Adipocyte signaling affects thyroid-specific gene expression via down-regulation of TTF-2/FOXE1

in Journal of Molecular Endocrinology
Authors:
Michela ZamboniInstitute of Biochemistry and Cell Biology, National Council of Research, Monterotondo, Rome, Italy

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Georgios StrimpakosInstitute of Biochemistry and Cell Biology, National Council of Research, Monterotondo, Rome, Italy

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Eleonora PoggiogalleDepartment of Experimental Medicine – Medical Pathophysiology, Food Science and Endocrinology Section, Sapienza University of Rome, Rome, Italy

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Lorenzo M DoniniDepartment of Experimental Medicine – Medical Pathophysiology, Food Science and Endocrinology Section, Sapienza University of Rome, Rome, Italy

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Donato CivitarealeInstitute of Biochemistry and Cell Biology, National Council of Research, Monterotondo, Rome, Italy

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https://orcid.org/0000-0001-5719-9098
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Correspondence should be addressed to D Civitareale: donato.civitareale@ibbc.cnr.it
DOI:
https://doi.org/10.1530/JME-22-0129
Volume/Issue:
Volume 70: Issue 1
Article Type:
Research Article
Article ID:
e220129
Online Publication Date:
12 Dec 2022
Copyright:
© Society for Endocrinology 2022
Restricted access

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Obesity affects thyroid gland function. Hypothyroidism, thyroid nodules, goiter, and thyroid cancer are more frequent in patients with higher BMI values. Although these data are supported by many clinical and epidemiological studies, our knowledge is very scarce at the molecular level. In this study, we present the first experimental evidence that adipocyte signaling downregulates the expression of thyroid-specific transcription factor 2 (TTF-2/FoxE1). It plays a crucial role in thyroid development and thyroid homeostasis and it is strictly connected to thyroid cancer as well. We provide in vivo and in vitro evidence that inhibition of TTF-2/FoxE1 gene expression is mediated by adipocyte signaling.

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Full Text Views 383 383 3
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Print ISSN:
0952-5041
Online ISSN:
1479-6813
Copyright:
© Society for Endocrinology 2022
Article ID:
e220129
Article Type:
Research Article
Received Date:
10 Oct 2022
Accepted Date:
08 Nov 2022
Print Publication Date:
01 Jan 2023
Online Publication Date:
12 Dec 2022
Keywords:
thyroid; obesity; signaling; TTF-2/FoxE1

  • Avgerinos KI, Spyrou N, Mantzoros CS & Dalamaga M 2019 Obesity and cancer risk: emerging biological mechanisms and perspectives. Metabolism: Clinical and Experimental 92 121–135. (https://doi.org/10.1016/j.metabol.2018.11.001)

    • Search Google Scholar
    • Export Citation

  • Aza-Blanc P, Di Lauro R & Santisteban P 1993 Identification of a cis-regulatory element and a thyroid-specific nuclear factor mediating the hormonal regulation of rat thyroid peroxidase promoter activity. Molecular Endocrinology 7 1297–1306. (https://doi.org/10.1210/mend.7.10.8264661)

    • Search Google Scholar
    • Export Citation

  • Bazzara LG, Vélez ML, Costamagna ME, Cabanillas AM, Fozzatti L, Lucero AM, Pellizas CG & Masini-Repiso AM 2007 Nitric oxide/cGMP signaling inhibits TSH-stimulated iodide uptake and expression of thyroid peroxidase and thyroglobulin mRNA in FRTL-5 thyroid cells. Thyroid 17 717–727. (https://doi.org/10.1089/thy.2007.0086)

    • Search Google Scholar
    • Export Citation

  • Bolin AP, Sousa-Filho CPB, Dos Santos GTN, Ferreira LT, de Andrade PBM, Figueira ACM, Batista FAH & Otton R 2020 Adipogenic commitment induced by green tea polyphenols remodel adipocytes to a thermogenic phenotype. Journal of Nutritional Biochemistry 83 108429. (https://doi.org/10.1016/j.jnutbio.2020.108429)

    • Search Google Scholar
    • Export Citation

  • Buettner R, Schölmerich J & Bollheimer LC 2007 High-fat diets: modeling the metabolic disorders of human obesity in rodents. Obesity 15 798–808. (https://doi.org/10.1038/oby.2007.608)

    • Search Google Scholar
    • Export Citation

  • Chen X, Wang JJ, Yu L, Wang HY & Sun H 2021 The association between BMI, smoking, drinking and thyroid disease: a cross-sectional study in Wuhan, China. BMC Endocrine Disorders 21 184. (https://doi.org/10.1186/s12902-021-00852-0)

    • Search Google Scholar
    • Export Citation

  • Coelho M, Oliveira T & Fernandes R 2013 Biochemistry of adipose tissue: an endocrine organ. Archives of Medical Science 9 191–200. (https://doi.org/10.5114/aoms.2013.33181)

    • Search Google Scholar
    • Export Citation

  • Colin IM, Poncin S, Levêque P, Gallez B & Gérard AC 2014 Differential regulation of the production of reactive oxygen species in Th1 cytokine-treated thyroid cells. Thyroid 24 441–452. (https://doi.org/10.1089/thy.2013.0142)

    • Search Google Scholar
    • Export Citation

  • Conlee KM, Stephens ML, Rowan AN & King LA 2005 Carbon dioxide for euthanasia: concerns regarding pain and distress, with special reference to mice and rats. Laboratory Animals 39 137–161. (https://doi.org/10.1258/0023677053739747)

    • Search Google Scholar
    • Export Citation

  • Cortés JMR & Zerón HM 2019 Genetics of thyroid disorders. Folia Medica 61 172–179. (https://doi.org/10.2478/folmed-2018-0078)

  • Credendino SC, Moccia C, Amendola E, D’Avino G, Di Guida L, Clery E, Greco A, Bellevicine C, Brunetti A & De Felice M et al.2020 FOXE1 gene dosage affects thyroid cancer histology and differentiation in vivo. International Journal of Molecular Sciences 22 E25. (https://doi.org/10.3390/ijms22010025)

    • Search Google Scholar
    • Export Citation

  • Damante G, Tell G & Di Lauro R 2001 A unique combination of transcription factors controls differentiation of thyroid cells. Progress in Nucleic Acid Research and Molecular Biology 66 307–356. (https://doi.org/10.1016/s0079-6603(0066033-6)

    • Search Google Scholar
    • Export Citation

  • De Felice M, Ovitt C, Biffali E, Rodriguez-Mallon A, Arra C, Anastassiadis K, Macchia PE, Mattei MG, Mariano A & Schöler H et al.1998 A mouse model for hereditary thyroid dysgenesis and cleft palate. Nature Genetics 19 395–398. (https://doi.org/10.1038/1289)

    • Search Google Scholar
    • Export Citation

  • De Leo R, Miccadei S, Zammarchi E & Civitareale D 2000 Role for p300 in Pax 8 induction of thyroperoxidase gene expression. Journal of Biological Chemistry 275 34100–34105. (https://doi.org/10.1074/jbc.M003043200)

    • Search Google Scholar
    • Export Citation

  • Deng T, Lyon CJ, Bergin S, Caligiuri MA & Hsueh WA 2016 Obesity, inflammation, and cancer. Annual Review of Pathology 11 421–449. (https://doi.org/10.1146/annurev-pathol-012615-044359)

    • Search Google Scholar
    • Export Citation

  • Denny JC, Crawford DC, Ritchie MD, Bielinski SJ, Basford MA, Bradford Y, Chai HS, Bastarache L, Zuvich R & Peissig P et al.2011 Variants near FOXE1 are associated with hypothyroidism and other thyroid conditions: using electronic medical records for genome- and phenome-wide studies. American Journal of Human Genetics 89 529–542. (https://doi.org/10.1016/j.ajhg.2011.09.008)

    • Search Google Scholar
    • Export Citation

  • Ellulu MS, Patimah I, Khaza’ai H, Rahmat A & Abed Y 2017 Obesity and inflammation: the linking mechanism and the complications. Archives of Medical Science 13 851–863. (https://doi.org/10.5114/aoms.2016.58928)

    • Search Google Scholar
    • Export Citation

  • Engeland A, Tretli S, Akslen LA & Bjørge T 2006 Body size and thyroid cancer in two million Norwegian men and women. British Journal of Cancer 95 366–370. (https://doi.org/10.1038/sj.bjc.6603249)

    • Search Google Scholar
    • Export Citation

  • Fernández LP, López-Márquez A, Martínez AM, Gómez-López G & Santisteban P 2013 New insights into FoxE1 functions: identification of direct FoxE1 targets in thyroid cells. PLoS One 8 e62849. (https://doi.org/10.1371/journal.pone.0062849)

    • Search Google Scholar
    • Export Citation

  • Fernández LP, López-Márquez A & Santisteban P 2015 Thyroid transcription factors in development, differentiation and disease. Nature Reviews. Endocrinology 11 29–42. (https://doi.org/10.1038/nrendo.2014.186)

    • Search Google Scholar
    • Export Citation

  • Gudmundsson J, Sulem P, Gudbjartsson DF, Jonasson JG, Sigurdsson A, Bergthorsson JT, He H, Blondal T, Geller F & Jakobsdottir M et al.2009 Common variants on 9q22.33 and 14q13.3 predispose to thyroid cancer in European populations. Nature Genetics 41 460–464. (https://doi.org/10.1038/ng.339)

    • Search Google Scholar
    • Export Citation

  • Hata T, Dal Molin M, Hong SM, Tamura K, Suenaga M, Yu J, Sedogawa H, Weiss MJ, Wolfgang CL & Lennon AM et al.2017 Predicting the grade of dysplasia of pancreatic cystic neoplasms using cyst fluid DNA methylation markers. Clinical Cancer Research 23 3935–3944. (https://doi.org/10.1158/1078-0432.CCR-16-2244)

    • Search Google Scholar
    • Export Citation

  • Hotamisligil GS, Shargill NS & Spiegelman BM 1993 Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 259 87–91. (https://doi.org/10.1126/science.7678183)

    • Search Google Scholar
    • Export Citation

  • Jafari H, Hussain S & Campbell MJ 2022 Nuclear receptor coregulators in hormone-dependent cancers. Cancers 14 2402. (https://doi.org/10.3390/cancers14102402)

    • Search Google Scholar
    • Export Citation

  • Khodamoradi K, Khosravizadeh Z, Seetharam D, Mallepalli S, Farber N & Arora H 2022 The role of leptin and low testosterone in obesity. International Journal of Impotence Research 34 704–713. (https://doi.org/10.1038/s41443-022-00534-y)

    • Search Google Scholar
    • Export Citation

  • Kimura T, Van Keymeulen A, Golstein J, Fusco A, Dumont JE & Roger PP 2001 Regulation of thyroid cell proliferation by TSH and other factors: a critical evaluation of in vitro models. Endocrine Reviews 22 631–656. (https://doi.org/10.1210/edrv.22.5.0444)

    • Search Google Scholar
    • Export Citation

  • Kwan HY, Chen M, Xu K & Chen B 2021 The impact of obesity on adipocyte-derived extracellular vesicles. Cellular and Molecular Life Sciences 78 7275–7288. (https://doi.org/10.1007/s00018-021-03973-w)

    • Search Google Scholar
    • Export Citation

  • Landa I, Ruiz-Llorente S, Montero-Conde C, Inglada-Pérez L, Schiavi F, Leskelä S, Pita G, Milne R, Maravall J & Ramos I et al.2009 The variant rs1867277 in FOXE1 gene confers thyroid cancer susceptibility through the recruitment of USF1/USF2 transcription factors. PLOS Genetics 5 e1000637. (https://doi.org/10.1371/journal.pgen.1000637)

    • Search Google Scholar
    • Export Citation

  • Lang P, Hasselwander S, Li H & Xia N 2019 Effects of different diets used in diet-induced obesity models on insulin resistance and vascular dysfunction in C57BL/6 mice. Scientific Reports 9 19556. (https://doi.org/10.1038/s41598-019-55987-x)

    • Search Google Scholar
    • Export Citation

  • Lee MH, Lee JU, Joung KH, Kim YK, Ryu MJ, Lee SE, Kim SJ, Chung HK, Choi MJ & Chang JY et al.2015 Thyroid dysfunction associated with follicular cell steatosis in obese male mice and humans. Endocrinology 156 1181–1193. (https://doi.org/10.1210/en.2014-1670)

    • Search Google Scholar
    • Export Citation

  • Li L, Li Y, Timothy Sembiring Meliala I, Kasim V & Wu S 2020 Biological roles of Yin Yang 2: Its implications in physiological and pathological events. Journal of Cellular and Molecular Medicine 24 12886–12899. (https://doi.org/10.1111/jcmm.15919)

    • Search Google Scholar
    • Export Citation

  • Li W & Ain KB 2010 Human sodium-iodide symporter (hNIS) gene expression is inhibited by a trans-active transcriptional repressor, NIS-repressor, containing PARP-1 in thyroid cancer cells. Endocrine-Related Cancer 17 383–398. (https://doi.org/10.1677/ERC-09-0156)

    • Search Google Scholar
    • Export Citation

  • Lutz TA & Woods SC 2012 Overview of animal models of obesity. Current Protocols in Pharmacology Chapter 5 Unit 5.61. (https://doi.org/10.1002/0471141755.ph0561s58)

    • Search Google Scholar
    • Export Citation

  • Mello DF, Trevisan R, Rivera N, Geitner NK, Di Giulio RT, Wiesner MR, Hsu-Kim H & Meyer JN 2020 Caveats to the use of MTT, neutral red, Hoechst and resazurin to measure silver nanoparticle cytotoxicity. Chemico-Biological Interactions 315 108868. (https://doi.org/10.1016/j.cbi.2019.108868)

    • Search Google Scholar
    • Export Citation

  • Menendez D, Inga A & Resnick MA 2009 The expanding universe of p53 targets. Nature Reviews. Cancer 9 724–737. (https://doi.org/10.1038/nrc2730)

    • Search Google Scholar
    • Export Citation

  • Miyazaki A, Shimura H, Endo T, Haraguchi K & Onaya T 1999 Tumor necrosis factor-alpha and interferon-gamma suppress both gene expression and deoxyribonucleic acid-binding of TTF-2 in FRTL-5 cells. Endocrinology 140 4214–4220. (https://doi.org/10.1210/endo.140.9.6982)

    • Search Google Scholar
    • Export Citation

  • Montesinos Mdel M, Nicola JP, Nazar M, Peyret V, Lucero AM, Pellizas CG & Masini-Repiso AM 2016 Nitric oxide-repressed Forkhead factor FoxE1 expression is involved in the inhibition of TSH-induced thyroid peroxidase levels. Molecular and Cellular Endocrinology 420 105–115. (https://doi.org/10.1016/j.mce.2015.11.020)

    • Search Google Scholar
    • Export Citation

  • Ortiz L, Zannini M, Di Lauro R & Santisteban P 1997 Transcriptional control of the forkhead thyroid transcription factor TTF-2 by thyrotropin, insulin, and insulin-like growth factor I. Journal of Biological Chemistry 272 23334–23339. (https://doi.org/10.1074/jbc.272.37.23334)

    • Search Google Scholar
    • Export Citation

  • Panveloski-Costa AC, Serrano-Nascimento C, Bargi-Souza P, Poyares LL, Viana GS & Nunes MT 2018 Beneficial effects of thyroid hormone on adipose inflammation and insulin sensitivity of obese Wistar rats. Physiological Reports 6 e13550. (https://doi.org/10.14814/phy2.13550)

    • Search Google Scholar
    • Export Citation

  • Penna-Martinez M, Epp F, Kahles H, Ramos-Lopez E, Hinsch N, Hansmann ML, Selkinski I, Grünwald F, Holzer K & Bechstein WO et al.2014 FOXE1 association with differentiated thyroid cancer and its progression. Thyroid 24 845–851. (https://doi.org/10.1089/thy.2013.0274)

    • Search Google Scholar
    • Export Citation

  • Perrone L, Pasca di Magliano M, Zannini M & Di Lauro R 2000 The thyroid transcription factor 2 (TTF-2) is a promoter-specific DNA-binding independent transcriptional repressor. Biochemical and Biophysical Research Communications 275 203–208. (https://doi.org/10.1006/bbrc.2000.3232)

    • Search Google Scholar
    • Export Citation

  • Popovic V & Duntas LH 2005 Leptin TRH and ghrelin: influence on energy homeostasis at rest and during exercise. Hormone and Metabolic Research 37 533–537. (https://doi.org/10.1055/s-2005-870418)

    • Search Google Scholar
    • Export Citation

  • Ramírez-Zacarías JL, Castro-Muñozledo F & Kuri-Harcuch W 1992 Quantitation of adipose conversion and triglycerides by staining intracytoplasmic lipids with Oil Red O. Histochemistry 97 493–497. (https://doi.org/10.1007/BF00316069)

    • Search Google Scholar
    • Export Citation

  • Reinehr T 2011 Thyroid function in the nutritionally obese child and adolescent. Current Opinion in Pediatrics 23 415–420. (https://doi.org/10.1097/MOP.0b013e328344c393)

    • Search Google Scholar
    • Export Citation

  • Rosen OM, Smith CJ, Hirsch A, Lai E & Rubin CS 1979 Recent studies of the 3T3-L1 adipocyte-like cell line. Recent Progress in Hormone Research 35 477–499. (https://doi.org/10.1016/b978-0-12-571135-7.50015-1)

    • Search Google Scholar
    • Export Citation

  • Santisteban P, Acebrón A, Polycarpou-Schwarz M & Di Lauro R 1992 Insulin and insulin-like growth factor I regulate a thyroid-specific nuclear protein that binds to the thyroglobulin promoter. Molecular Endocrinology 6 1310–1317. (https://doi.org/10.1210/mend.6.8.1406708)

    • Search Google Scholar
    • Export Citation

  • Takahashi M, Saenko VA, Rogounovitch TI, Kawaguchi T, Drozd VM, Takigawa-Imamura H, Akulevich NM, Ratanajaraya C, Mitsutake N & Takamura N et al.2010 The FOXE1 locus is a major genetic determinant for radiation-related thyroid carcinoma in Chernobyl. Human Molecular Genetics 19 2516–2523. (https://doi.org/10.1093/hmg/ddq123)

    • Search Google Scholar
    • Export Citation

  • Venza I, Visalli M, Tripodo B, De Grazia G, Loddo S, Teti D & Venza M 2010 FOXE1 is a target for aberrant methylation in cutaneous squamous cell carcinoma. British Journal of Dermatology 162 1093–1097. (https://doi.org/10.1111/j.1365-2133.2009.09560.x)

    • Search Google Scholar
    • Export Citation

  • Wang CY & Liao JK 2012 A mouse model of diet-induced obesity and insulin resistance. Methods in Molecular Biology 821 421–433. (https://doi.org/10.1007/978-1-61779-430-8_27)

    • Search Google Scholar
    • Export Citation

  • Wang Y, Lin H, Li Q, Guan L, Zhao M, Zhong F, Liu J, Yuan Z, Guo H & Song Y et al.2021 Association between different obesity phenotypes and hypothyroidism: a study based on a longitudinal health management cohort. Endocrine 72 688–698. (https://doi.org/10.1007/s12020-021-02677-2)

    • Search Google Scholar
    • Export Citation

  • Zaccolo M & Movsesian MA 2007 cAMP and cGMP signaling cross-talk: role of phosphodiesterases and implications for cardiac pathophysiology. Circulation Research 100 1569–1578. (https://doi.org/10.1161/CIRCRESAHA.106.144501)

    • Search Google Scholar
    • Export Citation

  • Zannini M, Avantaggiato V, Biffali E, Arnone MI, Sato K, Pischetola M, Taylor BA, Phillips SJ, Simeone A & Di Lauro R 1997 TTF-2, a new forkhead protein, shows a temporal expression in the developing thyroid which is consistent with a role in controlling the onset of differentiation. EMBO Journal 16 3185–3197. (https://doi.org/10.1093/emboj/16.11.3185)

    • Search Google Scholar
    • Export Citation

  • Zhao ZG, Guo XG, Ba CX, Wang W, Yang YY, Wang J & Cao HY 2012 Overweight, obesity and thyroid cancer risk: a meta-analysis of cohort studies. Journal of International Medical Research 40 2041–2050. (https://doi.org/10.1177/030006051204000601)

    • Search Google Scholar
    • Export Citation