Skip to main content

Advertisement

SpringerLink
Log in

Thyroid hormone metabolites and analogues

  • Review
  • Published:
Endocrine Aims and scope Submit manuscript

Abstract

Several metabolic products that derive from l-thyroxine (T4) and 3,3′5-l-triiodothyronine (T3), the main thyroid hormones secreted by the thyroid gland, possess biologic activities. Among these metabolites or derivatives showing physiological actions some have received greater attention: diiodothyronines, iodothyronamines, acetic acid analogues. It is known that increased thyroid hormone (T3 and T4) levels can improve serum lipid profiles and reduce body fat. These positive effects are, however, counterbalanced by adverse effects on the heart, muscle and bone, limiting their use. In addition to the naturally occurring metabolites, thyroid hormone analogues have been developed that either have selective effects on specific tissues or bind selectively to thyroid hormone receptor (TR) isoform. Among these GC-1, KB141, KB2115, and DITPA were deeply investigated and displayed promising therapeutic results in the potential treatment of conditions such as dyslipidemias and obesity. In this review, we summarize the current knowledge of metabolites and analogues of T4 and T3 with reference to their possible clinical application in the treatment of human diseases.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. M.A. Kowalik, A. Columbano, A. Perra, Thyroid hormones, thyromimetics and their metabolites in the treatment of liver disease. Front Endocrinol. (Lausanne) 9, 382 (2018). https://doi.org/10.3389/fendo.2018.00382

    Article  Google Scholar 

  2. G. Chiellini, J.W. Apriletti, H.A. Yoshihara, J.D. Baxter, R.C. Ribeiro, T.S. Scanlan, A high-affinity subtype-selective agonist ligand for the thyroid hormone receptor. Chem. Biol. 5(6), 299–306 (1998)

    Article  CAS  Google Scholar 

  3. S.U. Trost, E. Swanson, B. Gloss, D.B. Wang-Iverson, H. Zhang, T. Volodarsky, G.J. Grover, J.D. Baxter, G. Chiellini, T.S. Scanlan, W.H. Dillmann, The thyroid hormone receptor-beta-selective agonist GC-1 differentially affects plasma lipids and cardiac activity. Endocrinology 141(9), 3057–3064 (2000). https://doi.org/10.1210/endo.141.9.7681

    Article  CAS  PubMed  Google Scholar 

  4. L. Johansson, M. Rudling, T.S. Scanlan, T. Lundasen, P. Webb, J. Baxter, B. Angelin, P. Parini, Selective thyroid receptor modulation by GC-1 reduces serum lipids and stimulates steps of reverse cholesterol transport in euthyroid mice. Proc. Natl Acad. Sci. USA 102(29), 10297–10302 (2005). https://doi.org/10.1073/pnas.0504379102

    Article  CAS  PubMed  Google Scholar 

  5. J.Z. Lin, A.J. Martagon, W.A. Hsueh, J.D. Baxter, J.A. Gustafsson, P. Webb, K.J. Phillips, Thyroid hormone receptor agonists reduce serum cholesterol independent of the LDL receptor. Endocrinology 153(12), 6136–6144 (2012). https://doi.org/10.1210/en.2011-2081

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. A. Goncalves, C.C. Tolentino, F.R. Souza, J.C. Huss, L. Zinato Kde, L.T. Lopes, R. Furlanetto Junior, A. Neves Fde, The thyroid hormone receptor beta-selective agonist GC-1 does not affect tolerance to exercise in hypothyroid rats. Arch. Endocrinol. Metab. 59(2), 141–147 (2015). https://doi.org/10.1590/2359-3997000000027

    Article  PubMed  Google Scholar 

  7. L. Ye, Y.L. Li, K. Mellstrom, C. Mellin, L.G. Bladh, K. Koehler, N. Garg, A.M. Garcia Collazo, C. Litten, B. Husman, K. Persson, J. Ljunggren, G. Grover, P.G. Sleph, R. George, J. Malm, Thyroid receptor ligands. 1. Agonist ligands selective for the thyroid receptor beta1. J. Med Chem. 46(9), 1580–1588 (2003). https://doi.org/10.1021/jm021080f

    Article  CAS  PubMed  Google Scholar 

  8. G.J. Grover, K. Mellstrom, L. Ye, J. Malm, Y.L. Li, L.G. Bladh, P.G. Sleph, M.A. Smith, R. George, B. Vennstrom, K. Mookhtiar, R. Horvath, J. Speelman, D. Egan, J.D. Baxter, Selective thyroid hormone receptor-beta activation: a strategy for reduction of weight, cholesterol, and lipoprotein (a) with reduced cardiovascular liability. Proc. Natl Acad. Sci. USA 100(17), 10067–10072 (2003). https://doi.org/10.1073/pnas.1633737100

    Article  CAS  PubMed  Google Scholar 

  9. A. Berkenstam, J. Kristensen, K. Mellstrom, B. Carlsson, J. Malm, S. Rehnmark, N. Garg, C.M. Andersson, M. Rudling, F. Sjoberg, B. Angelin, J.D. Baxter, The thyroid hormone mimetic compound KB2115 lowers plasma LDL cholesterol and stimulates bile acid synthesis without cardiac effects in humans. Proc. Natl Acad. Sci. USA 105(2), 663–667 (2008). https://doi.org/10.1073/pnas.0705286104

    Article  PubMed  Google Scholar 

  10. D.F. Vatner, D. Weismann, S.A. Beddow, N. Kumashiro, D.M. Erion, X.H. Liao, G.J. Grover, P. Webb, K.J. Phillips, R.E. Weiss, J.S. Bogan, J. Baxter, G.I. Shulman, V.T. Samuel, Thyroid hormone receptor-beta agonists prevent hepatic steatosis in fat-fed rats but impair insulin sensitivity via discrete pathways. Am. J. Physiol. Endocrinol. Metab. 305(1), E89–E100 (2013). https://doi.org/10.1152/ajpendo.00573.2012

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. P.W. Ladenson, J.D. Kristensen, E.C. Ridgway, A.G. Olsson, B. Carlsson, I. Klein, J.D. Baxter, B. Angelin, Use of the thyroid hormone analogue eprotirome in statin-treated dyslipidemia. N. Engl. J. Med 362(10), 906–916 (2010). https://doi.org/10.1056/NEJMoa0905633

    Article  CAS  PubMed  Google Scholar 

  12. Bio, K.: Karo Bio terminates the eprotirome program. (2010). http://www.karobio.com/investormedia/pressreleaser/pressrelease?pid=639535

  13. B. Sjouke, G. Langslet, R. Ceska, S.J. Nicholls, S.E. Nissen, M. Ohlander, P.W. Ladenson, A.G. Olsson, G.K. Hovingh, J.J. Kastelein, Eprotirome in patients with familial hypercholesterolaemia (the AKKA trial): a randomised, double-blind, placebo-controlled phase 3 study. Lancet Diabetes Endocrinol. 2(6), 455–463 (2014). https://doi.org/10.1016/S2213-8587(14)70006-3

    Article  CAS  PubMed  Google Scholar 

  14. R. Taub, E. Chiang, M. Chabot-Blanchet, M.J. Kelly, R.A. Reeves, M.C. Guertin, J.C. Tardif, Lipid lowering in healthy volunteers treated with multiple doses of MGL-3196, a liver-targeted thyroid hormone receptor-beta agonist. Atherosclerosis 230(2), 373–380 (2013). https://doi.org/10.1016/j.atherosclerosis.2013.07.056

    Article  CAS  PubMed  Google Scholar 

  15. G.D. Pennock, T.E. Raya, J.J. Bahl, S. Goldman, E. Morkin, Cardiac effects of 3,5-diiodothyropropionic acid, a thyroid hormone analog with inotropic selectivity. J. Pharm. Exp. Ther. 263(1), 163–169 (1992)

    CAS  Google Scholar 

  16. S. Goldman, M. McCarren, E. Morkin, P.W. Ladenson, R. Edson, S. Warren, J. Ohm, H. Thai, L. Churby, J. Barnhill, T. O’Brien, I. Anand, A. Warner, B. Hattler, M. Dunlap, J. Erikson, M.C. Shih, P. Lavori, DITPA (3,5-Diiodothyropropionic Acid), a thyroid hormone analog to treat heart failure: phase II trial veterans affairs cooperative study. Circulation 119(24), 3093–3100 (2009). https://doi.org/10.1161/CIRCULATIONAHA.108.834424

    Article  CAS  PubMed  Google Scholar 

  17. P.W. Ladenson, M. McCarren, E. Morkin, R.G. Edson, M.C. Shih, S.R. Warren, J.G. Barnhill, L. Churby, H. Thai, T. O’Brien, I. Anand, A. Warner, B. Hattler, M. Dunlap, J. Erikson, S. Goldman, Effects of the thyromimetic agent diiodothyropropionic acid on body weight, body mass index, and serum lipoproteins: a pilot prospective, randomized, controlled study. J. Clin. Endocrinol. Metab. 95(3), 1349–1354 (2010). https://doi.org/10.1210/jc.2009-1209

    Article  CAS  PubMed  Google Scholar 

  18. C. Di Cosmo, X.H. Liao, A.M. Dumitrescu, R.E. Weiss, S. Refetoff, A thyroid hormone analog with reduced dependence on the monocarboxylate transporter 8 for tissue transport. Endocrinology 150(9), 4450–4458 (2009). https://doi.org/10.1210/en.2009-0209

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. A.M. Ferrara, X.H. Liao, H. Ye, R.E. Weiss, A.M. Dumitrescu, S. Refetoff, The thyroid hormone analog DITPA ameliorates metabolic parameters of male mice with Mct8 deficiency. Endocrinology 156(11), 3889–3894 (2015). https://doi.org/10.1210/en.2015-1234

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. C.F. Verge, D. Konrad, M. Cohen, C. Di Cosmo, A.M. Dumitrescu, T. Marcinkowski, S. Hameed, J. Hamilton, R.E. Weiss, S. Refetoff, Diiodothyropropionic acid (DITPA) in the treatment of MCT8 deficiency. J. Clin. Endocrinol. Metab. 97(12), 4515–4523 (2012). https://doi.org/10.1210/jc.2012-2556

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. M.B. Dratman, On the mechanism of action of thyroxin, an amino acid analog of tyrosine. J. Theor. Biol. 46(1), 255–270 (1974)

    Article  CAS  Google Scholar 

  22. C.S. Hoefig, T. Wuensch, E. Rijntjes, I. Lehmphul, H. Daniel, U. Schweizer, J. Mittag, J. Kohrle, Biosynthesis of 3-Iodothyronamine from T4 in murine intestinal tissue. Endocrinology 156(11), 4356–4364 (2015). https://doi.org/10.1210/en.2014-1499

    Article  CAS  PubMed  Google Scholar 

  23. C.S. Hoefig, J. Kohrle, G. Brabant, K. Dixit, B. Yap, C.J. Strasburger, Z. Wu, Evidence for extrathyroidal formation of 3-iodothyronamine in humans as provided by a novel monoclonal antibody-based chemiluminescent serum immunoassay. J. Clin. Endocrinol. Metab. 96(6), 1864–1872 (2011). https://doi.org/10.1210/jc.2010-2680

    Article  CAS  PubMed  Google Scholar 

  24. T.S. Scanlan, K.L. Suchland, M.E. Hart, G. Chiellini, Y. Huang, P.J. Kruzich, S. Frascarelli, D.A. Crossley, J.R. Bunzow, S. Ronca-Testoni, E.T. Lin, D. Hatton, R. Zucchi, D.K. Grandy, 3-Iodothyronamine is an endogenous and rapid-acting derivative of thyroid hormone. Nat. Med 10(6), 638–642 (2004). https://doi.org/10.1038/nm1051

    Article  CAS  PubMed  Google Scholar 

  25. A. Saba, G. Chiellini, S. Frascarelli, M. Marchini, S. Ghelardoni, A. Raffaelli, M. Tonacchera, P. Vitti, T.S. Scanlan, R. Zucchi, Tissue distribution and cardiac metabolism of 3-iodothyronamine. Endocrinology 151(10), 5063–5073 (2010). https://doi.org/10.1210/en.2010-0491

    Article  CAS  PubMed  Google Scholar 

  26. V. Mariotti, E. Melissari, C. Iofrida, M. Righi, M. Di Russo, R. Donzelli, A. Saba, S. Frascarelli, G. Chiellini, R. Zucchi, S. Pellegrini, Modulation of gene expression by 3-iodothyronamine: genetic evidence for a lipolytic pattern. PLoS ONE 9(11), e106923 (2014). https://doi.org/10.1371/journal.pone.0106923

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. M.E. Manni, G. De Siena, A. Saba, M. Marchini, E. Landucci, E. Gerace, M. Zazzeri, C. Musilli, D. Pellegrini-Giampietro, R. Matucci, R. Zucchi, L. Raimondi, Pharmacological effects of 3-iodothyronamine (T1AM) in mice include facilitation of memory acquisition and retention and reduction of pain threshold. Br. J. Pharm. 168(2), 354–362 (2013). https://doi.org/10.1111/j.1476-5381.2012.02137.x

    Article  CAS  Google Scholar 

  28. M. Rogowski, L. Gollahon, G. Chellini, F.M. Assadi-Porter, Uptake of 3-iodothyronamine hormone analogs inhibits the growth and viability of cancer cells. FEBS Open Bio 7(4), 587–601 (2017). https://doi.org/10.1002/2211-5463.12205

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. F. Goglia, J. Torresani, P. Bugli, A. Barletta, G. Liverini, In vitro binding of triiodothyronine to rat liver mitochondria. Pflug. Arch. 390(2), 120–124 (1981)

    Article  CAS  Google Scholar 

  30. C. Horst, H. Rokos, H.J. Seitz, Rapid stimulation of hepatic oxygen consumption by 3,5-di-iodo-L-thyronine. Biochem J. 261(3), 945–950 (1989). https://doi.org/10.1042/bj2610945

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. R. Senese, P. de Lange, G. Petito, M. Moreno, F. Goglia, A. Lanni, 3,5-Diiodothyronine: a novel thyroid hormone metabolite and potent modulator of energy metabolism. Front Endocrinol. (Lausanne) 9, 427 (2018). https://doi.org/10.3389/fendo.2018.00427

    Article  Google Scholar 

  32. R.A. Louzada, D.P. Carvalho, Similarities and differences in the peripheral actions of thyroid hormones and their metabolites. Front Endocrinol. (Lausanne) 9, 394 (2018). https://doi.org/10.3389/fendo.2018.00394

    Article  Google Scholar 

  33. G. Sacripanti, N.M. Nguyen, L. Lorenzini, S. Frascarelli, A. Saba, R. Zucchi, S. Ghelardoni, 3,5-Diiodo-l-thyronine increases glucose consumption in cardiomyoblasts without affecting the contractile performance in rat heart. Front Endocrinol. (Lausanne) 9, 282 (2018). https://doi.org/10.3389/fendo.2018.00282

    Article  Google Scholar 

  34. M. Moreno, A. Lombardi, L. Beneduce, E. Silvestri, G. Pinna, F. Goglia, A. Lanni, Are the effects of T3 on resting metabolic rate in euthyroid rats entirely caused by T3 itself? Endocrinology 143(2), 504–510 (2002). https://doi.org/10.1210/endo.143.2.8613

    Article  CAS  PubMed  Google Scholar 

  35. I. Lehmphul, G. Brabant, H. Wallaschofski, M. Ruchala, C.J. Strasburger, J. Kohrle, Z. Wu, Detection of 3,5-diiodothyronine in sera of patients with altered thyroid status using a new monoclonal antibody-based chemiluminescence immunoassay. Thyroid 24(9), 1350–1360 (2014). https://doi.org/10.1089/thy.2013.0688

    Article  CAS  PubMed  Google Scholar 

  36. P.J. Davis, F. Goglia, J.L. Leonard, Nongenomic actions of thyroid hormone. Nat. Rev. Endocrinol. 12(2), 111–121 (2016). https://doi.org/10.1038/nrendo.2015.205

    Article  CAS  PubMed  Google Scholar 

  37. M. Moreno, A. Giacco, C. Di Munno, F. Goglia, Direct and rapid effects of 3,5-diiodo-L-thyronine (T2). Mol. Cell Endocrinol. 458, 121–126 (2017). https://doi.org/10.1016/j.mce.2017.02.012

    Article  CAS  PubMed  Google Scholar 

  38. P. Navarrete-Ramirez, M. Luna, R.C. Valverde, A. Orozco, 3,5-di-iodothyronine stimulates tilapia growth through an alternate isoform of thyroid hormone receptor beta1. J. Mol. Endocrinol. 52(1), 1–9 (2014). https://doi.org/10.1530/JME-13-0145

    Article  CAS  PubMed  Google Scholar 

  39. A. Lanni, M. Moreno, A. Lombardi, F. Goglia, 3,5-Diiodo-L-thyronine and 3,5,3’-triiodo-L-thyronine both improve the cold tolerance of hypothyroid rats, but possibly via different mechanisms. Pflug. Arch. 436(3), 407–414 (1998). https://doi.org/10.1007/s004240050650

    Article  CAS  Google Scholar 

  40. A. Lombardi, R. De Matteis, M. Moreno, L. Napolitano, R.A. Busiello, R. Senese, P. de Lange, A. Lanni, F. Goglia, Responses of skeletal muscle lipid metabolism in rat gastrocnemius to hypothyroidism and iodothyronine administration: a putative role for FAT/CD36. Am. J. Physiol. Endocrinol. Metab. 303(10), E1222–E1233 (2012). https://doi.org/10.1152/ajpendo.00037.2012

    Article  CAS  PubMed  Google Scholar 

  41. E. Silvestri, A. Lombardi, M. Coppola, A. Gentile, F. Cioffi, R. Senese, F. Goglia, A. Lanni, M. Moreno, P. de Lange, Differential effects of 3,5-diiodo-l-thyronine and 3,5,3′-triiodo-l-thyronine on mitochondrial respiratory pathways in liver from hypothyroid rats. Cell Physiol. Biochem 47(6), 2471–2483 (2018). https://doi.org/10.1159/000491620

    Article  CAS  PubMed  Google Scholar 

  42. A. Lanni, M. Moreno, A. Lombardi, P. de Lange, E. Silvestri, M. Ragni, P. Farina, G.C. Baccari, P. Fallahi, A. Antonelli, F. Goglia, 3,5-diiodo-L-thyronine powerfully reduces adiposity in rats by increasing the burning of fats. FASEB J. 19(11), 1552–1554 (2005). https://doi.org/10.1096/fj.05-3977fje

    Article  CAS  PubMed  Google Scholar 

  43. P. de Lange, F. Cioffi, R. Senese, M. Moreno, A. Lombardi, E. Silvestri, R. De Matteis, L. Lionetti, M.P. Mollica, F. Goglia, A. Lanni, Nonthyrotoxic prevention of diet-induced insulin resistance by 3,5-diiodo-L-thyronine in rats. Diabetes 60(11), 2730–2739 (2011). https://doi.org/10.2337/db11-0207

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. E. Silvestri, F. Cioffi, D. Glinni, M. Ceccarelli, A. Lombardi, P. de Lange, A. Chambery, V. Severino, A. Lanni, F. Goglia, M. Moreno, Pathways affected by 3,5-diiodo-l-thyronine in liver of high fat-fed rats: evidence from two-dimensional electrophoresis, blue-native PAGE, and mass spectrometry. Mol. Biosyst. 6(11), 2256–2271 (2010). https://doi.org/10.1039/c0mb00040j

    Article  CAS  PubMed  Google Scholar 

  45. M. Moreno, E. Silvestri, R. De Matteis, P. de Lange, A. Lombardi, D. Glinni, R. Senese, F. Cioffi, A.M. Salzano, A. Scaloni, A. Lanni, F. Goglia, 3,5-Diiodo-L-thyronine prevents high-fat-diet-induced insulin resistance in rat skeletal muscle through metabolic and structural adaptations. FASEB J. 25(10), 3312–3324 (2011). https://doi.org/10.1096/fj.11-181982

    Article  CAS  PubMed  Google Scholar 

  46. M.P. Mollica, L. Lionetti, M. Moreno, A. Lombardi, P. De Lange, A. Antonelli, A. Lanni, G. Cavaliere, A. Barletta, F. Goglia, 3,5-diiodo-l-thyronine, by modulating mitochondrial functions, reverses hepatic fat accumulation in rats fed a high-fat diet. J. Hepatol. 51(2), 363–370 (2009). https://doi.org/10.1016/j.jhep.2009.03.023

    Article  CAS  PubMed  Google Scholar 

  47. E. Grasselli, A. Voci, I. Demori, G. Vecchione, A.D. Compalati, G. Gallo, F. Goglia, R. De Matteis, E. Silvestri, L. Vergani, Triglyceride Mobilization from lipid droplets sustains the anti-steatotic action of iodothyronines in cultured rat hepatocytes. Front Physiol. 6, 418 (2015). https://doi.org/10.3389/fphys.2015.00418

    Article  PubMed  Google Scholar 

  48. E. Grasselli, A. Voci, I. Demori, L. Canesi, R. De Matteis, F. Goglia, A. Lanni, G. Gallo, L. Vergani, 3,5-Diiodo-L-thyronine modulates the expression of genes of lipid metabolism in a rat model of fatty liver. J. Endocrinol. 212(2), 149–158 (2012). https://doi.org/10.1530/JOE-11-0288

    Article  CAS  PubMed  Google Scholar 

  49. L.F. Iannucci, F. Cioffi, R. Senese, F. Goglia, A. Lanni, P.M. Yen, R.A. Sinha, Metabolomic analysis shows differential hepatic effects of T2 and T3 in rats after short-term feeding with high fat diet. Sci. Rep. 7(1), 2023 (2017). https://doi.org/10.1038/s41598-017-02205-1

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. P. Fallahi, S.M. Ferrari, E. Santini, S. Camastra, G. Frenzilli, M. Puccini, F. Goglia, A. Lanni, P. Marchetti, A. Antonelli, Both 3,5-diiodo-L-thyronine (T2) and T3 modulate glucose-induced insulin secretion. J. Biol. Regul. Homeost. Agents 31(2), 503–508 (2017)

    CAS  PubMed  Google Scholar 

  51. A. Lombardi, R. Senese, R. De Matteis, R.A. Busiello, F. Cioffi, F. Goglia, A. Lanni, 3,5-Diiodo-L-thyronine activates brown adipose tissue thermogenesis in hypothyroid rats. PLoS ONE 10(2), e0116498 (2015). https://doi.org/10.1371/journal.pone.0116498

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. R. Senese, F. Cioffi, R. De Matteis, G. Petito, P. de Lange, E. Silvestri, A. Lombardi, M. Moreno, F. Goglia, A. Lanni, 3,5 diiodo-l-thyronine (T(2)) promotes the browning of white adipose tissue in high-fat diet-induced overweight male rats housed at thermoneutrality. Cells 8(3) (2019). https://doi.org/10.3390/cells8030256

  53. S. da Silva Teixeira, C. Filgueira, D.H. Sieglaff, C. Benod, R. Villagomez, L.J. Minze, A. Zhang, P. Webb, M.T. Nunes, 3,5-diiodothyronine (3,5-T2) reduces blood glucose independently of insulin sensitization in obese mice. Acta Physiol. (Oxf.) 220(2), 238–250 (2017). https://doi.org/10.1111/apha.12821

    Article  CAS  Google Scholar 

  54. E. Silvestri, R. Senese, F. Cioffi, R. De Matteis, D. Lattanzi, A. Lombardi, A. Giacco, A.M. Salzano, A. Scaloni, M. Ceccarelli, M. Moreno, F. Goglia, A. Lanni, P. de Lange, 3,5-diiodo-l-thyronine exerts metabolically favorable effects on visceral adipose tissue of rats receiving a high-fat diet. Nutrients 11(2) (2019). https://doi.org/10.3390/nu11020278

  55. E. Silvestri, F. Cioffi, R. De Matteis, R. Senese, P. de Lange, M. Coppola, A.M. Salzano, A. Scaloni, M. Ceccarelli, F. Goglia, A. Lanni, M. Moreno, A. Lombardi, 3,5-diiodo-l-thyronine affects structural and metabolic features of skeletal muscle mitochondria in high-fat-diet fed rats producing a co-adaptation to the glycolytic fiber phenotype. Front Physiol. 9, 194 (2018). https://doi.org/10.3389/fphys.2018.00194

    Article  PubMed  PubMed Central  Google Scholar 

  56. A. Lombardi, A. Lanni, M. Moreno, M.D. Brand, F. Goglia, Effect of 3,5-di-iodo-L-thyronine on the mitochondrial energy-transduction apparatus. Biochem J. 330(Pt 1), 521–526 (1998). https://doi.org/10.1042/bj3300521

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. A. Cavallo, F. Taurino, F. Damiano, L. Siculella, A.M. Sardanelli, A. Gnoni, Acute administration of 3,5-diiodo-L-thyronine to hypothyroid rats stimulates bioenergetic parameters in liver mitochondria. J. Bioenerg. Biomembr. 48(5), 521–529 (2016). https://doi.org/10.1007/s10863-016-9686-4

    Article  CAS  PubMed  Google Scholar 

  58. A. Cavallo, A. Gnoni, E. Conte, L. Siculella, F. Zanotti, S. Papa, G.V. Gnoni, 3,5-diiodo-L-thyronine increases FoF1-ATP synthase activity and cardiolipin level in liver mitochondria of hypothyroid rats. J. Bioenerg. Biomembr. 43(4), 349–357 (2011). https://doi.org/10.1007/s10863-011-9366-3

    Article  CAS  PubMed  Google Scholar 

  59. A. Lombardi, P. de Lange, E. Silvestri, R.A. Busiello, A. Lanni, F. Goglia, M. Moreno, 3,5-Diiodo-L-thyronine rapidly enhances mitochondrial fatty acid oxidation rate and thermogenesis in rat skeletal muscle: AMP-activated protein kinase involvement. Am. J. Physiol. Endocrinol. Metab. 296(3), E497–E502 (2009). https://doi.org/10.1152/ajpendo.90642.2008

    Article  CAS  PubMed  Google Scholar 

  60. F. Cioffi, R. Senese, G. Petito, P. Lasala, P. de Lange, E. Silvestri, A. Lombardi, M. Moreno, F. Goglia, A. Lanni, Both 3,3′,5-triiodothyronine and 3,5-diodo-L-thyronine are able to repair mitochondrial DNA damage but by different mechanisms. Front Endocrinol. (Lausanne) 10, 216 (2019). https://doi.org/10.3389/fendo.2019.00216

    Article  Google Scholar 

  61. A. Antonelli, P. Fallahi, S.M. Ferrari, A. Di Domenicantonio, M. Moreno, A. Lanni, F. Goglia, 3,5-diiodo-L-thyronine increases resting metabolic rate and reduces body weight without undesirable side effects. J. Biol. Regul. Homeost. Agents 25(4), 655–660 (2011)

    CAS  PubMed  Google Scholar 

  62. W.J. Wood, T. Geraci, A. Nilsen, A.E. DeBarber, T.S. Scanlan, Iodothyronamines are oxidatively deaminated to iodothyroacetic acids in vivo. Chembiochem 10(2), 361–365 (2009). https://doi.org/10.1002/cbic.200800607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. S. Groeneweg, R.P. Peeters, T.J. Visser, W.E. Visser, Triiodothyroacetic acid in health and disease. J. Endocrinol. 234(2), R99–R121 (2017). https://doi.org/10.1530/JOE-17-0113

    Article  CAS  PubMed  Google Scholar 

  64. S.I. Sherman, P.W. Ladenson, Octreotide therapy of growth hormone excess in the McCune-Albright syndrome. J. Endocrinol. Invest 15(3), 185–190 (1992). https://doi.org/10.1007/BF03348702

    Article  CAS  PubMed  Google Scholar 

  65. S.I. Sherman, M.D. Ringel, M.J. Smith, H.A. Kopelen, W.A. Zoghbi, P.W. Ladenson, Augmented hepatic and skeletal thyromimetic effects of tiratricol in comparison with levothyroxine. J. Clin. Endocrinol. Metab. 82(7), 2153–2158 (1997). https://doi.org/10.1210/jcem.82.7.4054

    Article  CAS  PubMed  Google Scholar 

  66. S. Kersseboom, S. Horn, W.E. Visser, J. Chen, E.C. Friesema, C. Vaurs-Barriere, R.P. Peeters, H. Heuer, T.J. Visser, In vitro and mouse studies supporting therapeutic utility of triiodothyroacetic acid in MCT8 deficiency. Mol. Endocrinol. 28(12), 1961–1970 (2014). https://doi.org/10.1210/me.2014-1135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. J. Delbaere, P. Vancamp, S.L. Van Herck, N.M. Bourgeois, M.J. Green, R.J. Wingate, V.M. Darras, MCT8 deficiency in Purkinje cells disrupts embryonic chicken cerebellar development. J. Endocrinol. 232(2), 259–272 (2017). https://doi.org/10.1530/JOE-16-0323

    Article  CAS  PubMed  Google Scholar 

  68. D. Zada, A. Tovin, T. Lerer-Goldshtein, L. Appelbaum, Pharmacological treatment and BBB-targeted genetic therapy for MCT8-dependent hypomyelination in zebrafish. Dis. Model Mech. 9(11), 1339–1348 (2016). https://doi.org/10.1242/dmm.027227

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. J.M. Kunitake, N. Hartman, L.C. Henson, J. Lieberman, D.E. Williams, M. Wong, J.M. Hershman, 3,5,3′-triiodothyroacetic acid therapy for thyroid hormone resistance. J. Clin. Endocrinol. Metab. 69(2), 461–466 (1989). https://doi.org/10.1210/jcem-69-2-461

    Article  CAS  PubMed  Google Scholar 

  70. D. Harrus, H. Demene, E. Vasquez, A. Boulahtouf, P. Germain, A.C. Figueira, M.L. Privalsky, W. Bourguet, A. le Maire, Pathological interactions between mutant thyroid hormone receptors and corepressors and their modulation by a thyroid hormone analogue with therapeutic potential. Thyroid 28(12), 1708–1722 (2018). https://doi.org/10.1089/thy.2017.0551

    Article  CAS  PubMed  Google Scholar 

  71. S. Horn, S. Kersseboom, S. Mayerl, J. Muller, C. Groba, M. Trajkovic-Arsic, T. Ackermann, T.J. Visser, H. Heuer, Tetrac can replace thyroid hormone during brain development in mouse mutants deficient in the thyroid hormone transporter mct8. Endocrinology 154(2), 968–979 (2013). https://doi.org/10.1210/en.2012-1628

    Article  CAS  PubMed  Google Scholar 

  72. S. Groeneweg, R.P. Peeters, T.J. Visser, W.E. Visser, Therapeutic applications of thyroid hormone analogues in resistance to thyroid hormone (RTH) syndromes. Mol. Cell Endocrinol. 458, 82–90 (2017). https://doi.org/10.1016/j.mce.2017.02.029

    Article  CAS  PubMed  Google Scholar 

  73. Y.T. Chin, Z.R. He, C.L. Chen, H.C. Chu, Y. Ho, P.Y. Su, Y.S.H. Yang, K. Wang, Y.J. Shih, Y.R. Chen, J.Z. Pedersen, S. Incerpi, A.W. Nana, H.Y. Tang, H.Y. Lin, S.A. Mousa, P.J. Davis, J. Whang-Peng, Corrigendum: tetrac and NDAT Induce Anti-proliferation via Integrin alphavbeta3 in Colorectal Cancers With Different K-RAS Status. Front Endocrinol. (Lausanne) 10, 241 (2019). https://doi.org/10.3389/fendo.2019.00241

    Article  Google Scholar 

  74. P.J. Davis, H.Y. Tang, A. Hercbergs, H.Y. Lin, K.A. Keating, S.A. Mousa, Bioactivity of thyroid hormone analogs at cancer cells. Front Endocrinol. (Lausanne) 9, 739 (2018). https://doi.org/10.3389/fendo.2018.00739

    Article  Google Scholar 

  75. G. Medina-Gomez, R.M. Calvo, M.J. Obregon, T3 and Triac inhibit leptin secretion and expression in brown and white rat adipocytes. Biochim Biophys. Acta 1682(1–3), 38–47 (2004). https://doi.org/10.1016/j.bbalip.2004.01.007

    Article  CAS  PubMed  Google Scholar 

  76. H.C. Ha, J.M. Jang, D. Zhou, H.G. Kim, M.J. Back, I.C. Shin, S.Y. Yun, Y. Piao, J.M. Choi, J.H. Won, D.K. Kim, 3, 5, 3′-Triiodothyroacetic acid (TRIAC) is an anti-inflammatory drug that targets toll-like receptor 2. Arch. Pharm. Res 41(10), 995–1008 (2018). https://doi.org/10.1007/s12272-018-1057-8

    Article  CAS  PubMed  Google Scholar 

  77. J.L. Leonard, Non-genomic actions of thyroid hormone in brain development. Steroids 73(9–10), 1008–1012 (2008). https://doi.org/10.1016/j.steroids.2007.12.016

    Article  CAS  PubMed  Google Scholar 

  78. J.T. Domingues, D. Cattani, P.A. Cesconetto, B.A. Nascimento de Almeida, P. Pierozan, K. Dos Santos, G. Razzera, F.R. Mena Barreto Silva, R. Pessoa-Pureur, A. Zamoner, Reverse T3 interacts with alphavbeta3 integrin receptor and restores enzyme activities in the hippocampus of hypothyroid developing rats: Insight on signaling mechanisms. Mol. Cell Endocrinol. 470, 281–294 (2018). https://doi.org/10.1016/j.mce.2017.11.013

    Article  CAS  PubMed  Google Scholar 

  79. H.Y. Lin, H.Y. Tang, M. Leinung, S.A. Mousa, A. Hercbergs, P.J. Davis, Action of Reverse T3 on Cancer Cells. Endocr Res, 1–5 (2019). https://doi.org/10.1080/07435800.2019.1600536

  80. F. Economidou, E. Douka, M. Tzanela, S. Nanas, A. Kotanidou, Thyroid function during critical illness. Horm. (Athens) 10(2), 117–124 (2011). https://doi.org/10.14310/horm.2002.1301

    Article  Google Scholar 

  81. L. Rastogi, M.M. Godbole, R.A. Sinha, S. Pradhan, Reverse triiodothyronine (rT3) attenuates ischemia-reperfusion injury. Biochem Biophys. Res Commun. 506(3), 597–603 (2018). https://doi.org/10.1016/j.bbrc.2018.10.031

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This research was financially supported by a “FAR” grant from the University of Sannio and was supported by University of Campania “Luigi Vanvitelli” Programma VALERE: Vanvitelli per la Ricerca.

Author contributions

All authors listed have made a substantial, direct, and intellectual contribution to the work, and approved it for publication.

Author information

Author notes

  1. These authors contributed equally: Rosalba Senese, Federica Cioffi

Authors and Affiliations

  1. Department of Environmental, Biological and Pharmaceutical Sciences and Technologies, University of Campania “L. Vanvitelli”, Caserta, Italy

    Rosalba Senese, Giuseppe Petito & Antonia Lanni

  2. Department of Sciences and Technologies, University of Sannio, Benevento, Italy

    Federica Cioffi & Fernando Goglia

Authors
  1. Rosalba Senese
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Federica Cioffi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Giuseppe Petito
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fernando Goglia
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Antonia Lanni
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Antonia Lanni.

Ethics declarations

Conflict of interest

The authors declare that they have no conflict of interest.

Additional information

Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Senese, R., Cioffi, F., Petito, G. et al. Thyroid hormone metabolites and analogues. Endocrine 66, 105–114 (2019). https://doi.org/10.1007/s12020-019-02025-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12020-019-02025-5

Search

Navigation