P JOSEPH-BRAVO and others History of TRH 226:2 T85–T100 Thematic Review 60 YEARS OF NEUROENDOCRINOLOGY TRH, the first hypophysiotropic releasing hormone isolated: control of the pituitary–thyroid axis Correspondence Patricia Joseph-Bravo, Lorraine Jaimes-Hoy, Rosa-Marı´a Uribe and Jean-Louis Charli should be addressed to P Joseph-Bravo Departamento de Gene´ tica del Desarrollo y Fisiologı´a Molecular, Instituto de Biotecnologı´a, Universidad Nacional Email Auto´ noma de Me´ xico (UNAM), A.P. 510-3, Cuernavaca, Morelos 62250, Mexico [email protected] Abstract This review presents the findings that led to the discovery of TRH and the understanding of Key Words the central mechanisms that control hypothalamus–pituitary–thyroid axis (HPT) activity. " HPT axis The earliest studies on thyroid physiology are now dated a century ago when basal " TRH metabolic rate was associated with thyroid status. It took over 50 years to identify the key " TRH receptor elements involved in the HPT axis. Thyroid hormones (TH: T4 and T3) were characterized first, " TSH followed by the semi-purification of TSH whose later characterization paralleled that of TRH. " PPII Studies on the effects of TH became possible with the availability of synthetic hormones. " cold DNA recombinant techniques permitted the identification of all the elements involved in the " fasting HPT axis, including their mode of regulation. Hypophysiotropic TRH neurons, which control " stress Journal of Endocrinology the pituitary–thyroid axis, were identified among other hypothalamic neurons which " metabolism express TRH. Three different deiodinases were recognized in various tissues, as well as their " prolactin involvement in cell-specific modulation of T3 concentration. The role of tanycytes in setting " energy balance TRH levels due to the activity of deiodinase type 2 and the TRH-degrading ectoenzyme was unraveled. TH-feedback effects occur at different levels, including TRH and TSH synthesis and release, deiodinase activity, pituitary TRH-receptor and TRH degradation. The activity of TRH neurons is regulated by nutritional status through neurons of the arcuate nucleus, which sense metabolic signals such as circulating leptin levels. Trh expression and the HPT axis are activated by energy demanding situations, such as cold and exercise, whereas it is inhibited by negative energy balance situations such as fasting, inflammation or chronic stress. New approaches are being used to understand the activity of TRHergic neurons within metabolic circuits. Journal of Endocrinology (2015) 226, T85–T100 A historical perspective on the hypothalamic control of the thyroid axis The advancement of any scientific field requires the thyroid axis (HPT) is no exception (Figs 1 and 2). Since combination of creative new ideas with the development the end of the 19th century, European physicians and of technologies and knowledge in related areas; under- surgeons associated neck swelling (thyroid enlargement, standing the function of the hypothalamus–pituitary– goiter), with iodine deficiency, cretinism, and myxoedema, http://joe.endocrinology-journals.org Ñ 2015 Society for Endocrinology This paper is part of a thematic review section on 60 years of neuroendocrinology. DOI: 10.1530/JOE-15-0124 Printed in Great Britain The Guest Editors for this section were Ashley Grossman and Clive Coen Published by Bioscientifica Ltd. Downloaded from Bioscientifica.com at 09/28/2021 02:11:45AM via free access Thematic Review P JOSEPH-BRAVO and others History of TRH 226:2 T86 Harris Hormones regulate Hypothalamic transcription control of pituitary Electrophoresis RNA polymerases Nuclear receptors cDNAs Ion exchange, paper Secretory pathways chromatography PubMed (1997) POMC: one Genome analysis Cell culture NGF gene ≠ one Transgenic mice Leptin Enzymology protein Proteome Single cell recording cAMP Converting enzymes Metabolome Identification of Recombinant DNA Circuitome secretory Sequence first Mass Epigenetics WW 1 granules WW 2 protein (insulin) RIA HPLC ISH spectrometry IEGs 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010 BMR Pituitary control Assay for TRH structure TRH Human TRH TRH–HPT- TSH in serum cDNA cloning of the thyroid membrane pathological Purification of T4 gland TSH subunits inactivation conditions ME-‘TSH’ TSH TRH KO T3 TRH–TSH TRH–hypophysio- PVN in vivo tropic neurons TR-KO Thyroid Pituitary-portal ME-‘TSH’ extract circulation TH in nucleus Rat Trh cDNA TR a, b T3-downregulates TRF TRH transcription Neural secretion TH cytoplasm Rat Trh gene ‘TRF’/PVN T3 protein synthesis TH transporters negative T3-downregulates feedback T3 TRH-binding TSH transcription mitochondria pituitary ↑ TSH in cold protein membranes Deiodinases Human TSH ↓ TSH in synthesis cDNA cloning starvation TRH brain distribution TRH degradation Figure 1 Time line. Figure depicts the principal discoveries that contributed to the work, and some examples represent the ideas and paradigms of various Journal of Endocrinology actual understanding of TRH neurons and regulation of the hypothalamus– authors. BMR, basal metabolic rate; IEGs, immediate early genes; ISH, in situ pituitary–thyroid axis (HPT). Above the blue line are marked some of the hybridization; KO, knock out; ME, median eminence; NGF, nerve growth main findings in techniques or in cellular biology. Below are those related factor; POMC, proopiomelanocortin; PVN, paraventricular nucleus; to the HPT axis. Space constraints makes it impossible to cite each piece of TH, thyroid hormones; TRF, thyrotropin-releasing factor. defining hypothyroid conditions. Magnus-Levy (1895) was propylthiouracil (PTU), aided in the cure of hyperthyroid- the first to demonstrate that respiratory metabolism was ism (Astwood 1943). PTU became useful in researching increased in hyperthyroidism and decreased in myxoe- thyroid hormone (TH) metabolism, and in the discovery of dema. Indirect calorimetry allowed measurements of basal different deiodinases (Escobar del Rey et al. 1961, Visser metabolic rate (BMR) and the evaluation of thyroid activity et al. 1983). The inhibition of T3-induced BMR activation in in clinical practice (Du Bois & Du Bois 1915, Harris & hypothyroid rats by cycloheximide helped to elucidate that Benedict 1918). Soon it was recognized that stressful the actions of T3 require protein synthesis (Tata et al. 1962). conditions such as fever, acidosis, or starvation modify The identification of TH receptors (THRs) followed (Tata BMR (Rowe 1920). In 1919, levothyroxine (3,30,5,50- 2013), unraveling the multiplicity of effects of TH on tetraiodothyronine or T4) was characterized, and then energy metabolism (Mullur et al. 2014). The pituitary 0 synthesized in 1926. Triiodothyronine (3,3 ,5-triiodo-L- control of thyroid activity had been recognized since the thyronine or T3), which proved more active than T4, was beginning of the 20th century, although the purification discovered 30 years later (reviewed in Tata 2013). Since RIAs and identification of thyroid-stimulating hormone (TSH) were not available until the 1960s (Yalow & Berson 1959), spanned several decades (Magner 2014). Semi-purified TSH thyroid function was initially assessed in animals and later preparations from bovine pituitaries demonstrated a in humans, by administering 131I and measuring radio- similar structure to other pituitary hormones. It is activity in the neck at different times (Astwood & Stanley composed of two subunits (a and b) and contains 1947), or by cytological methods (de Robertis 1948). complex carbohydrate moieties that are essential for The discovery of inhibitors of thyroid function, such as bioactivity and clearance (Pierce et al. 1971, Weintraub http://joe.endocrinology-journals.org Ñ 2015 Society for Endocrinology Published by Bioscientifica Ltd DOI: 10.1530/JOE-15-0124 Printed in Great Britain Downloaded from Bioscientifica.com at 09/28/2021 02:11:45AM via free access Thematic Review P JOSEPH-BRAVO and others History of TRH 226:2 T87 PVN Trh mRNA THRb2 aMSH NPY/AgRP III v (–) Y1 receptor (+) ARC MC4R Tanycytes Capillaries TRH ME PPII released OATP1C1 D2 Tsha mRNA Association Tshb mRNA of a and b chains D2 BAT T3 T4 Pituitary TSH TSH glycosylation D1 T3 T4 D2 T4 rT3 T4 T3 T3 Thyroid Liver Journal of Endocrinology Figure 2 Elements involved in HPT regulation. At the level of the paraventricular project to the PVN and activate or inhibit (respectively) TRH neurons. hypothalamic nucleus (PVN), Trh mRNA is transcribed, its expression is Released TRH may be degraded by PPII before reaching portal vessels that regulated by multiple effectors, processed TRH is released from terminals transport it to the pituitary where it controls synthesis of TSHb and localized at the median eminence (ME) in yuxtaposition with tanycytes that glycosylation of both TSH subunits (a and b) to form bioactive TSH. At the contain deiodinase 2 (D2) and pyroglutamyl peptidase II (PPII). In response thyroid, TSH stimulates synthesis and release of T4 that is modified at target to nutrient status, arcuate neurons synthesizing POMC/CART or NPY/AgRP tissues by deiodinases (e.g. D1 and D2). et al. 1989). TSH extracted from bovine or human hTSH isolated from post-mortem tissues (Weintraub & post-mortem pituitaries was used in research, RIA and Szkudlinski 1999). clinic for almost three decades. RIA determinations of Physiological support for the existence of the hypo- plasma TSH concentration facilitated the conclusive thalamic control of pituitary–thyroid function started demonstration of the negative feedback effects of TH on with the pioneering