Diet-Induced Obesity Mediated by the JNK/DIO2 Signal Transduction Pathway
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A Family-Based Association Study of DIO2 and Children Mental Retardation in the Qinba Region of China
Journal of Human Genetics (2012) 57, 14–17 & 2012 The Japan Society of Human Genetics All rights reserved 1434-5161/12 $32.00 www.nature.com/jhg ORIGINAL ARTICLE A Family-based Association Study of DIO2 and children mental retardation in the Qinba region of China Kejin Zhang1,4, Heng Xi1,2,4, Xiying Wang1, Yale Guo3, Shaoping Huang3, Zijian Zheng2, Fuchang Zhang1,2 and Xiaocai Gao1,2 Deiodinase enzyme II (DIO2) has an important role in individuals’ thyroid hormones’ level, the development of central and peripheral nervous systems and characterized by mental retardation (MR). The DIO2 gene was genotyped by using five haplotype-tagging single-nucleotide polymorphisms (SNPs) in 157 Chinese MR high-density family pedigrees, including 452 nuclear families and 41460 persons. The single marker and haplotype analyses were performed by Family-based Association Tests (FBAT). Three SNPs had P-values o0.05 in at least one inherited model survived with the correction. Several haplotypes composed of these SNPs were also associated with MR. The in silico analyses identified that one of the SNPs, rs1388378, may be a functional SNP. However, further in vitro studies of this SNP should be considered in elucidating its effect on gene expression and the possible role in MR susceptibility. Journal of Human Genetics (2012) 57, 14–17; doi:10.1038/jhg.2011.121; published online 3 November 2011 Keywords: deiodinase enzyme II (DIO2); Family Based Association Tests (FBAT); mental retardation (MR); thyroid hormone (TH) INTRODUCTION Deiodinase enzyme II (DIO2) has an important role in the Thyroid hormone is essential for the development of the brain and conversion of pro-hormone thyroxine (T4) to the active hormone nervous system both in the basic processes of neurogenesis and the 3,5,3¢-L-triiodothyronine (T3). -
Role of the Intracellular Domains in the Regulation and the Signaling of the Human Bradykinin B2 Receptor
Aus der Abteilung für Klinische Chemie und Klinische Biochemie in der Chirurgischen Klinik-Innenstadt der Ludwig-Maximilians-Universität München Leiterin der Abteilung: Prof. Dr. rer. nat. Dr. med. habil. Marianne Jochum Role of the intracellular domains in the regulation and the signaling of the human bradykinin B2 receptor Dissertation zum Erwerb des Doktorgrades der Humanbiologie an der Medizinischen Fakultät der Ludwig-Maximilians-Universität zu München Vorgelegt von Göran Wennerberg aus Stockholm 2010 Mit Genehmigung der Medizinischen Fakultät der Ludwig-Maximilians-Universität München Berichterstatter: PD Dr. rer. nat. Alexander Faussner Mitberichterstatter: Prof. Dr. Nikolaus Plesnila Prof. Dr. Franz-Xaver Beck Mitbetreuung durch den promovierten Mitarbeiter: Dekan: Prof. Dr. med. Dr. h.c. M. Reiser, FACR,FRCR Tag der mündlichen Prüfung: 27.01.2010 CONTENTS………………………………………………………………………………………I ABBREVIATIONS………………………………………………………………………………V A ZUSAMMENFASSUNG ............................................................................................ 1 B INTRODUCTION ....................................................................................................... 4 B.1 The kallikrein-kinin system (KKS) B.1.1 Historic background............................................................................................................................................4 B.1.2 Kinins...................................................................................................................................................................4 -
Skeletal Muscle Deiodinase Type 2 Regulation During Illness in Mice
263 Skeletal muscle deiodinase type 2 regulation during illness in mice J Kwakkel, H C van Beeren, M T Ackermans1, M C Platvoet-ter Schiphorst, E Fliers, W M Wiersinga and A Boelen Department of Endocrinology and Metabolism, 1Laboratory of Endocrinology, Department of Clinical Chemistry, Academic Medical Center, University of Amsterdam, F5-165, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands (Correspondence should be addressed to J Kwakkel; Email: [email protected]) Abstract We have previously shown that skeletal muscle deiodinase During chronic inflammation the increased muscle D2 type 2 (D2) mRNA (listed as Dio2 in MGI Database) is expression is associated with the activation of the cAMP upregulated in an animal model of acute illness. However, pathway. The normalization of D2 5 days after turpentine human studies on the expression of muscle D2 during injection coincides with increased Wsb1 and tumor illness report conflicting data. Therefore, we evaluated the necrosis factor a expression. Muscle interleukin-1b (Il1b) expression of skeletal muscle D2 and D2-regulating factors expression correlated with decreased D2 mRNA expression in two mouse models of illness that differ in timing and after S. pneumoniae infection. In conclusion, muscle D2 severity of illness: 1) turpentine-induced inflammation, and expression is differentially regulated during illness, probably 2) Streptococcus pneumoniae infection. During turpentine- related to differences in the inflammatory response and type induced inflammation, D2 mRNA and activity increased of pathology. D2 mRNA and activity increases in skeletal compared to pair-fed controls, most prominently at day 1 muscle during the acute phase of chronic inflammation and 2, whereas after S. -
Mouse Dio2 Conditional Knockout Project (CRISPR/Cas9)
https://www.alphaknockout.com Mouse Dio2 Conditional Knockout Project (CRISPR/Cas9) Objective: To create a Dio2 conditional knockout Mouse model (C57BL/6J) by CRISPR/Cas-mediated genome engineering. Strategy summary: The Dio2 gene (NCBI Reference Sequence: NM_010050 ; Ensembl: ENSMUSG00000007682 ) is located on Mouse chromosome 12. 2 exons are identified, with the ATG start codon in exon 1 and the TAG stop codon in exon 2 (Transcript: ENSMUST00000082432). Exon 2 will be selected as conditional knockout region (cKO region). Deletion of this region should result in the loss of function of the Mouse Dio2 gene. To engineer the targeting vector, homologous arms and cKO region will be generated by PCR using BAC clone RP24-82B20 as template. Cas9, gRNA and targeting vector will be co-injected into fertilized eggs for cKO Mouse production. The pups will be genotyped by PCR followed by sequencing analysis. Note: Mice homozygous for a knock-out allele display elevated thyroxine (T4) and thyroid-stimulating hormone levels, changes in the metabolism and excretion of iodothyronines, and impaired adaptive thermogenesis. Exon 2 covers 72.18% of the coding region. Start codon is in exon 1, and stop codon is in exon 2. The size of intron 1 for 5'-loxP site insertion: 8072 bp. The size of effective cKO region: ~849 bp. The cKO region does not have any other known gene. Page 1 of 7 https://www.alphaknockout.com Overview of the Targeting Strategy gRNA region Wildtype allele T A 5' gRNA region G 3' 1 2 Targeting vector T A G Targeted allele T A G Constitutive KO allele (After Cre recombination) Legends Exon of mouse Dio2 Homology arm cKO region loxP site Page 2 of 7 https://www.alphaknockout.com Overview of the Dot Plot Window size: 10 bp Forward Reverse Complement Sequence 12 Note: The sequence of homologous arms and cKO region is aligned with itself to determine if there are tandem repeats. -
Importance of Thyroid Hormone Level and Genetic
www.nature.com/scientificreports OPEN Importance of Thyroid Hormone level and Genetic Variations in Deiodinases for Patients after Acute Myocardial Infarction: A Longitudinal Observational Study Nijole Kazukauskiene1, Daina Skiriute2, Olivija Gustiene3, Julius Burkauskas4 ✉ , Violeta Zaliunaite5, Narseta Mickuviene6 & Julija Brozaitiene4 This study aimed to examine the infuence of thyroid hormone (TH) levels and genetic polymorphisms of deiodinases on long-term outcomes after acute myocardial infarction (AMI). In total, 290 patients who have experienced AMI were evaluated for demographic, clinical characteristics, risk factors, TH and NT-pro-BNP. Polymorphisms of TH related genes were included deiodinase 1 (DIO1) (rs11206244-C/T, rs12095080-A/G, rs2235544-A/C), deiodinase 2 (DIO2) (rs225015-G/A, rs225014-T/C) and deiodinase 3 (DIO3) (rs945006-T/G). Both all-cause and cardiac mortality was considered key outcomes. Cox regression model showed that NT-pro-BNP (HR = 2.11; 95% CI = 1.18– 3.78; p = 0.012), the frst quartile of fT3, and DIO1 gene rs12095080 were independent predictors of cardiac-related mortality (HR = 1.74; 95% CI = 1.04–2.91; p = 0.034). The DIO1 gene rs12095080 AG genotype (OR = 3.97; 95% CI = 1.45–10.89; p = 0.005) increased the risk for cardiac mortality. Lower fT3 levels and the DIO1 gene rs12095080 are both associated with cardiac-related mortality after AMI. Recent clinical research in cardiovascular disease as well as in coronary artery disease (CAD) has provided evi- dence that altered thyroid hormone (TH) metabolism, including low total triiodothyronine (T3) syndrome or pre-existing subclinical primary hypothyroidism, is an important indicator of adverse short-term and long-term outcomes, including mortality1–5. -
Mice with Targeted Disruption of the Dio2 Gene Have
Mice with Targeted Disruption of the Dio2 Gene Have Cold-Induced Overexpression of the Uncoupling Protein 1 Gene but Fail to Increase Brown Adipose Tissue Lipogenesis and Adaptive Thermogenesis Marcelo A. Christoffolete,1 Camila C.G. Linardi,2 Lucia de Jesus,1 Katia Naomi Ebina,3 Suzy D. Carvalho,2 Miriam O. Ribeiro,4 Rogerio Rabelo,2 Cyntia Curcio,1 Luciane Martins,3 Edna T. Kimura,3 and Antonio C. Bianco1 The Dio2 gene encodes the type 2 deiodinase (D2) that activates thyroxine (T4) to 3,3,5-triiodothyronine -T3), the disruption of which (Dio2؊/؊) results in brown dequate quantities of thyroid hormone are re) adipose tissue (BAT)-specific hypothyroidism in an oth- quired for the maintenance of basal energy erwise euthyroid animal. In the present studies, cold expenditure (1,2) and are also critical for ad- exposure increased Dio2؊/؊ BAT sympathetic stimula- A justments in energy homeostasis during acute tion ϳ10-fold (normal ϳ4-fold); as a result, lipolysis, as exposure to cold, without which survival is not possible well as the mRNA levels of uncoupling protein 1, (3). These adjustments in nonshivering adaptive thermo- guanosine monophosphate reductase, and peroxisome genesis are initiated by an increase in the activity of the proliferator–activated receptor ␥ coactivator 1, in- sympathetic nervous system (SNS). In human newborns creased well above the levels detected in the cold- ؊/؊ and other small mammals, brown adipose tissue (BAT) is exposed wild-type animals. The sustained Dio2 BAT the main site of the sympathetic-mediated adaptive ther- adrenergic hyperresponse suppressed the three- to mogenesis. During cold exposure, there is an acute ϳ50- fourfold stimulation of BAT lipogenesis normally seen fold increase in type 2 iodothyronine deiodinase (D2) after 24–48 h in the cold. -
Molecular Cloning, Expression and Radiation Hybrid Mapping of the Bovine Deiodinase Type II (DIO2) and Deiodinase Type III (DIO3) Genes1
SHORT COMMUNICATION doi:10.1111/j.1365-2052.2005.01282.x Molecular cloning, expression and radiation hybrid mapping of the bovine deiodinase type II (DIO2) and deiodinase type III (DIO3) genes1 E. E. Connor*, E. C. Laiakis*, V. M. Fernandes*, J. L. Williams† and A. V. Capuco* *Beltsville Agricultural Research Center, ARS, USDA, 10300 Baltimore Ave., Beltsville, MD 20705, USA. †Roslin Institute (Edinburgh), Roslin, Midlothian EH25 9PS, UK Summary Thyroid hormones play a critical role in mammalian development and metabolism. Their activity is regulated in a complex, tissue-specific manner by three isoforms of deiodinases. The goal of this study was to sequence the full-length bovine type II deiodinase (DIO2) and type III deiodinase (DIO3) cDNAs and characterize mRNA expression levels of each of the three deiodinase isoforms in several bovine tissues. Sequencing of bovine DIO2 and DIO3 cDNAs revealed a high degree of predicted amino acid sequence identity with their orthologs in other mammalian species and demonstrated the conservation of selenocysteine residues within the catalytic domains of both bovine proteins. Bovine DIO2 and DIO3 were posi- tioned on chromosomes 10 and 21, respectively, by radiation hybrid mapping. Expression patterns of the three deiodinase isoforms were similar for deiodinase type I (DIO1) and DIO2 to those observed in other species. Expression level of DIO3 transcripts was greatest in mammary gland and kidney, although low-level expression was detected in most tissues sampled. Results of this work will aid in the study of deiodinase gene expression and thyroid hormone regulation in cattle. Keywords deiodinase, gene expression, gene mapping, thyroid hormone metabolism. -
Species-Specific Pharmacology of Maximakinin, An
Species-specific pharmacology of maximakinin, an amphibian homologue of bradykinin: putative prodrug activity at the human B2 receptor and peptidase resistance in rats Xavier Charest-Morin1,*, Hélène Bachelard2,*, Melissa Jean2 and Francois Marceau1 1 Axe Microbiologie-Infectiologie et Immunologie, CHU de Québec-Université Laval and Université Laval, Québec, QC, Canada 2 Axe endocrinologie et néphrologie, CHU de Québec-Université Laval and Université Laval, Québec, QC, Canada * These authors contributed equally to this work. ABSTRACT Maximakinin (MK), an amphibian peptide possessing the C-terminal sequence of bradykinin (BK), is a BK B2 receptor (B2R) agonist eliciting prolonged signaling. We reinvestigated this 19-mer for species-specific pharmacologic profile, in vivo confirmation of resistance to inactivation by angiotensin converting enzyme (ACE), value as a module for the design of fusion proteins that bind to the B2R in mammalian species and potential activity as a histamine releaser. Competition of the binding 3 of [ H]BK to recombinant human myc-B2Rs in cells that express these receptors revealed that MK possessed a tenuous fraction (<0.1%) of the affinity of BK, despite being only ∼20-fold less potent than BK in a contractility assay based on the human isolated umbilical vein. These findings are reconciled by the generation of C-terminal fragments, like Lys-Gly-Pro-BK and Gly-Pro-BK, when the latent MK is incubated with Submitted 24 October 2016 human venous tissue (LC-MS), supporting activation via hydrolysis upstream of the Accepted 14 December 2016 BK sequence. At the rat recombinant myc-B2R, MK had a lesser affinity than that of BK, Published 18 January 2017 but with a narrower margin (6.2-fold, radioligand binding competition). -
DIO2 Antibody / Type II Iodothyronine Deiodinase (F54462)
DIO2 Antibody / Type II Iodothyronine Deiodinase (F54462) Catalog No. Formulation Size F54462-0.4ML In 1X PBS, pH 7.4, with 0.09% sodium azide 0.4 ml F54462-0.08ML In 1X PBS, pH 7.4, with 0.09% sodium azide 0.08 ml Bulk quote request Availability 1-3 business days Species Reactivity Human, Mouse Format Purified Clonality Polyclonal (rabbit origin) Isotype Rabbit IgG Purity Antigen affinity purified UniProt Q92813 Applications Western blot : 1:500-1:2000 Flow cytometry : 1:25 (1x10e6 cells) Immunohistochemistry (FFPE) : 1:25 Limitations This DIO2 antibody is available for research use only. Western blot testing of 1) mouse heart and 2) human skeletal muscle lysate with DIO2 antibody. Predicted molecular weight ~31 kDa. Western blot testing of human 1) heart and 2) skeletal muscle lysate with DIO2 antibody. Predicted molecular weight ~31 kDa. Western blot testing of human MCF7 cell lysate with DIO2 antibody. Predicted molecular weight ~31 kDa. IHC testing of FFPE mouse brain tissue with DIO2 antibody. HIER: steam section in pH6 citrate buffer for 20 min and allow to cool prior to staining. Flow cytometry testing of human MCF7 cells with DIO2 antibody; Blue=isotype control, Green= DIO2 antibody. Description DIO2 belongs to the iodothyronine deiodinase family. It activates thyroid hormone by converting the prohormone thyroxine (T4) by outer ring deiodination (ORD) to bioactive 3,3',5-triiodothyronine (T3). Application Notes The stated application concentrations are suggested starting points. Titration of the DIO2 antibody may be required due to differences in protocols and secondary/substrate sensitivity. Immunogen A portion of amino acids 165-191 from the human protein was used as the immunogen for the DIO2 antibody. -
Thermogenesis in Adipose Tissue Activated by Thyroid Hormone
International Journal of Molecular Sciences Review Thermogenesis in Adipose Tissue Activated by Thyroid Hormone Winifred W. Yau 1 and Paul M. Yen 1,2,* 1 Laboratory of Hormonal Regulation, Cardiovascular and Metabolic Disorders Program, Duke NUS Medical School, Singapore 169857, Singapore; [email protected] 2 Duke Molecular Physiology Institute, Duke University, Durham, NC 27708, USA * Correspondence: [email protected]; Tel.: +65-6516-7666 Received: 23 March 2020; Accepted: 22 April 2020; Published: 24 April 2020 Abstract: Thermogenesis is the production of heat that occurs in all warm-blooded animals. During cold exposure, there is obligatory thermogenesis derived from body metabolism as well as adaptive thermogenesis through shivering and non-shivering mechanisms. The latter mainly occurs in brown adipose tissue (BAT) and muscle; however, white adipose tissue (WAT) also can undergo browning via adrenergic stimulation to acquire thermogenic potential. Thyroid hormone (TH) also exerts profound effects on thermoregulation, as decreased body temperature and increased body temperature occur during hypothyroidism and hyperthyroidism, respectively. We have termed the TH-mediated thermogenesis under thermoneutral conditions “activated” thermogenesis. TH acts on the brown and/or white adipose tissues to induce uncoupled respiration through the induction of the uncoupling protein (Ucp1) to generate heat. TH acts centrally to activate the BAT and browning through the sympathetic nervous system. However, recent studies also show that TH acts peripherally on the BAT to directly stimulate Ucp1 expression and thermogenesis through an autophagy-dependent mechanism. Additionally, THs can exert Ucp1-independent effects on thermogenesis, most likely through activation of exothermic metabolic pathways. This review summarizes thermogenic effects of THs on adipose tissues. -
The Vasopressin Receptor 2 Mutant R137L Linked to The
cells Article The Vasopressin Receptor 2 Mutant R137L Linked to the Nephrogenic Syndrome of Inappropriate Antidiuresis (NSIAD) Signals through an Alternative Pathway that Increases AQP2 Membrane Targeting Independently of S256 Phosphorylation Marianna Ranieri 1 , Maria Venneri 1, Tommaso Pellegrino 1, Mariangela Centrone 1, 1 1 1,2, 1,2,3, , Annarita Di Mise , Susanna Cotecchia , Grazia Tamma y and Giovanna Valenti * y 1 Department of Biosciences, Biotechnologies and Biopharmaceutics, University of Bari, 70125 Bari, Italy; [email protected] (M.R.); [email protected] (M.V.); [email protected] (T.P.); [email protected] (M.C.); [email protected] (A.D.M.); [email protected] (S.C.); [email protected] (G.T.) 2 Istituto Nazionale di Biostrutture e Biosistemi, 00136 Roma, Italy 3 Center of Excellence in Comparative Genomics (CEGBA), University of Bari, 70125 Bari, Italy * Correspondence: [email protected]; Tel.: +39-080-5443444 The authors contributed equally to this work. y Received: 8 May 2020; Accepted: 27 May 2020; Published: 29 May 2020 Abstract: NSIAD is a rare X-linked condition, caused by activating mutations in the AVPR2 gene coding for the vasopressin V2 receptor (V2R) associated with hyponatremia, despite undetectable plasma vasopressin levels. We have recently provided in vitro evidence that, compared to V2R-wt, expression of activating V2R mutations R137L, R137C and F229V cause a constitutive redistribution of the AQP2 water channel to the plasma membrane, higher basal water permeability and significantly higher basal levels of p256-AQP2 in the F229V mutant but not in R137L or R137C. In this study, V2R mutations were expressed in collecting duct principal cells and the associated signalling was dissected. -
Natural and Synthetic Inhibitors of Kallikrein-Related Peptidases (Klks)
Biochimie 92 (2010) 1546e1567 Contents lists available at ScienceDirect Biochimie journal homepage: www.elsevier.com/locate/biochi Review Natural and synthetic inhibitors of kallikrein-related peptidases (KLKs) Peter Goettig a,*, Viktor Magdolen b, Hans Brandstetter a a Division of Structural Biology, Department of Molecular Biology, University of Salzburg, Billrothstrasse 11, 5020 Salzburg, Austria b Klinische Forschergruppe der Frauenklinik, Klinikum rechts der Isar der TU München, Ismaninger Strasse 22, 81675 München, Germany article info abstract Article history: Including the true tissue kallikrein KLK1, kallikrein-related peptidases (KLKs) represent a family of fifteen Received 24 February 2010 mammalian serine proteases. While the physiological roles of several KLKs have been at least partially Accepted 29 June 2010 elucidated, their activation and regulation remain largely unclear. This obscurity may be related to the fact Available online 6 July 2010 that a given KLK fulfills many different tasks in diverse fetal and adult tissues, and consequently, the timescale of some of their physiological actions varies significantly. To date, a variety of endogenous þ Keywords: inhibitors that target distinct KLKs have been identified. Among them are the attenuating Zn2 ions, Tissue kallikrein fi active site-directed proteinaceous inhibitors, such as serpins and the Kazal-type inhibitors, or the huge, Speci city pockets fi Inhibitory compound unspeci c compartment forming a2-macroglobulin. Failure of these inhibitory systems can lead to certain Zinc pathophysiological conditions. One of the most prominent examples is the Netherton syndrome, which is Rule of five caused by dysfunctional domains of the Kazal-type inhibitor LEKTI-1 which fail to appropriately regulate KLKs in the skin.