University of Wollongong Research Online Faculty of Science - Papers (Archive) Faculty of Science, Medicine and Health 1-1-2000 Thyroid hormones and their effects: a new perspective A. J. Hulbert University of Wollongong, [email protected] Follow this and additional works at: https://ro.uow.edu.au/scipapers Part of the Life Sciences Commons, Physical Sciences and Mathematics Commons, and the Social and Behavioral Sciences Commons Recommended Citation Hulbert, A. J.: Thyroid hormones and their effects: a new perspective 2000. https://ro.uow.edu.au/scipapers/29 Research Online is the open access institutional repository for the University of Wollongong. For further information contact the UOW Library: [email protected] Thyroid hormones and their effects: a new perspective Abstract The thyroid hormones are very hydrophobic and those that exhibit biological activity are 3',5',3,5-ltetraiodothyronine (T4), 3',5,3-l-triiodothyronine (T3), 3',5',3-l-triiodothyronine (rT3) and 3,5,- ldiiodothyronine (3,5-T2). At physiological pH, dissociation of the phenolic -OH group of these iodothyronines is an important determinant of their physical chemistry that impacts on their biological effects. When non-ionized these iodothyronines are strongly amphipathic. It is proposed that iodothyronines are normal constituents of biological membranes in vertebrates. In plasma of adult vertebrates, unbound T4 and T3 are regulated in the picomolar range whilst protein-bound T4 and T3 are maintained in the nanomolar range. The function of thyroid-hormone-binding plasma proteins is to ensure an even distribution throughout the body. Various iodothyronines are produced by three types of membrane-bound cellular deiodinase enzyme systems in vertebrates. The distribution of deiodinases varies between tissues and each has a distinct developmental profile. Thyroid hormones have many effects in vertebrates. It is proposed that there are several modes of action of these hormones. (1) The nuclear receptor mode is especially important in the thyroid hormone axis that controls plasma and cellular levels of these hormones. (2) These hormones are strongly associated with membranes in tissues and normally rigidify these membranes. (3) They also affect the acyl composition of membrane bilayers and it is suggested that this is due to the cells responding to thyroid-hormone-induced membrane rigidification. Both their immediate effects on the physical state of membranes and the consequent changes in membrane composition result in several other thyroid hormone effects. Effects on metabolism may be due primarily to membrane acyl changes. There are other actions of thyroid hormones involving membrane receptors and influences on cellular interactions with the extracellular matrix. The effects of thyroid hormones are reviewed and appear to be combinations of these various modes of action. During development, vertebrates show a surge in T4 and other thyroid hormones, as well as distinctive profiles in the appearance of the deiodinase enzymes and nuclear receptors. Evidence from the use of analogues supports multiple modes of action. Re-examination of data from the early 1960s supports a membrane action. Findings from receptor 'knockout' mice supports an important role for receptors in the development of the thyroid axis. These iodothyronines may be better thought of as 'vitamone'-like molecules than traditional hormonal messengers. Disciplines Life Sciences | Physical Sciences and Mathematics | Social and Behavioral Sciences Publication Details This article was originally published as Hulbert, AJ, Thyroid hormones and their effects: a new perspective, Biological Review, 75, 2000, 519-631. Copyright Cambridge Philosophical Society. Original journal available here. This journal article is available at Research Online: https://ro.uow.edu.au/scipapers/29 Biol. Rev. (2000), 75, pp. 519–631 Printed in the United Kingdom # Cambridge Philosophical Society 519 Thyroid hormones and their effects: a new perspective A. J. HULBERT Metabolic Research Centre, and Department of Biological Sciences, University of Wollongong, Wollongong, N.S.W. 2522 Australia (e-mail: hulbert!uow.edu.au) (Received 21 May 1999; revised 30 May 2000; accepted 7 June 2000) ABSTRACT The thyroid hormones are very hydrophobic and those that exhibit biological activity are 3h,5h,3,5-- tetraiodothyronine (T4), 3h,5,3--triiodothyronine (T3), 3h,5h,3--triiodothyronine (rT3) and 3,5,-- diiodothyronine (3,5-T2). At physiological pH, dissociation of the phenolic kOH group of these iodothyronines is an important determinant of their physical chemistry that impacts on their biological effects. When non-ionized these iodothyronines are strongly amphipathic. It is proposed that iodothyronines are normal constituents of biological membranes in vertebrates. In plasma of adult vertebrates, unbound T4 and T3 are regulated in the picomolar range whilst protein-bound T4 and T3 are maintained in the nanomolar range. The function of thyroid-hormone-binding plasma proteins is to ensure an even distribution throughout the body. Various iodothyronines are produced by three types of membrane-bound cellular deiodinase enzyme systems in vertebrates. The distribution of deiodinases varies between tissues and each has a distinct developmental profile. Thyroid hormones have many effects in vertebrates. It is proposed that there are several modes of action of these hormones. (1) The nuclear receptor mode is especially important in the thyroid hormone axis that controls plasma and cellular levels of these hormones. (2) These hormones are strongly associated with membranes in tissues and normally rigidify these membranes. (3) They also affect the acyl composition of membrane bilayers and it is suggested that this is due to the cells responding to thyroid-hormone-induced membrane rigidification. Both their immediate effects on the physical state of membranes and the consequent changes in membrane composition result in several other thyroid hormone effects. Effects on metabolism may be due primarily to membrane acyl changes. There are other actions of thyroid hormones involving membrane receptors and influences on cellular interactions with the extracellular matrix. The effects of thyroid hormones are reviewed and appear to be combinations of these various modes of action. During development, vertebrates show a surge in T4 and other thyroid hormones, as well as distinctive profiles in the appearance of the deiodinase enzymes and nuclear receptors. Evidence from the use of analogues supports multiple modes of action. Re-examination of data from the early 1960s supports a membrane action. Findings from receptor ‘knockout’ mice supports an important role for receptors in the development of the thyroid axis. These iodothyronines may be better thought of as ‘vitamone’-like molecules than traditional hormonal messengers. Key words: thyroxine, triiodothyronine, diiodothyronine, nuclear receptors, membranes, deiodinases, metabolism, growth, development, antioxidants. CONTENTS I. Introduction ............................................................................................................................ 520 (1) Some prejudices ................................................................................................................ 521 II. Thyroid hormones ................................................................................................................... 522 (1) Structure and physical chemistry...................................................................................... 522 (2) Plasma concentrations and distribution to the tissues....................................................... 523 (3) Cellular uptake, cellular location and hormone metabolism ............................................ 534 520 A. J. Hulbert III. Effects of thyroid hormones..................................................................................................... 542 (1) When studying the effects of thyroid hormones................................................................ 542 (2) Hypotheses regarding thyroid hormone action ................................................................. 544 (a) Nuclear receptors and thyroid response elements...................................................... 545 (b) Thyroid hormones and the membrane bilayer ........................................................... 549 (3) Effects on the thyroid hormone axis ................................................................................. 558 (4) Effects on metabolism and thermogenesis......................................................................... 560 (5) Effects on excitable tissues ................................................................................................ 571 (6) Effects on growth .............................................................................................................. 574 (7) Other effects...................................................................................................................... 576 IV. Thyroid hormones and vertebrate development...................................................................... 580 (1) Thyroid axis during vertebrate development.................................................................... 580 (2) Effects of thyroid hormones on vertebrate development................................................... 586 V. Some perspectives ...................................................................................................................