cells in the hypothalamus, and investigated whether photoperiod regulated this system. TRH-immunoreactive (ir) cell somata and preproTRH mRNA expression were found to be widely distributed throughout the medial hypothalamus, with particular clusters in the paraventricular nucleus, the medial preoptic area and periventricular nucleus, and in the dorsomedial hypothalamus extending into the lateral hypothalamic area. A partial sequence encoding TRH-R1 was cloned from Hamster hypothalamic cDNA and used to generate a riboprobe for in situ hybridisation studies. TRH-R1 mRNA expressing cells were abundant throughout the hypothalamus, corresponding to the widespread presence of TRH-ir fibres. Photoperiod did not affect the expression of preproTRH mRNA in any region, and the only significant change in TRH-R1 expression was in the dorsomedial posterior arcuate region. This wide distribution of TRH-producing and receptive cells in the hypothalamus is consistent with its hypothesised neuromodulatory roles in the short-term homeostatic control of appetite, thermoregulation and energy expenditure, but the lack of photoperiodic change in TRH mRNA expression does not support the hypothesis that changes in this system underlie long-term seasonal changes in body weight.
Julian G Mercer - One of the best experts on this subject based on the ideXlab platform.
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photoperiod dependent regulation of carboxypeptidase e affects the selective processing of neuropeptides in the seasonal Siberian Hamster phodopus sungorus
Journal of Neuroendocrinology, 2013Co-Authors: Michael Helwig, Annika Herwig, Julian G Mercer, Gerhard Heldmaier, Perry Barrett, Martin KlingensporAbstract:: The production of bioactive peptides from biologically inactive precursors involves extensive post-translational processing, including enzymatic cleavage by proteolytic peptidases. Endoproteolytic prohormone-convertases initially cleave the precursors of many neuropeptides at specific amino acid sequences to generate intermediates with basic amino acid extensions on their C-termini. Subsequently, the related exopeptidases, carboxypeptidases D and E (CPD and CPE), are responsible for removing these amino acids before the peptides achieve biological activity. We investigated the effect of photoperiod on the processing of the neuropeptide precursor pro-opiomelanocortin (POMC) and its derived neuropeptides, α-melanocyte-stimulating hormone (MSH) and β-endorphin (END), within the hypothalamus of the seasonal Siberian Hamster (Phodopus sungorus). We thus compared hypothalamic distribution of CPD, CPE, α-MSH and β-END using immunohistochemistry and measured the enzyme activity of CPE and concentrations of C-terminally cleaved α-MSH in short-day (SD; 8 : 16 h light/dark) and long-day (LD; 16 : 8 h light/dark) acclimatised Hamsters. Increased immunoreactivity (-IR) of CPE, as well as higher CPE activity, was observed in SD. This increase was accompanied by more β-END-IR cells and substantially higher levels of C- terminally cleaved α-MSH, as determined by radioimmunoassay. Our results suggest that exoproteolytic cleavage of POMC-derived neuropeptides is tightly regulated by photoperiod in the Siberian Hamster. Higher levels of biological active α-MSH- and β-END in SD are consistent with the hypothesis that post-translational processing is a key event in the regulation of seasonal energy balance.
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short photoperiod induced decrease of histamine h3 receptors facilitates activation of hypothalamic neurons in the Siberian Hamster
Endocrinology, 2009Co-Authors: Perry Barrett, Peter J Morgan, Julian G Mercer, Timothy J Bartness, David Wilson, C K Song, David SpanswickAbstract:Nonhibernating seasonal mammals have adapted to temporal changes in food availability through behavioral and physiological mechanisms to store food and energy during times of predictable plenty and conserve energy during predicted shortage. Little is known, however, of the hypothalamic neuronal events that lead to a change in behavior or physiology. Here we show for the first time that a shift from long summer-like to short inter-like photoperiod, which induces physiological adaptation to winter in the Siberian Hamster, including a body weight decrease of up to 30%, increases neuronal activity in the dorsomedial region of the arcuate nucleus (dmpARC) assessed by electro physiological patch-clamping recording. Increased neuronal activity in short days is dependent on a photoperiod-driven down-regulation of H3 receptor expression and can be mimicked in long-day dmpARC neurons by the application of the H3 receptor antagonist, clobenproprit. Short-day activation of dmpARC neurons results in increased c-Fos expression. Tract tracing with the trans-synaptic retrograde tracer, pseudorabies virus, delivered into adipose tissue reveals a multisynaptic neuronal sympathetic outflow from dmpARC to white adipose tissue. These data strongly suggest that increased activity of dmpARC neurons, as a consequence of down-regulation of the histamine H3 receptor, contributes to the physiological adaptation of body weight regulation in seasonal photoperiod.
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Photoperiodic regulation of satiety mediating neuropeptides in the brainstem of the seasonal Siberian Hamster (Phodopus sungorus)
Journal of Comparative Physiology A, 2009Co-Authors: Michael Helwig, Julian G Mercer, Zoë A. Archer, Gerhard Heldmaier, Alexander Tups, Martin KlingensporAbstract:Central regulation of energy balance in seasonal mammals such as the Siberian Hamster is dependent on the precise integration of short-term satiety information arising from the gastrointestinal tract with long-term signals on the status of available energy reserves (e.g. leptin) and prevailing photoperiod. Within the central nervous system, the brainstem nucleus of the solitary tract (NTS) and the parabrachial nucleus (PBN) are major relay nuclei that transmit information from the gastrointestinal tract to higher forebrain centres. We extended studies on the seasonal programming of the hypothalamus to examine the effect of the photoperiod on neuropeptidergic circuitries of this gut–brain axis. In the NTS and PBN we performed gene expression and immunoreactivity (-ir) studies on selected satiety-related neuropeptides and receptors: alpha-melanocyte stimulating hormone, melanocortin-3 receptor, melanocortin-4 receptor (MC4-R), growth hormone secretagogue-receptor, cocaine- and amphetamine-regulated transcript, preproglucagon (PPG), glucagon-like peptide 1 (GLP-1), cholecystokinin (CCK), peptide YY, galanin, neurotensin, and corticotrophin releasing hormone (CRH). Gene expression of PPG and MC4-R, and -ir of CCK and GLP-1, in the NTS were up-regulated after 14 weeks in long-day photoperiod (16 h light:8 h dark) compared to short-days (8 h light:16 h dark), whereas CRH-ir and NT-ir were increased in short-days within the PBN. We suggest that brainstem neuroendocrine mechanisms contribute to the long-term regulation of body mass in the Siberian Hamster by a photoperiod-related modulation of satiety signalling.
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photoperiod regulates genes encoding melanocortin 3 and serotonin receptors and secretogranins in the dorsomedial posterior arcuate of the Siberian Hamster
Journal of Neuroendocrinology, 2009Co-Authors: Alexander W Ross, Julian G Mercer, Francis J P Ebling, Zoë A. Archer, Kanishka N Nilaweera, Gillian Patricia Campbell, Clausdieter Mayer, A Balik, Peter J MorganAbstract:: The mechanism(s) involved in the regulation of the seasonal-appropriate body weight of the Siberian Hamster are currently unknown. We have identified photoperiodically regulated genes including VGF in a sub-region of the arcuate nucleus termed the dorsomedial posterior arcuate (dmpARC). Gene expression changes in this nucleus so far account for a significant number of those reported as photoperiodically regulated and are therefore likely to contribute to seasonal physiological responses of the Hamsters. The present study aimed to identify additional genes expressed in the dmpARC regulated by photoperiod that could be involved in regulating the activity of this nucleus with respect to seasonal physiology of the Siberian Hamster. Using laser capture microdissection coupled with a microarray analysis and a candidate gene approach, we have identified several photoperiodically regulated genes in the dmpARC that are known to have roles in secretory and intracellular signalling pathways. These include secretogranin (sg) III and SgVI (secretory pathway), melanocortin 3 receptor (MC3-R) and serotonin (5-HT) receptors 2A and 7 (signalling pathway), all of which increase in expression under a short photoperiod. The spatial relationship between receptor signalling and potential secretory pathways was investigated by dual in situ hybridisation, which revealed that 5-HT2A and 5-HT7 receptors are expressed in neurones expressing VGF mRNA and that a sub-population (approximately 40%) of these neurones express MC3-R. These gene expression changes in dmpARC neurones may reflect the functional requirement of these neurones for seasonal physiological responses of the Hamster.
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the thyrotropin releasing hormone secretory system in the hypothalamus of the Siberian Hamster in long and short photoperiods
Journal of Neuroendocrinology, 2008Co-Authors: Francis J P Ebling, Peter J Morgan, Julian G Mercer, Dana Wilson, J Wood, D Hughes, Perry BarrettAbstract:Thyrotropin-releasing hormone (TRH) is not only essential for the regulation of the pituitary-thyroid axis, but also exerts complementary effects on energy metabolism within the brain. We hypothesised that increased activity of the TRH secretory system may contribute to seasonal adaptations in the Siberian Hamster whereby food intake is decreased in winter, and catabolism of fat stores is increased to support thermogenesis. We determined the distribution of TRH producing neurones and TRH-R1 receptor expressing cells in the hypothalamus, and investigated whether photoperiod regulated this system. TRH-immunoreactive (ir) cell somata and preproTRH mRNA expression were found to be widely distributed throughout the medial hypothalamus, with particular clusters in the paraventricular nucleus, the medial preoptic area and periventricular nucleus, and in the dorsomedial hypothalamus extending into the lateral hypothalamic area. A partial sequence encoding TRH-R1 was cloned from Hamster hypothalamic cDNA and used to generate a riboprobe for in situ hybridisation studies. TRH-R1 mRNA expressing cells were abundant throughout the hypothalamus, corresponding to the widespread presence of TRH-ir fibres. Photoperiod did not affect the expression of preproTRH mRNA in any region, and the only significant change in TRH-R1 expression was in the dorsomedial posterior arcuate region. This wide distribution of TRH-producing and receptive cells in the hypothalamus is consistent with its hypothesised neuromodulatory roles in the short-term homeostatic control of appetite, thermoregulation and energy expenditure, but the lack of photoperiodic change in TRH mRNA expression does not support the hypothesis that changes in this system underlie long-term seasonal changes in body weight.
Michael H Hastings - One of the best experts on this subject based on the ideXlab platform.
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the circadian cycle of mper clock gene products in the suprachiasmatic nucleus of the Siberian Hamster encodes both daily and seasonal time
European Journal of Neuroscience, 2000Co-Authors: Barbara Nuessleinhildesheim, Francis J P Ebling, John A Obrien, Elizabeth S Maywood, Michael H HastingsAbstract:The circadian clock in the hypothalamic suprachiasmatic nuclei (SCN) regulates the pattern of melatonin secretion from the pineal gland such that the duration of release reflects the length of the night. This seasonally specific endocrine cue mediates annual timing in photoperiodic mammals. The aim of this study was to investigate how changes in photoperiod influence the cyclic expression of recently identified clock gene products (mPER and mTIM) in the SCN of a highly seasonal mammal, the Siberian Hamster (Phodopus sungorus). Immunocytochemical studies indicate that the abundance of both mPER1 and mPER2 (but not mTIM) in the SCN exhibits very pronounced, synchronous daily cycles, peaking approximately 12 h after lights-on. These rhythms are circadian in nature as they continue approximately under free-running conditions. Their circadian waveform is modulated by photoperiod such that the phase of peak mPER expression is prolonged under long photoperiods. mPER1 protein is also expressed in the pars tuberalis of Siberian Hamsters. In Hamsters adapted to long days, the expression of mPER1 is elevated at the start of the light phase. In contrast, there is no clear elevation in mPER1 levels in the pars tuberalis of Hamsters held on short photoperiods. These results indicate that core elements of the circadian clockwork are sensitive to seasonal time, and that encoding and decoding of seasonal information may be mediated by the actions of these transcriptional modulators.
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investigation into the regulation of the circadian system by dopamine and melatonin in the adult Siberian Hamster phodopus sungorus
Journal of Neuroendocrinology, 1998Co-Authors: Giles E Duffield, Michael H Hastings, Francis J P EblingAbstract:: Dopamine and melatonin have both been implicated in mediating maternal influences on the developing circadian system of altricial rodents. The aim of these studies was to investigate their role in the entrainment of the circadian system of the adult Siberian Hamster (Phodopus sungorus). In-situ hybridization revealed that D1-dopamine receptor (D1-R) mRNA was expressed in the adult suprachiasmatic nucleus (SCN) at levels comparable to neonates. As dopamine has been postulated to mimic photic stimulation during early development, experiment 1 compared the effects of a D1-R agonist and a light pulse on free-running wheel running rhythms in Hamsters maintained in constant dim red light. A phase response curve to light was generated, revealing clear phase delays early in the subjective night, and large phase advances in the late subjective night. However, the D1-R agonist (SKF 81297, 2 mg/kg, s.c.) did not produce consistent phase shifts at any circadian phase. Experiment 2 tested the ability of this dopaminergic agonist to modulate photic responses of the circadian system. Free-running animals were pre-treated with SKF 81297 (2 mg/kg, s.c.) 30 min before a 15 min light pulse given early or late in the subjective night. This agonist had no effect on the magnitude of phase shifts at either circadian time. In experiment 3, light pulses at CT13-15 induced expression of the immediate early gene c-fos in the SCN, as assessed by immunocytochemistry for the protein product. In contrast, SKF 81297 (2 mg/kg, s.c.) at the same phase did not induce c-fos in the SCN, despite marked c-fos induction in the caudate-putamen, nor did it affect photic induction of c-fos in the SCN. To investigate whether dopamine might be involved in nonphotic regulation of the circadian system in adult Hamsters, experiment 4 compared the response of free-running Hamsters to a series of injections of SKF 81297 (2 mg/kg, s.c.) or melatonin (1 mg/kg, s.c.), since melatonin receptor expression in the SCN also persists into adulthood. Animals were treated every 23.5 h for 6 days. The serial injections of melatonin produced cumulative phase advances of up to 3 h when delivered in late subjective day, but not when presented in late subjective night. Hamsters did not respond to SKF 81297 or vehicle treatment at either circadian phase. Moreover, pre-treatment with the dopaminergic agonist did not affect the phase-advancing effects of melatonin when both were given in the serial injection protocol. These results demonstrate clear phase-dependent effects of light pulses and melatonin on circadian rhythms in Siberian Hamsters, but suggest that D1-Rs in the SCN no longer modulate photic or melatonin-dependent entrainment pathways in the adult.
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fosb in the suprachiasmatic nucleus of the syrian and Siberian Hamster
Brain Research Bulletin, 1996Co-Authors: Francis J P Ebling, Shaun Mcnulty, Elizabeth S Maywood, Mit Mehta, David C Hancock, Joe De Bono, Sarah J Bray, Michael H HastingsAbstract:Abstract The suprachiasmatic nucleus (SCN) generates circadian rhythms of behavior and hormone secretion in mammals, and integrates responses to light and nonphotic stimuli to synchronize such rhythms with the external environment. Previous studies have demonstrated a close association between the induction of the immediate early gene (IEG) c-fos in the SCN by light and phase shifts of circadian rhythms induced by light, but nonphotic stimuli (e.g., arousal), which also cause phase shifts, do not increase c-fos expression in the SCN. Because c-fos is now known to be a member of a large family of IEGs which can regulate transcription and thus cellular function, the aim of the current study was to determine whether induction of another member of this immediate early gene family, fosB , is associated with photic and nonphotic phase shifts. An antiserum that recognizes a unique peptide sequence derived from FosB was produced so that the expression of fosB could be investigated in cells within the SCN by immunocytochemical detection of its protein product. The regional distribution of FosB-immunoreactive (ir) cells in the SCN of Syrian and Siberian Hamsters was broadly similar to that for c-Fos-ir cells. However, whereas c-fos expression in the SCN was constitutively low, but could be massively induced by light at particular circadian phases, FosB-ir cells were present at all circadian phases studied, irrespective of photic stimulation, and light only produced marginal increases in the number of FosB-ir cells compared with nonstimulated controls. Moreover, blockade of glutamatergic neurotransmission by pretreatment of Hamsters with the NMDA receptor antagonist MK801 significantly reduced photic induction of c-Fos-ir cells, but did not influence the number of FosB-ir cells in the SCN. Finally, an arousing nonphotic stimulus known to cause phase advances in wheel-running behavior in Syrian Hamsters did not alter significantly the number of FosB-ir cells in the SCN. These observations indicate that light and nonphotic stimuli are not potent regulators of fosB expression in the SCN. However, because fosB and c-fos can be present in the SCN at the same time after a light pulse, these studies indicate the potential for interactions with each other and with members of the Jun family in the regulation of the circadian timing system. Copyright 1996 Elsevier Science Inc.
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regional distribution of iodomelatonin binding sites within the suprachiasmatic nucleus of the syrian Hamster and the Siberian Hamster
Journal of Neuroendocrinology, 1995Co-Authors: Elizabeth S Maywood, Peter J Morgan, Francis J P Ebling, Perry Barrett, Eric L Bittman, Michael H HastingsAbstract:The pineal hormone melatonin is a potent regulator of seasonal and circadian rhythms in vertebrates. In order to characterize potential target tissues of melatonin, the distribution of iodomelatonin (IMEL)-binding sites was examined within neurochemically and anatomically defined subdivisions of the suprachiasmatic nucleus (SCN), a structure necessary for seasonal and circadian rhythms in mammals. Studies were carried out in both the adult Syrian (Mesocricetus auratus) and Siberian (Phodopus sungorus) Hamster. The retinoreceptive zone of the SCN was identified anatomically by immunocytochemical (ICC) visualization of cholera toxin B subunit tracer (ChTB-ir) following its intra-ocular injection. Photically-responsive SCN cells were identified by immunostaining for the protein product of the immediate-early gene c-fos (Fos-ir) following exposure of the animal to light. The non-photoresponsive zone of the SCN was identified using in situ hybridization (ISH) for arginine vasopressin (AVP) mRNA, whilst sites of IMEL-binding in the SCN were identified by in vitro film autoradiography using the specific ligand 2-[125l]-iodomelatonin. To compare directly the distribution of IMEL-binding sites and one of the functional zones of the nucleus, alternate serial coronal sections through the SCN were processed for autoradiography for IMEL and one of the following: ICC for ChTB-ir or Fos-ir, or ISH for AVP mRNA. Overall, the regional distribution of the various markers within the SCN was comparable in the two species. The retinorecipient (ChTB-ir) and photically-responsive (Fos-ir) zones of the SCN mapped together to the middle and caudal thirds of the nucleus, predominantly in its ventro-lateral division. IMEL-binding was present throughout the full rostro-caudal extent of the SCN, but by far the most extensive area of IMEL-binding was in the rostral half of the nucleus, leading to a clear dissociation along the rostro-caudal axis of the principal zone of IMEL-binding and the retinorecipient zone of the nucleus. In the Syrian Hamster, in coronal sections of the caudal SCN which did contain significant amounts of both IMEL-binding and Fos-ir, IMEL-binding was confined to the medial zone, distinct from the Fos-ir region of the ventro-lateral SCN. The segregation was less clear-cut in the Siberian Hamster where the area of IMEL-binding was more extensive. The dissociation of IMEL-binding and photically-responsive cells in the Syrian Hamster was confirmed in a series of sagittal sections which were processed alternately for Fos-ir and IMEL-binding. Whereas Fos-ir was confined to the ventro-lateral SCN, IMEL-binding was concentrated in the medial zone of the nucleus. In both species, mRNA for AVP was found throughout the rostro-caudal extent of the SCN, but the peak area was located in the rostral half, and so was segregated from the principal retinorecipient zone. The distribution of mRNA for AVP along the rostro-caudal and medio-lateral axes was in direct register with the IMEL-binding in both species. These studies suggest that melatonin acts upon pathways within the SCN different to those addressed by light, and that it may influence directly the efferent activity of the nucleus, possibly via an effect on vasopressinergic cells.