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PMID: 11696583 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

The type 2 iodothyronine deiodinase is essential for adaptive thermogenesis in brown adipose tissue.

The Journal of clinical investigation ·Vol. 108 ·No. 9 ·2001-11-00 ·Pages 1379-85

de Jesus LA, Carvalho SD, Ribeiro MO, Schneider M, Kim SW, Harney JW, Larsen PR, Bianco AC

Abstract

Type 2 iodothyronine deiodinase (D2) is a selenoenzyme, the product of the recently cloned cAMP-dependent Dio2 gene, which increases 10- to 50-fold during cold stress only in brown adipose tissue (BAT). Here we report that despite a normal plasma 3,5,3'-triiodothyronine (T3) concentration, cold-exposed mice with targeted disruption of the Dio2 gene (Dio2(-/-)) become hypothermic due to impaired BAT thermogenesis and survive by compensatory shivering with consequent acute weight loss. This occurs despite normal basal mitochondrial uncoupling protein 1 (UCP1) concentration. In Dio2(-/-) brown adipocytes, the acute norepinephrine-, CL316,243-, or forskolin-induced increases in lipolysis, UCP1 mRNA, and O(2) consumption are all reduced due to impaired cAMP generation. These hypothyroid-like abnormalities are completely reversed by a single injection of T3 14 hours earlier. Recent studies suggest that UCP1 is primarily dependent on thyroid hormone receptor beta (TR beta) while the normal sympathetic response of brown adipocytes requires TR alpha. Intracellularly generated T3 may be required to saturate the TR alpha, which has an approximately fourfold lower T3-binding affinity than does TR beta. Thus, D2 is an essential component in the thyroid-sympathetic synergism required for thermal homeostasis in small mammals.

MeSH Terms
Adipose Tissue, Brown/metabolism,physiology Animals Body Weight Cells, Cultured Colforsin/pharmacology Cyclic AMP/metabolism Dioxoles/pharmacology Dose-Response Relationship, Drug Homeostasis Hypoglycemic Agents/pharmacology Iodide Peroxidase/chemistry,genetics,physiology Mice Mice, Inbred C57BL Mice, Transgenic Mitochondria/metabolism Models, Biological Oxygen/metabolism RNA, Messenger/metabolism Temperature Time Time Factors Triglycerides/metabolism Triiodothyronine/blood Weight Loss
Chemicals
Dioxoles Hypoglycemic Agents RNA, Messenger Triglycerides Triiodothyronine disodium (R,R)-5-(2-((2-(3-chlorophenyl)-2-hydroxyethyl)-amino)propyl)-1,3-benzodioxole-2,3-dicarboxylate Colforsin Cyclic AMP iodothyronine deiodinase type II Iodide Peroxidase Oxygen
Authors & Affiliations
8 authors, click to expand affiliations / ORCID
de Jesus L A
Thyroid Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.
Carvalho S D
Ribeiro M O
Schneider M
Kim S W
Harney J W
Larsen P R
Bianco A C
References (48)
48 references, click to expand
  1. Thyroid-catecholamine interactions in isolated rat brown adipocytes.
    Metabolism. 1984 Nov;33(11):1028-33 PMID: 6092828
  2. Thermogenic mechanisms in brown fat.
    Physiol Rev. 1984 Jan;64(1):1-64 PMID: 6320232
  3. Nuclear 3,5,3'-triiodothyronine (T3) in brown adipose tissue: receptor occupancy and sources of T3 as determined by in vivo techniques.
    Endocrinology. 1987 Jan;120(1):55-62 PMID: 3780570
  4. Intracellular conversion of thyroxine to triiodothyronine is required for the optimal thermogenic function of brown adipose tissue.
    J Clin Invest. 1987 Jan;79(1):295-300 PMID: 3793928
  5. Stimulation of S14 mRNA and lipogenesis in brown fat by hypothyroidism, cold exposure, and cafeteria feeding: evidence supporting a general role for S14 in lipogenesis and lipogenesis in the maintenance of thermogenesis.
    Proc Natl Acad Sci U S A. 1987 May;84(9):3070-4 PMID: 3472252
  6. Optimal response of key enzymes and uncoupling protein to cold in BAT depends on local T3 generation.
    Am J Physiol. 1987 Sep;253(3 Pt 1):E255-63 PMID: 3631256
  7. The effects and interactions of substrates, inhibitors, and the cellular thiol-disulfide balance on the regulation of type II iodothyronine 5'-deiodinase.
    Endocrinology. 1988 May;122(5):1860-8 PMID: 3359966
  8. Cold exposure rapidly induces virtual saturation of brown adipose tissue nuclear T3 receptors.
    Am J Physiol. 1988 Oct;255(4 Pt 1):E496-503 PMID: 3177636
  9. Triiodothyronine amplifies norepinephrine stimulation of uncoupling protein gene transcription by a mechanism not requiring protein synthesis.
    J Biol Chem. 1988 Dec 5;263(34):18168-75 PMID: 3192531
  10. Inhibition of 5'-deiodination of thyroxine suppresses the cold-induced increase in brown adipose tissue messenger ribonucleic acid for mitochondrial uncoupling protein without influencing lipoprotein lipase activity.
    Endocrinology. 1990 May;126(5):2550-4 PMID: 2328697
  11. Binding of 3,5,3'-triiodothyronine (T3) and its analogs to the in vitro translational products of c-erbA protooncogenes: differences in the affinity of the alpha- and beta-forms for the acetic acid analog and failure of the human testis and kidney alpha-2 products to bind T3.
    Mol Endocrinol. 1990 Feb;4(2):227-34 PMID: 2158622
  12. Brown adipose tissue thermogenesis: interdisciplinary studies.
    FASEB J. 1990 Aug;4(11):2890-8 PMID: 2199286
  13. Effect of iodine deficiency and cold exposure on thyroxine 5'-deiodinase activity in various rat tissues.
    Am J Physiol. 1991 Feb;260(2 Pt 1):E175-82 PMID: 1996620
  14. Central role of brown adipose tissue thyroxine 5'-deiodinase on thyroid hormone-dependent thermogenic response to cold.
    Endocrinology. 1991 Apr;128(4):2149-59 PMID: 2004619
  15. Triiodothyronine causes rapid reversal of alpha 1/cyclic adenosine monophosphate synergism on brown adipocyte respiration and type II deiodinase activity.
    Metabolism. 1991 Dec;40(12):1327-32 PMID: 1683679
  16. Transcriptional and posttranscriptional mechanisms in uncoupling protein mRNA response to cold.
    Am J Physiol. 1992 Jan;262(1 Pt 1):E58-67 PMID: 1733251
  17. Adenosine 3',5'-monophosphate and thyroid hormone control of uncoupling protein messenger ribonucleic acid in freshly dispersed brown adipocytes.
    Endocrinology. 1992 May;130(5):2625-33 PMID: 1374009
  18. Hormonal regulation of malic enzyme and glucose-6-phosphate dehydrogenase in brown adipose tissue.
    Am J Physiol. 1993 Jun;264(6 Pt 1):E874-81 PMID: 8333512
  19. Regulation of the uncoupling protein gene (Ucp) by beta 1, beta 2, and beta 3-adrenergic receptor subtypes in immortalized brown adipose cell lines.
    J Biol Chem. 1995 May 5;270(18):10723-32 PMID: 7738011
  20. Effects of thyroid hormone on norepinephrine signaling in brown adipose tissue. I. Beta 1- and beta 2-adrenergic receptors and cyclic adenosine 3',5'-monophosphate generation.
    Endocrinology. 1995 Aug;136(8):3267-76 PMID: 7628360
  21. Thyroid hormone and norepinephrine signaling in brown adipose tissue. II: Differential effects of thyroid hormone on beta 3-adrenergic receptors in brown and white adipose tissue.
    Endocrinology. 1995 Aug;136(8):3277-84 PMID: 7628361
  22. Effect of 3,5,3'-Triiodothyronine (T3) administration on dio1 gene expression and T3 metabolism in normal and type 1 deiodinase-deficient mice.
    Endocrinology. 1995 Nov;136(11):4842-9 PMID: 7588215
  23. Biogenesis of thermogenic mitochondria in brown adipose tissue of Djungarian hamsters during cold adaptation.
    Biochem J. 1996 Jun 1;316 ( Pt 2):607-13 PMID: 8687407
  24. T3 potentiates the adrenergic stimulation of type II 5'-deiodinase activity in cultured rat brown adipocytes.
    Am J Physiol. 1996 Jul;271(1 Pt 1):E15-23 PMID: 8760076
  25. Presence and mRNA expression of T3 receptors in differentiating rat brown adipocytes.
    Mol Cell Endocrinol. 1996 Jul 23;121(1):37-46 PMID: 8865164
  26. Effects of hypothyroidism on brown adipose tissue adenylyl cyclase activity.
    Endocrinology. 1996 Dec;137(12):5519-29 PMID: 8940379
  27. Mice lacking mitochondrial uncoupling protein are cold-sensitive but not obese.
    Nature. 1997 May 1;387(6628):90-4 PMID: 9139827
  28. Thermoregulatory and metabolic phenotypes of mice lacking noradrenaline and adrenaline.
    Nature. 1997 May 1;387(6628):94-7 PMID: 9139828
  29. Characterization of the 5'-flanking and 5'-untranslated regions of the cyclic adenosine 3',5'-monophosphate-responsive human type 2 iodothyronine deiodinase gene.
    Endocrinology. 2000 Jan;141(1):229-37 PMID: 10614643
  30. Thyroxine 5'-deiodination mediates norepinephrine-induced lipogenesis in dispersed brown adipocytes.
    Endocrinology. 1998 Feb;139(2):571-8 PMID: 9449627
  31. Direct measurement of the contributions of type I and type II 5'-deiodinases to whole body steady state 3,5,3'-triiodothyronine production from thyroxine in the rat.
    Endocrinology. 1998 Nov;139(11):4626-33 PMID: 9794474
  32. The mechanism of proton transport mediated by mitochondrial uncoupling proteins.
    FEBS Lett. 1998 Oct 30;438(1-2):10-4 PMID: 9821950
  33. 3,5,3'-Triiodothyronine actively stimulates UCP in brown fat under minimal sympathetic activity.
    Am J Physiol. 1999 Jan;276(1 Pt 1):E179-87 PMID: 9886965
  34. Role of the thyroid in metabolic responses to a cold environment.
    Am J Physiol. 1950 Oct;163(1):81-91 PMID: 14771277
  35. Towards a molecular understanding of adaptive thermogenesis.
    Nature. 2000 Apr 6;404(6778):652-60 PMID: 10766252
  36. Evidence of UCP1-independent regulation of norepinephrine-induced thermogenesis in brown fat.
    Am J Physiol Endocrinol Metab. 2000 Aug;279(2):E314-22 PMID: 10913031
  37. Isolation and characterization of the 5'-upstream and untranslated regions of the mouse type II iodothyronine deiodinase gene.
    Mol Cell Endocrinol. 2000 Jul 25;165(1-2):189-98 PMID: 10940497
  38. UCP1: the only protein able to mediate adaptive non-shivering thermogenesis and metabolic inefficiency.
    Biochim Biophys Acta. 2001 Mar 1;1504(1):82-106 PMID: 11239487
  39. Thyroid hormone--sympathetic interaction and adaptive thermogenesis are thyroid hormone receptor isoform--specific.
    J Clin Invest. 2001 Jul;108(1):97-105 PMID: 11435461
  40. The human type 2 iodothyronine deiodinase is a selenoprotein highly expressed in a mesothelioma cell line.
    J Biol Chem. 2001 Aug 10;276(32):30183-7 PMID: 11425850
  41. Targeted disruption of the type 2 selenodeiodinase gene (DIO2) results in a phenotype of pituitary resistance to T4.
    Mol Endocrinol. 2001 Dec;15(12):2137-48 PMID: 11731615
  42. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding.
    Anal Biochem. 1976 May 7;72:248-54 PMID: 942051
  43. Mitochondrial protein alteration in active brown fat: a soidum dodecyl sulfate-polyacrylamide gel electrophoretic study.
    Biochem Biophys Res Commun. 1976 Dec 6;73(3):577-83 PMID: 1008874
  44. Brown-adipose-tissue mitochondria: photoaffinity labelling of the regulatory site of energy dissipation.
    Eur J Biochem. 1978 Jan 16;82(2):515-21 PMID: 624284
  45. Force development and metabolism in skeletal muscle of euthyroid and hypothyroid rats.
    Acta Endocrinol (Copenh). 1981 Jun;97(2):221-5 PMID: 7234289
  46. Relationships between circulating and intracellular thyroid hormones: physiological and clinical implications.
    Endocr Rev. 1981 Winter;2(1):87-102 PMID: 6271545
  47. Adrenergic activation of triiodothyronine production in brown adipose tissue.
    Nature. 1983 Oct 20-26;305(5936):712-3 PMID: 6633638
  48. Potential of brown adipose tissue type II thyroxine 5'-deiodinase as a local and systemic source of triiodothyronine in rats.
    J Clin Invest. 1985 Dec;76(6):2296-305 PMID: 4077981
Article Info
Journal
The Journal of clinical investigation
Abbr.
J Clin Invest
ISSN
0021-9738
DOI
10.1172/JCI13803
Published
2001-11-00
Pages
1379-85
Language
English
Region
United States
NLM ID
7802877
PMCID
PMC209445
Subset
IM
Grants
NIDDK NIH HHS · R01 DK042271 · United States
NIDDK NIH HHS · R01 DK036256 · United States
NICHD NIH HHS · HD-09020 · United States
NIDDK NIH HHS · DK-36256 · United States
NIDDK NIH HHS · DK-42271 · United States
NICHD NIH HHS · R01 HD009020 · United States
External Links
PubMed source DOI: 10.1172/JCI13803 PMC Full Text View journal details
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