DOCSLIB.ORG

THEMATIC REVIEW Deiodinases: the Balance of Thyroid Hormone Local

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
THEMATIC REVIEW Deiodinases: the Balance of Thyroid Hormone Local 261 THEMATIC REVIEW Deiodinases: the balance of thyroid hormone Local control of thyroid hormone action: role of type 2 deiodinase Graham R Williams and J H Duncan Bassett Molecular Endocrinology Group, Department of Medicine and Medical Research Council Clinical Sciences Centre, Imperial College London, Hammersmith Hospital, Commonwealth Building 7th Floor, Du Cane Road, London W12 0NN, UK (Correspondence should be addressed to G R Williams; Email: [email protected]) Abstract The thyroid gland predominantly secretes the pro-hormone have revealed new and important roles for the enzyme thyroxine (T4) that is converted to the active hormone during development and in adulthood in diverse tissues 0 3,5,3 -L-triiodothyronine (T3) in target cells. Conversion of including the cochlea, skeleton, brown fat, pituitary, and T4 to T3 is catalyzed by the type 2 iodothyronine deiodinase hypothalamus. In this review, we discuss the molecular enzyme (DIO2), and T3 action in target tissues is determined mechanisms by which DIO2 controls intracellular T3 by DIO2-regulated local availability of T3 to its nuclear availability and action. receptors, TRa and TRb. Studies of Dio2 knockout mice Journal of Endocrinology (2011) 209, 261–272 Introduction Thyroid physiology Thyroid hormones are important homeostatic regulators that The hypothalamic–pituitary–thyroid axis act via nuclear thyroid hormone receptors (TRs) in virtually all Circulating thyroid hormone concentrations are maintained tissues during development and throughout postnatal life. 3,5,30, 0 in the euthyroid range by a classical negative feedback loop 5 -L-tetraiodothyronine (thyroxine, T ) is a pro-hormone that 4 (Fig. 1). Thyrotropin-releasing hormone (TRH) is syn- circulates at a high concentration in peripheral blood relative to 0 thesized in the hypothalamic para-ventricular nucleus (PVN) the active hormone 3,5,3 -L-triiodothyronine (T ). Concentra- 3 and stimulates synthesis and release of TSH from thyrotroph tions of T and T in target tissues are controlled by metabolism; 4 3 cells in the anterior pituitary gland. TSH in turn acts via the local conversion of T to T is catalyzed by the type 2 iodo- 4 3 TSH receptor (TSHR) in thyroid follicular cells to stimulate thyronine deiodinase enzyme (DIO2), while the type 3 enzyme cellular growth and the synthesis and release of T4 and T3 into (DIO3) prevents activation of T4 and inactivates T3.Thispre- the circulation (Kopp 2001). Thyroid hormone action is receptor control of ligand availability to TRs in target cells is a mediated in target tissues by TRs, but thyroid hormones also crucial mechanism that regulates the timing of cellular responses to inhibit TRH and TSH synthesis and secretion in the thyroid hormones in a tissue-specific manner. The physiological hypothalamus and pituitary to complete a negative feedback importance of this coordinated process has been demonstrated in loop (Forrest et al. 1996b, Nikrodhanond et al. 2006). This several organ systems by a series of elegant in vivo studies, and in this negative feedback loop maintains circulating thyroid hor- study, we review recent developments with particular emphasis mones and TSH in a physiological inverse relationship that on the importance of hormone activation mediated by DIO2. defines the hypothalamic–pituitary–thyroid (HPT) axis set- point (Bassett & Williams 2008). Circulating thyroid hormones and uptake into target cells This paper is one of 3 papers that form part of a Thematic review section on deiodinases: the balance of thyroid hormone. The Guest Editor for this The thyroid gland predominantly secretes the inactive pro- section was Domenico Salvatore, University of Naples, Italy. hormone T4, as well as small amounts of the physiologically Journal of Endocrinology (2011) 209, 261–272 DOI: 10.1530/JOE-10-0448 0022–0795/11/0209–261 q 2011 Society for Endocrinology Printed in Great Britain Online version via http://www.endocrinology-journals.org Downloaded from Bioscientifica.com at 09/28/2021 07:01:47PM via free access 262 G R WILLIAMS and J H D BASSETT . Local control of T3 action by Dio2 active thyroid hormone T3. Both T4 and T3 are lipophilic Thyroid hormone metabolism and poorly soluble in water, and over 95% of thyroid hormones are protein bound in the circulation. Thyroxine- Deiodinase enzymes binding globulin (TBG), transthyretin, albumin, and several The iodothyronine deiodinases are selenocysteine-containing lipoproteins function as the transport proteins for T and T 4 3 enzymes that metabolize thyroid hormones to active or in plasma. Free thyroid hormone levels are thus dependent inactive products (Bianco et al. 2002). The type 1 deiodinase upon the concentrations and saturations of these proteins. enzyme (DIO1) is rather inefficient with an apparent The unbound free T fraction represents 0.3% of the total K K 3 Michaelis constant (K )of10 6–10 7 M and catalyzes T concentration in plasma, but because of its higher m 3 removal of inner or outer ring iodine atoms in equimolar binding affinity for TBG, the free T fraction represents just 4 proportions to generate T , reverse T (rT ), or 3,30- 0.02% of the total plasma T concentration. Thus, despite 3 3 3 4 diiodothyronine (T ) depending on the substrate. Most of the total T concentration being 50-fold greater than total 2 4 the circulating T is derived from conversion of T to T by T , the circulating free T concentration is only fourfold 3 4 3 3 4 the actions of DIO1, which is localized to the plasma higher. T is exclusively synthesized and secreted by thyroid 4 membrane and expressed in liver and kidney. Nevertheless, follicular cells, whereas the majority of circulating T is 3 activity of the DIO2 enzyme in skeletal muscle may also generated in peripheral tissues by enzymatic removal of a contribute to circulating levels of T , although its role is 50-iodine from T . Due to their lipophilic nature, thyroid 3 4 controversial and may differ between species (Bianco et al. hormones had been likely to enter target cells by a passive 2002, Maia et al. 2005, Bianco & Kim 2006, Heemstra et al. process of diffusion (Friesema et al. 2005). In fact, the free 2009b, Larsen 2009). The DIO2 enzyme is considerably more hormones enter target cells via an energy-dependent, ATP- efficient than DIO1, catalyzing only the removal of an outer requiring, stereospecific, and saturable transport mechanism ring iodine atom from the pro-hormone T4 with a Km of that is mediated by the monocarboxylate transporter 8 K9 10 M to generate the physiologically active product T . (MCT8; Friesema et al. 2003, 2006, Dumitrescu et al. 3 The major role of DIO2 is to control the intracellular T 2006), MCT10, and other transporter proteins including 3 C concentration, its availability to the nucleus, and the OATP1c1, a member of the Na -independent organic saturation of the nuclear T3 receptor in target tissues. anion transporter protein (OATP) family ( Jansen et al. Moreover, DIO2 is likely to protect tissues from the 2005, Heuer 2007, van der Deure et al. 2010; Fig. 2). detrimental effects of hypothyroidism because its low Km Transport via MCT8, for example, increases uptake of T4 continues to permit the efficient local conversion of T4 to T3. and T3 by tenfold (Friesema et al. 2003). T4 treatment of cells, in which MCT8 and DIO2 are co-expressed, results in increased T3 target gene expression (Friesema et al. 2006), indicating that thyroid hormone uptake and metabolism coordinately regulate T3 action. By contrast, the DIO3 enzyme irreversibly inactivates T3,or β – PVN T4 DIO2? T3 TR 2 prevents T4 being activated, by catalyzing removal of an inner K9 Hypothalamus ring iodine atom with a Km of 10 M to generate T2 or rT3 respectively. Thus, inactivating DIO3 prevents thyroid hormone access to specific tissues at critical times and reduces TRH TR saturation (Bianco et al. 2002, Bianco & Kim 2006). + Pituitary Control of intracellular T availability β 3 T4 DIO2 T3 TR 2 – The relative activities of DIO2 and DIO3, which have the TSH same Km values for substrate, consequently regulate intra- + cellular concentrations of T3 and its availability to the nuclear TR (Bianco et al. 2002, Bianco & Kim 2006, St Germain et al. Thyroid 2009). In conjunction with serum-derived T3, DIO2 and DIO3 are important local modulators of thyroid hormone T4 + T3 responsiveness in vivo. Expression of both enzymes is regulated Figure 1 Negative feedback regulation of the hypothalamic– in a temporo-spatial and tissue-specific manner, resulting in pituitary–thyroid axis. The role of DIO2 in negative feedback varying levels of T3 action in individual tissues at distinct times control of the HPT axis occurs predominantly in thyrotrophs of the during development (Bates et al. 1999, St Germain et al. 2009). anterior pituitary gland. PVN, para-ventricular nucleus; TRH, Acting together, DIO2 and DIO3 thus control cellular T thyrotropin-releasing hormone; DIO2, type 2 deiodinase enzyme; 3 0 availability by a mechanism that is largely independent of TRb2, thyroid hormone receptor b2; T4, thyroxine; T3, 3,5,3 -L- triiodothyronine. serum thyroid hormone concentrations (Bianco & Kim 2006). Journal of Endocrinology (2011) 209, 261–272 www.endocrinology-journals.org Downloaded from Bioscientifica.com at 09/28/2021 07:01:47PM via free access Local control of T3 action by Dio2 . G R WILLIAMS and J H D BASSETT 263 MCT8 MCT10 OATP1C1 T 4 T4 T3 DIO2 T3 T3 DIO3 T3 rT3 RXR TR T2 TRE Figure 2 Regulation of intracellular supplies of T3 to the nucleus of T3 target cells. MCT8 and MCT10, monocarboxylate transporters 8 and 10; OATP1C1, organic acid transporter protein-1C1; DIO2 and DIO3, type 2 and 3 deiodinase enzymes; TR, thyroid hormone 0 receptor, RXR, retinoid X receptor; T4, thyroxine; T3, 3,5,3 -L-triiodothyronine; rT3, 0 0 0 3,3 ,5 -triiodothyronine; T2, 3,3 -diiodothyronine.
Load more

Recommended publications
  • Diet-Induced Obesity Mediated by the JNK/DIO2 Signal Transduction Pathway
    Downloaded from genesdev.cshlp.org on September 24, 2021 - Published by Cold Spring Harbor Laboratory Press Diet-induced obesity mediated by the JNK/DIO2 signal transduction pathway Santiago Vernia,1 Julie Cavanagh-Kyros,1,2 Tamera Barrett,1,2 Dae Young Jung,1 Jason K. Kim,1,3 and Roger J. Davis1,2,4 1Program in Molecular Medicine, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA; 2Howard Hughes Medical Institute, Worcester, Massachusetts 01605, USA; 3Department of Medicine, Division of Endocrinology, Metabolism, and Diabetes, University of Massachusetts Medical School, Worcester, Massachusetts 01605, USA The cJun N-terminal kinase (JNK) signaling pathway is a key mediator of metabolic stress responses caused by consuming a high-fat diet, including the development of obesity. To test the role of JNK, we examined diet- induced obesity in mice with targeted ablation of Jnk genes in the anterior pituitary gland. These mice exhibited an increase in the pituitary expression of thyroid-stimulating hormone (TSH), an increase in the blood concentration of thyroid hormone (T4), increased energy expenditure, and markedly reduced obesity compared with control mice. The increased amount of pituitary TSH was caused by reduced expression of type 2 iodothyronine deiodinase (Dio2), a gene that is required for T4-mediated negative feedback regulation of TSH expression. These data establish a molecular mechanism that accounts for the regulation of energy expenditure and the development of obesity by the JNK signaling pathway. [Keywords: DIO2; JNK; obesity; pituitary gland; thyroid hormone] Supplemental material is available for this article. Received June 5, 2013; revised version accepted October 3, 2013.
    [Show full text]
  • 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).
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • 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.
    [Show full text]
  • Brief Genetics Report
    Brief Genetics Report Association Between a Novel Variant of the Human Type 2 Deiodinase Gene Thr92Ala and Insulin Resistance Evidence of Interaction With the Trp64Arg Variant of the ␤-3-Adrenergic Receptor Daniela Mentuccia,1,2 Laura Proietti-Pannunzi,3 Keith Tanner,1 Vincenzo Bacci,4 Toni I. Pollin,1 Eric T. Poehlman,5 Alan R. Shuldiner,1,6 and Francesco S. Celi3 Thyroid hormone action is an important determinant of energy and glucose metabolism. T4 metabolism is regu- lated by the deiodinases of which type 2 is expressed in he cluster of obesity, hypertension, insulin resis- humans in skeletal muscle and brown adipose tissue, tance, and glucose intolerance/diabetes (Syn- where its transcription is stimulated by the ␤-3 adren- drome X) is a polygenic multifactorial condition ergic pathway. We performed molecular scanning of the in which the phenotype is the net result of the human type 2 deiodinase (DIO2) gene and evaluated a T interaction between environmental factors and genetic novel variant for associations with obesity and insulin resistance, assessing both the main effect and interac- predisposition deriving from variations in genes encoding tion with the Trp64Arg ␤-3–adrenergic receptor (ADRB3) proteins involved in metabolic pathways (1). In fact, variant. Molecular scanning of DIO2 in 50 obese Cauca- polymorphisms in several candidate genes, such as the ␤-3 sians demonstrated a Thr92Ala variant. Association adrenergic receptor (ADRB3) (2,3), insulin receptor sub- studies in 972 nondiabetic patients, 135 of whom under- strate-1 (4), peroxisome proliferator–activated receptor-␥ went euglycemic-hyperinsulinemic clamps, showed that (5), fatty acid binding protein-2 (6), and perhaps others, subjects with the Thr92Ala variant had lower glucose have shown association with various traits of Syndrome X.
    [Show full text]
  • 19-20 IFMNT COT Cardiometabolic More Genomics with Application Susan Allen-Evenson RDN, CCN, FMNS
    19-20 IFMNT COT CardioMetabolic More Genomics with Application Susan Allen-Evenson RDN, CCN, FMNS ©2020 COPYRIGHT. ALL RIGHTS RESERVED More CardioMetabolic SNPs • DIO1 and DIO2 • FUT2 • SLC19A1 • TCN2 • APOC3 • LPL • CETP • AGT • ACE DIO1 and DIO2 Deiodinase, iodothyronine Type I (DIO1) and Type II (DIO2) Deiodinases regulate thyroid hormone activity DIO1 and DIO2: • Both catalyze conversion of thyroxine (T4), secreted from the thyroid gland, into the bioactive thyroid hormone T3 through deiodination of T4 • They require selenium and cysteine (selenocysteine) for optimal function 1. DIO1 Gene (Protein Coding). GeneCards. https://www.genecards.org/cgi-bin/carddisp.pl?gene=DIO1. Accessed December 24, 2019. 2. DIO2 Gene (Protein Coding). GeneCards. https://www.genecards.org/cgi-bin/carddisp.pl?gene=DIO2. Accessed December 24, 2019 3. Ristic A. A Gene That Activates Thyroid Hormones (DIO1). SelfDecode. https://selfdecode.com/blog/article/low-thyroid-dio1-18. Accessed December 25, 2019.. ©2020 COPYRIGHT. ALL RIGHTS RESERVED DIO1 and DIO2 • DIO1 activity mainly localized in thyroid, liver and kidneys • DIO2 activity expresses at high levels in brain, pituitary, central nervous system, thyroid, heart and peripheral tissues (skeletal muscle) • DIO2 significance: Accounts for up to 60% of T3 production 1. Watson R, Watson, Ronald Ross (university Of Arizona, Mel And Enid Zu. Selenium and Senescence (Ch.21). In: Foods and Dietary Supplements in the Prevention and Treatment of Disease In. Elsevier Science Publishing Co; 2015:211-229. 2. Ristic A. The Gene Associated with "Hidden Hypothyroidism" (DIO2). SelfDecode. https://selfdecode.com/blog/article/hidden-hypothyroidism-dio2-36. Accessed January 4, 2020. ©2020 COPYRIGHT. ALL RIGHTS RESERVED Thyroid Affects Cardio Function • Thyroid hormones affect almost every aspect of the cardiovascular system • T3 increases force/speed of systolic contraction and speed of diastolic relaxation • T3 decreases vascular resistance, including coronary vascular tone, and increases coronary arteriolar angiogenesis 1.
    [Show full text]
  • USP33 Mediates Slitrobo Signaling in Inhibiting Colorectal Cancer Cell
    IJC International Journal of Cancer USP33 mediates Slit-Robo signaling in inhibiting colorectal cancer cell migration Zhaohui Huang1,2, Pushuai Wen3, Ruirui Kong3, Haipeng Cheng2, Binbin Zhang1, Cao Quan1, Zehua Bian1, Mengmeng Chen3, Zhenfeng Zhang4, Xiaoping Chen2, Xiang Du5, Jianghong Liu3, Li Zhu3, Kazuo Fushimi2, Dong Hua1 and Jane Y. Wu2,3 1 Wuxi Oncology Institute, the Affiliated Hospital of Jiangnan University, Wuxi, Jiangsu, China 2 Department of Neurology, Center for Genetic Medicine, Lurie Cancer Center, Northwestern University Feinberg School of Medicine, 303 E. Chicago Ave., Chicago, IL 3 State Key Laboratory of Brain and Cognitive Science, Institute of Biophysics, Chinese Academy of Sciences, Beijing, China 4 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Shanghai Jiao Tong University School of Medicine, Shanghai, China 5 Department of Pathology, Fudan University Shanghai Cancer Center, Shanghai, China Originally discovered in neuronal guidance, the Slit-Robo pathway is emerging as an important player in human cancers. How- ever, its involvement and mechanism in colorectal cancer (CRC) remains to be elucidated. Here, we report that Slit2 expression is reduced in CRC tissues compared with adjacent noncancerous tissues. Extensive promoter hypermethylation of the Slit2 gene has been observed in CRC cells, which provides a mechanistic explanation for the Slit2 downregulation in CRC. Func- tional studies showed that Slit2 inhibits CRC cell migration in a Robo-dependent manner. Robo-interacting ubiquitin-specific protease 33 (USP33) is required for the inhibitory function of Slit2 on CRC cell migration by deubiquitinating and stabilizing Robo1. USP33 expression is downregulated in CRC samples, and reduced USP33 mRNA levels are correlated with increased tumor grade, lymph node metastasis and poor patient survival.
    [Show full text]