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George E Bentley - One of the best experts on this subject based on the ideXlab platform.
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social cues regulate reciprocal switching of hypothalamic DIO2 dio3 and the transition into final follicle maturation in european starlings sturnus vulgaris
Endocrinology, 2015Co-Authors: Nicole Perfito, George E Bentley, Daisy Guardado, Tony D WilliamsAbstract:With final maturation of ovarian follicles, birds are committed to a major energetic investment: egg laying. Follicles develop in a 2-step process: 1) initial development of regressed follicles stimulated by long days and 2) yolk incorporation into hierarchical follicles, ovulation, and oviposition. We know little about how females transduce environmental cues into neuroendocrine signals regulating the second step. The present study measures gene expression in tissues within the hypothalamo-pituitary-gonadal axis. Females were housed in seminatural enclosures experiencing natural changes in photoperiod and environmental cues (eg, temperature, rainfall, etc), without males or with constant access to males (January to April). By April, females with males had begun to lay eggs, whereas those without males had not. In a second study, females without males for 3.5 months were then given access to males for 7 days. Restricting male access completely inhibited final follicle maturation, whereas 7-day male access stimulated full vitellogenesis and follicle maturation. Few gene expression changes were attributable to constant male access (January to March), but naive females given 7-day male access had increased type 2 deiodinase (DIO2) and decreased DIO3 synthesis in the hypothalamus, potentially influencing local thyroid hormone metabolism, increased expression of LH receptor and aromatase in follicles and vitellogenin in liver. Our data suggest that initial follicle development may be more heavily influenced by photoperiod, but the second step (final maturation) is sensitive to other cues such as social interactions. This is the first demonstration of a social effect on the DIO2/Dio3 system, previously thought only responsive to photoperiod cues.
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testicular growth and regression are not correlated with DIO2 expression in a wild male songbird sturnus vulgaris exposed to natural changes in photoperiod
Endocrinology, 2013Co-Authors: George E Bentley, Shanna Tucker, Heather Chou, Nicole PerfitoAbstract:Timing of seasonal breeding in birds and mammals is regulated by changing the day length and is dependent on the presence of thyroid hormones. A mechanism for thyroid-dependent control of seasonality has been proposed, in which exposure to long day lengths induces rapid local conversion of T4 to its bioactive form, T3, via the up-regulation of the enzyme type 2 iodothyronine deiodinase (DIO2) in the brain, and the down-regulation of Dio3 (which inactivates T3). Such changes were correlated with gonadotropin release and gonadal growth in quail. This mechanism was elucidated in a domesticated species (quail) exposed to unnatural acute changes in day length. Here we investigated the DIO2/Dio3 mechanism in a wild species, the European starling, under naturally changing day length. Although DIO2 expression varied seasonally, Dio3 did not. We found no correlation of DIO2 with photoperiod, seasonal regulation of GnRH, or testicular volume. The observed differences in data from starlings and quail could be a resu...
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testicular growth and regression are not correlated with DIO2 expression in a wild male songbird sturnus vulgaris exposed to natural changes in photoperiod
Endocrinology, 2013Co-Authors: George E Bentley, Shanna Tucker, Heather Chou, Michaela Hau, Nicole PerfitoAbstract:Timing of seasonal breeding in birds and mammals is regulated by changing the day length and is dependent on the presence of thyroid hormones. A mechanism for thyroid-dependent control of seasonality has been proposed, in which exposure to long day lengths induces rapid local conversion of T4 to its bioactive form, T3, via the up-regulation of the enzyme type 2 iodothyronine deiodinase (DIO2) in the brain, and the down-regulation of Dio3 (which inactivates T3). Such changes were correlated with gonadotropin release and gonadal growth in quail. This mechanism was elucidated in a domesticated species (quail) exposed to unnatural acute changes in day length. Here we investigated the DIO2/Dio3 mechanism in a wild species, the European starling, under naturally changing day length. Although DIO2 expression varied seasonally, Dio3 did not. We found no correlation of DIO2 with photoperiod, seasonal regulation of GnRH, or testicular volume. The observed differences in data from starlings and quail could be a resu...
Nicole Perfito - One of the best experts on this subject based on the ideXlab platform.
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social cues regulate reciprocal switching of hypothalamic DIO2 dio3 and the transition into final follicle maturation in european starlings sturnus vulgaris
Endocrinology, 2015Co-Authors: Nicole Perfito, George E Bentley, Daisy Guardado, Tony D WilliamsAbstract:With final maturation of ovarian follicles, birds are committed to a major energetic investment: egg laying. Follicles develop in a 2-step process: 1) initial development of regressed follicles stimulated by long days and 2) yolk incorporation into hierarchical follicles, ovulation, and oviposition. We know little about how females transduce environmental cues into neuroendocrine signals regulating the second step. The present study measures gene expression in tissues within the hypothalamo-pituitary-gonadal axis. Females were housed in seminatural enclosures experiencing natural changes in photoperiod and environmental cues (eg, temperature, rainfall, etc), without males or with constant access to males (January to April). By April, females with males had begun to lay eggs, whereas those without males had not. In a second study, females without males for 3.5 months were then given access to males for 7 days. Restricting male access completely inhibited final follicle maturation, whereas 7-day male access stimulated full vitellogenesis and follicle maturation. Few gene expression changes were attributable to constant male access (January to March), but naive females given 7-day male access had increased type 2 deiodinase (DIO2) and decreased DIO3 synthesis in the hypothalamus, potentially influencing local thyroid hormone metabolism, increased expression of LH receptor and aromatase in follicles and vitellogenin in liver. Our data suggest that initial follicle development may be more heavily influenced by photoperiod, but the second step (final maturation) is sensitive to other cues such as social interactions. This is the first demonstration of a social effect on the DIO2/Dio3 system, previously thought only responsive to photoperiod cues.
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testicular growth and regression are not correlated with DIO2 expression in a wild male songbird sturnus vulgaris exposed to natural changes in photoperiod
Endocrinology, 2013Co-Authors: George E Bentley, Shanna Tucker, Heather Chou, Nicole PerfitoAbstract:Timing of seasonal breeding in birds and mammals is regulated by changing the day length and is dependent on the presence of thyroid hormones. A mechanism for thyroid-dependent control of seasonality has been proposed, in which exposure to long day lengths induces rapid local conversion of T4 to its bioactive form, T3, via the up-regulation of the enzyme type 2 iodothyronine deiodinase (DIO2) in the brain, and the down-regulation of Dio3 (which inactivates T3). Such changes were correlated with gonadotropin release and gonadal growth in quail. This mechanism was elucidated in a domesticated species (quail) exposed to unnatural acute changes in day length. Here we investigated the DIO2/Dio3 mechanism in a wild species, the European starling, under naturally changing day length. Although DIO2 expression varied seasonally, Dio3 did not. We found no correlation of DIO2 with photoperiod, seasonal regulation of GnRH, or testicular volume. The observed differences in data from starlings and quail could be a resu...
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testicular growth and regression are not correlated with DIO2 expression in a wild male songbird sturnus vulgaris exposed to natural changes in photoperiod
Endocrinology, 2013Co-Authors: George E Bentley, Shanna Tucker, Heather Chou, Michaela Hau, Nicole PerfitoAbstract:Timing of seasonal breeding in birds and mammals is regulated by changing the day length and is dependent on the presence of thyroid hormones. A mechanism for thyroid-dependent control of seasonality has been proposed, in which exposure to long day lengths induces rapid local conversion of T4 to its bioactive form, T3, via the up-regulation of the enzyme type 2 iodothyronine deiodinase (DIO2) in the brain, and the down-regulation of Dio3 (which inactivates T3). Such changes were correlated with gonadotropin release and gonadal growth in quail. This mechanism was elucidated in a domesticated species (quail) exposed to unnatural acute changes in day length. Here we investigated the DIO2/Dio3 mechanism in a wild species, the European starling, under naturally changing day length. Although DIO2 expression varied seasonally, Dio3 did not. We found no correlation of DIO2 with photoperiod, seasonal regulation of GnRH, or testicular volume. The observed differences in data from starlings and quail could be a resu...
Nils Bomer - One of the best experts on this subject based on the ideXlab platform.
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DIO2 is a regulator of mitochondrial function morphology and upr mt in human cardiomyocytes
Social Science Research Network, 2021Co-Authors: Nils Bomer, Mario G Pavezgiani, Frederik E Deiman, Annet N Linders, Martijn F Hoes, Christiane L J Baierl, Silke U Oberdorfmaass, Rudolf A De Boer, Herman H W Sillje, Eugene BerezikovAbstract:Objectives: To elucidate the role of DIO2, member of the fetal-gene-program, in PSC-derived human cardiomyocytes and on mitochondrial dynamics and energetics, specifically. Background: Members of the fetal-gene-program may act as regulatory components to impede deleterious events that occur with cardiac remodeling and constitute potential novel therapeutic heart failure (HF) targets. Mitochondrial energy metabolic derangements occur both during early fetal development and in patients with HF. In HF, metabolic roadblocks and structural damage to mitochondria develop which deplete the heart of energy. Methods: RNA sequencing and pathway enrichment analysis was performed on mouse cardiac tissue at different time points during development, adult age and ischemia-induced HF. To determine the function of DIO2 in cardiomyocytes, a stable human pluripotent stem cell (hPSC)-line with a DIO2 short hairpin knockdown was made and used as the source for cardiomyocyte differentiation and mitochondrial dynamics were assessed. Results: We showed the selenoprotein, type II deiodinase (DIO2): the enzyme responsible for tissue-specific conversion of inactive (T4) into active thyroid hormone (T3), to be a member of fetal gene program. Silencing DIO2 resulted in increased reactive oxygen species, impaired activation of the mitochondrial unfolded protein response, severely impaired mitochondrial respiration and reduced cellular viability. Microscopical 3D reconstruction of the mitochondrial network displayed substantial mitochondrial fragmentation. Conclusion: We identified DIO2 to be a member of the fetal-gene-program and as a key regulator of mitochondrial performance in human cardiomyocytes. Our results suggest a key position of human DIO2 as a regulator of mitochondrial function in human cardiomyocytes.
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aberrant calreticulin expression in articular cartilage of DIO2 deficient mice
PLOS ONE, 2016Co-Authors: Nils Bomer, Y F Ramos, Wouter Den Hollander, Ruud Van Der Breggen, N Lakenberg, F M Cornelis, L Storms, Eline P Slagboom, Rik Lories, I MeulenbeltAbstract:Objective To identify intrinsic differences in cartilage gene expression profiles between wild-type- and DIO2-/--mice, as a mechanism to investigate factors that contribute to prolonged healthy tissue homeostasis. Methods Previously generated microarray-data (Illumina MouseWG-6 v2) of knee cartilage of wild-type and DIO2 -/- -mice were re-analyzed to identify differential expressed genes independent of mechanical loading conditions by forced treadmill-running. RT-qPCR and western blot analyses of overexpression and knockdown of Calr in mouse chondro-progenitor cells (ATDC5) were applied to assess the direct effect of differential Calr expression on cartilage deposition. Results Differential expression analyses of articular cartilage of DIO2-/- (N = 9) and wild-type-mice (N = 11) while applying a cutoff threshold (P |1,5|) resulted in 1 probe located in Calreticulin (Calr) that was found significantly downregulated in DIO2-/- mice (FC = -1.731; P = 0.044). Furthermore, overexpression of Calr during early chondrogenesis in ATDC5 cells leads to decreased proteoglycan deposition and corresponding lower Aggrecan expression, whereas knocking down Calr expression does not lead to histological differences of matrix composition. Conclusion We here demonstrate that the beneficial homeostatic state of articular cartilage in DIO2-/- mice is accompanied with significant lower expression of Calr. Functional analyses further showed that upregulation of Calr expression could act as an initiator of cartilage destruction. The consistent association between Calr and DIO2 expression suggests that enhanced expression of these genes facilitate detrimental effects on cartilage integrity.
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the effect of forced exercise on knee joints in DIO2 mice type ii iodothyronine deiodinase deficient mice are less prone to develop oa like cartilage damage upon excessive mechanical stress
Annals of the Rheumatic Diseases, 2016Co-Authors: Nils Bomer, Y F Ramos, I Meulenbelt, Wouter Den Hollander, Ruud Van Der Breggen, N Lakenberg, F M Cornelis, L Storms, Eline P Slagboom, Rik J L LoriesAbstract:Objective To further explore deiodinase iodothyronine type 2 ( DIO2 ) as a therapeutic target in osteoarthritis (OA) by studying the effects of forced mechanical loading on in vivo joint cartilage tissue homeostasis and the modulating effect herein of DIO2 deficiency. Methods Wild-type and C57BL/6- DIO2 −/− -mice were subjected to a forced running regime for 1 h per day for 3 weeks. Severity of OA was assessed by histological scoring for cartilage damage and synovitis. Genome-wide gene expression was determined in knee cartilage by microarray analysis (Illumina MouseWG-6 v2). STRING-db analyses were applied to determine enrichment for specific pathways and to visualise protein–protein interactions. Results In total, 158 probes representing 147 unique genes showed significantly differential expression with a fold-change ≥1.5 upon forced exercise. Among these are genes known for their association with OA (eg, Mef2c, Egfr, Ctgf, Prg4 and Ctnnb1 ), supporting the use of forced running as an OA model in mice. DIO2 -deficient mice showed significantly less cartilage damage and signs of synovitis. Gene expression response upon exercise between wild-type and knockout mice was significantly different for 29 genes. Conclusions Mice subjected to a running regime have significant increased cartilage damage and synovitis scores. Lack of DIO2 protected against cartilage damage in this model and was reflected in a specific gene expression profile, and either mark a favourable effect in the DIO2 knockout (eg, Gnas ) or an unfavourable effect in wild-type cartilage homeostasis (eg, Hmbg2 and Calr ). These data further support DIO2 activity as a therapeutic target in OA.
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underlying molecular mechanisms of DIO2 susceptibility in symptomatic osteoarthritis
Annals of the Rheumatic Diseases, 2015Co-Authors: Nils Bomer, S D Bos, Yolande Fm Ramos, Wouter Den Hollander, Ruud Van Der Breggen, N Lakenberg, Barry A Pepers, Annelies E Van Eeden, Arash Darvishan, Elmar W TobiAbstract:Objectives: To investigate how the genetic susceptibility gene DIO2 confers risk to osteoarthritis (OA) onset in humans and to explore whether counteracting the deleterious effect could contribute to novel therapeutic approaches. Methods: Epigenetically regulated expression of DIO2 was explored by assessing methylation of positional CpG-dinucleotides and the respective DIO2 expression in OA-affected and macroscopically preserved articular cartilage from end-stage OA patients. In a human in vitro chondrogenesis model, we measured the effects when thyroid signalling during culturing was either enhanced (excess T3 or lentiviral induced DIO2 overexpression) or decreased (iopanoic acid). Results: OA-related changes in methylation at a specific CpG dinucleotide upstream of DIO2 caused significant upregulation of its expression (?=4.96; p=0.0016). This effect was enhanced and appeared driven specifically by DIO2 rs225014 risk allele carriers (?=5.58, p=0.0006). During in vitro chondrogenesis, DIO2 overexpression resulted in a significant reduced capacity of chondrocytes to deposit extracellular matrix (ECM) components, concurrent with significant induction of ECM degrading enzymes (ADAMTS5, MMP13) and markers of mineralisation (ALPL, COL1A1). Given their concurrent and significant upregulation of expression, this process is likely mediated via HIF-2?/RUNX2 signalling. In contrast, we showed that inhibiting deiodinases during in vitro chondrogenesis contributed to prolonged cartilage homeostasis as reflected by significant increased deposition of ECM components and attenuated upregulation of matrix degrading enzymes. Conclusions: Our findings show how genetic variation at DIO2 could confer risk to OA and raised the possibility that counteracting thyroid signalling may be a novel therapeutic approach.
Charles R Tyler - One of the best experts on this subject based on the ideXlab platform.
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expression dynamics of genes in the hypothalamic pituitary thyroid hpt cascade and their responses to 3 3 5 triiodo l thyronine t3 highlights potential vulnerability to thyroid disrupting chemicals in zebrafish danio rerio embryo larvae
Aquatic Toxicology, 2020Co-Authors: Aoife Parsons, Anke Lange, Thomas H Hutchinson, Shinichi Miyagawa, Taisen Iguchi, Tetsuhiro Kudoh, Charles R TylerAbstract:Some chemicals in the environment disrupt thyroid hormone (TH) systems leading to alterations in organism development, but their effect mechanisms are poorly understood. In fish, this has been limited by a lack of fundamental knowledge on thyroid gene ontogeny and tissue expression in early life stages. Here we established detailed expression profiles for a suite of genes in the hypothalamic-pituitary-thyroid (HPT) axis of zebrafish (Danio rerio) between 24-120 h post fertilisation (hpf) and quantified their responses following exposure to 3,3',5-triiodo-L-thyronine (T3) using whole mount in situ hybridisation (WISH) and qRT-PCR (using whole-body extracts). All of the selected genes in the HPT axis demonstrated dynamic transcript expression profiles across the developmental stages examined. The expression of thyroid receptor alpha (thraa) was observed in the brain, gastrointestinal tract, craniofacial tissues and pectoral fins, while thyroid receptor beta (thrb) expression occurred in the brain, otic vesicles, liver and lower jaw. The TH deiodinases (dio1, DIO2 and dio3b) were expressed in the liver, pronephric ducts and brain and the patterns differed depending on life stage. Both dio1 and DIO2 were also expressed in the intestinal bulb (96-120 hpf), and DIO2 expression occurred also in the pituitary (48-120 hpf). Exposure of zebrafish embryo-larvae to T3 (30 and 100 μg L-1) for periods of 48, 96 or 120 hpf resulted in the up-regulation of thraa, thrb, dio3b, thyroid follicle synthesis proteins (pax8) and corticotropin-releasing hormone (crhb) and down-regulation of dio1, DIO2, glucuronidation enzymes (ugt1ab) and thyroid stimulating hormone (tshb) (assessed via qRT-PCR) and responses differed across life stage and tissues. T3 induced thraa expression in the pineal gland, pectoral fins, brain, somites, gastrointestinal tract, craniofacial tissues, liver and pronephric ducts. T3 enhanced thrb expression in the brain, jaw cartilage and intestine, while thrb expression was suppressed in the liver. T3 exposure suppressed the transcript levels of dio1 and DIO2 in the liver, brain, gastrointestinal tract and craniofacial tissues, while DIO2 signalling was also suppressed in the pituitary gland. Dio3b expression was induced by T3 exposure in the jaw cartilage, pectoral fins and brain. The involvement of THs in the development of numerous body tissues and the responsiveness of these tissues to T3 in zebrafish highlights their potential vulnerability to exposure to environmental thyroid-disrupting chemicals.
Niels Grarup - One of the best experts on this subject based on the ideXlab platform.
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studies of the common DIO2 thr92ala polymorphism and metabolic phenotypes in 7342 danish white subjects
The Journal of Clinical Endocrinology and Metabolism, 2007Co-Authors: Niels Grarup, Mette K Andersen, Camilla H Andreasen, Anders Albrechtsen, Knut Borchjohnsen, Torben Jorgensen, Johan Auwerx, Ole SchmitzAbstract:Context: The type 2 iodothyronine deiodinase (D2) catalyzes the conversion of T4 to the active form of thyroid hormone, which is a critical regulator of thermogenesis and glucose metabolism. A Thr92Ala polymorphism in the gene encoding D2 (DIO2) has been reported to associate with insulin resistance. Objective: The aim of the present study was to assess the impact of the DIO2 Thr92Ala variant on type 2 diabetes (T2D), obesity, and related quantitative metabolic traits including measures of insulin resistance. Because DIO2 is activated through a β-adrenergic receptor-dependent pathway, we further hypothesized that variation in the ADRB genes interacts with DIO2 Thr92Ala variant to influence metabolic traits. Design and Patients: The DIO2 polymorphism was genotyped in a total of 7342 white subjects including 1405 T2D patients. Results: We detected no significant association of the DIO2 Thr92Ala polymorphism with T2D or obesity. We observed nominal significant associations of genotype with increased area und...
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brief report studies of the common DIO2 thr92ala polymorphism and metabolic phenotypes in 7342 danish white subjects
2007Co-Authors: Niels Grarup, Mette K Andersen, Camilla H Andreasen, Anders Albrechtsen, Knut Borchjohnsen, Torben Jorgensen, Johan Auwerx, Ole Schmitz, Torben Hansen, Oluf PedersenAbstract:Context: The type 2 iodothyronine deiodinase (D2) catalyzes the conversion of T4 to the active form of thyroid hormone, which is a critical regulator of thermogenesis and glucose metabolism. A Thr92Ala polymorphism in the gene encoding D2 (DIO2) has been reported to associate with insulin resistance. Objective: The aim of the present study was to assess the impact of the DIO2 Thr92Ala variant on type 2 diabetes (T2D), obesity, and related quantitative metabolic traits including measures of insulin resistance. Because DIO2 is activated through a -adrenergic receptor-dependent pathway, we further hypothesized that variation in the ADRB genes interacts with DIO2 Thr92Ala variant to influence metabolic traits. Design and Patients: The DIO2 polymorphism was genotyped in a total of 7342 white subjects including 1405 T2D patients. Results: We detected no significant association of the DIO2 Thr92Ala polymorphism with T2D or obesity. We observed nominal significant associations of genotype with increased area under the serum insulin curve during an oral glucose tolerance test (P 0.03) and elevated fasting plasma glucose (P 0.02) in homozygous Ala92 allele carriers, the latter strengthened by epistasis with the ADRB2 Gly16Arg variant in a double recessive model (P 0.004). However, after permutation procedure, performed to correct for multiple hypothesis testing, the associations did not reach studywide significance. Conclusions: The DIO2 Thr92Ala variant does not confer an increased risk of T2D, obesity, or insulin resistance. (J Clin Endocrinol Metab 92: 363–366, 2007)