Effect of TRH on TSH Glycosylation and Biological Action

Weintraub, Bruce D.; Gesundheit, Neil; Taylor, Terry; Gyves, Peter W.

doi:10.1111/j.1749-6632.1989.tb46643.x

Cited by 36 publications

(22 citation statements)

References 38 publications

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“…TSH production falls, and simultaneously the pattern of glycosylation on newly synthesized TSH is altered so that the TSH that is produced is of reduced bioactivity (6). Thus, as a consequence of starvation, T4 and T3 levels fall, leading to central hypothyroidism.…”

Section: Figurementioning

confidence: 99%

Leptin, nutrition, and the thyroid: the why, the wherefore, and the wiring

Flier¹,

Harris²,

Hollenberg³

2000

J. Clin. Invest.

215

122

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The function of the thyroid gland is to produce the thyroid hormones T3 and T4, which regulate gene transcription throughout the body (1). In medical practice, the thyroid becomes an issue when its size or shape becomes abnormal or when it produces too much or too little hormone. Thus, we typically think of the thyroid with reference to the clinical states of goiter, or hyper-or hypothyroidism. But what is the physiology of the thyroid when the gland and the entire hypothalamic-pituitary-thyroid axis are intact? As first year medical students ask each year, Why exactly do we have a thyroid, at all?The usual presentation of thyroid physiology does not stress dynamic changes in hormone levels. Unlike insulin or cortisol levels, which are widely understood to fluctuate in response to food ingestion and stress, respectively, thyroid hormones are typically thought to be maintained at a basal level of hormone that keeps the metabolic machinery humming at the proper rate. In our opinion, this static view of thyroid physiology is mistaken.Nutrition and thyroid hormones. In addition to changes in thyroid hormone that occur in development, from tadpoles to mammals, thyroid hormone levels are subject to major physiologic regulation during the transition from the fed to the starved state. In the well-studied rodent model, starvation rapidly suppresses T4 and T3 levels (2, 3). The benefit of this suppression is clear: Starvation represents a severe threat to survival, and, in rodents, the capacity to survive without nutrition is measured in days. Because thyroid hormones set the basal metabolic rate, a drop in thyroid hormone levels should reduce the obligatory use of energy stores. As long as hypothyroidism does not impair the ability to obtain food, this adaptation would be expected to enhance survival. Because animals in the wild are thought to commonly experience periods of starvation, the thyroid response to starvation should be viewed as a major aspect of the regulatory biology of the thyroid gland.The thyroid system is regulated at multiple levels, one or more of which might account for nutritional adaptation. First, thyrotropin-releasing hormone, a neuropeptide produced in the paraventricular nucleus (PVN) of the hypothalamus, controls the release of thyroid-stimulating hormone (TSH) from the pituitary. TSH acts on receptors on the thyroid to promote synthesis and release of the thyroid hormones T4 and T3. In addition, a family of deiodinases metabolize the less-active T4 to the more-active T3 or to the inactive reverse T3. In primary hypothyroidism, when T3 and T4 levels fall because of a defect within the thyroid, a 2-part compensatory system kicks in. In the PVN of the hypothalamus, TRH expression increases because of the lack of negative feedback by thyroid hormones (4). In the pituitary thyrotroph, TSH production increases due to both increased TRH production and decreased negative feedback by thyroid hormones on the genes encoding TSH subunits (5). The increased TSH serves to drive the failing thyroid and is th...

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Section: Figurementioning

confidence: 99%

Leptin, nutrition, and the thyroid: the why, the wherefore, and the wiring

Flier¹,

Harris²,

Hollenberg³

2000

J. Clin. Invest.

215

122

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“…We hypothesized that the reduction in pit-D2 KO PVN TRH expression prolonged TSH half-life and decreased its biological activity by altering the TSH glycosylation pattern (18). To test this hypothesis, we used a previously characterized in vitro assay to estimate pit-D2 KO TSH biological activity.…”

Section: Figurementioning

confidence: 99%

Coordination of hypothalamic and pituitary T3 production regulates TSH expression

et al. 2013

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Type II deiodinase (D2) activates thyroid hormone by converting thyroxine (T4) to 3,5,3′-triiodothyronine (T3). This allows plasma T4 to signal a negative feedback loop that inhibits production of thyrotropin-releasing hormone (TRH) in the mediobasal hypothalamus (MBH) and thyroid-stimulating hormone (TSH) in the pituitary. To determine the relative contributions of these D2 pathways in the feedback loop, we developed 2 mouse strains with pituitary-and astrocyte-specific D2 knockdown (pit-D2 KO and astro-D2 KO mice, respectively). The pit-D2 KO mice had normal serum T3 and were systemically euthyroid, but exhibited an approximately 3-fold elevation in serum TSH levels and a 40% reduction in biological activity. This was the result of elevated serum T4 that increased D2-mediated T3 production in the MBH, thus decreasing Trh mRNA. That tanycytes, not astrocytes, are the cells within the MBH that mediate T4-to-T3 conversion was defined by studies using the astro-D2 KO mice. Despite near-complete loss of brain D2, tanycyte D2 was preserved in astro-D2 KO mice at levels that were sufficient to maintain both the T4-dependent negative feedback loop and thyroid economy. Taken together, these data demonstrated that the hypothalamic-thyroid axis is wired to maintain normal plasma T3 levels, which is achieved through coordination of T4-to-T3 conversion between thyrotrophs and tanycytes.

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“…The importance of the effects of TRH on TSH glycosylation and activity (Weintraub et al 1989) has been demonstrated by comparing the phenotypes of TRH-KO, THRb-KO, and the double mutant. Increased TSH serum levels but reduced TSH bioactivity accounts for the low circulating T 4 concentration (Nikrodhanond et al 2006), similar to that observed in humans with hypothalamic hypothyroidism (Beck-Peccoz et al 1985), or in TRHR1 K/K mice that have normal TSH levels but low circulating T 3 and T 4 concentrations (Rabeler et al 2004).…”

Section: Regulation Of Hpt Axis Activity By Trh and Negative Feedbackmentioning

confidence: 99%

Section: Regulation Of Hpt Axis Activity By Trh and Negative Feedbackmentioning

confidence: 99%

“…Transduction pathways involve Ca CC /calmodulin for TSHb activation or the PKC-MAPK pathway for TSHa (Hashimoto et al 2000). TRH regulates the glycosylation pattern of TSH, which increases its biological activity and half-life (Weintraub et al 1989, Szkudlinski et al 2002.TSH stimulates synthesis and release of TH which are transported in the blood by T 4 -bound globulin, transthyretin or albumin, in different proportions depending on the species (Zoeller et al 2007). More than 70% of TSH-stimulated TH release corresponds to T 4 (Maia et al 2011).…”

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confidence: 99%

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60 YEARS OF NEUROENDOCRINOLOGY: TRH, the first hypophysiotropic releasing hormone isolated: control of the pituitary–thyroid axis

Joseph‐Bravo

Jaimes-Hoy

Uribe

et al. 2015

Journal of Endocrinology

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This review presents the findings that led to the discovery of TRH and the understanding of the central mechanisms that control hypothalamus-pituitary-thyroid axis (HPT) activity. The earliest studies on thyroid physiology are now dated a century ago when basal metabolic rate was associated with thyroid status. It took over 50 years to identify the key elements involved in the HPT axis. Thyroid hormones (TH: T 4 and T 3 ) were characterized first, followed by the semi-purification of TSH whose later characterization paralleled that of TRH. Studies on the effects of TH became possible with the availability of synthetic hormones. DNA recombinant techniques permitted the identification of all the elements involved in the HPT axis, including their mode of regulation. Hypophysiotropic TRH neurons, which control the pituitary-thyroid axis, were identified among other hypothalamic neurons which express TRH. Three different deiodinases were recognized in various tissues, as well as their involvement in cell-specific modulation of T 3 concentration. The role of tanycytes in setting 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. A historical perspective on the hypothalamic control of the thyroid axisThe advancement of any scientific field requires the combination of creative new ideas with the development of technologies and knowledge in related areas; understanding the function of the hypothalamus-pituitarythyroid axis (HPT) is no exception (Figs 1 and 2). Since the end of the 19th century, European physicians and surgeons associated neck swelling (thyroid enlargement, goiter), with iodine deficiency, cretinism, and myxoedema, This paper is part of a thematic review section on 60 years of neuroendocrinology. The Guest Editors for this section were Ashley Grossman and Clive Coen defining hypothyroid conditions. Magnus-Levy (1895) was the first to demonstrate that respiratory metabolism was increased in hyperthyroidism and decreased in myxoedema. Indirect calorimetry allowed measurements of basal metabolic rate (BMR) and the evaluation of thyroid activity in clinical practice (Du Bois & Du Bois 1915, Harris & Benedict 1918. Soon it was recognized that stressful conditions such as fever, acidosis, or starvation modify BMR (Rowe 1920). In 1919, levothyroxine (3,3 0 ,5,5 0 -tetraiodothyronine or T 4 ) was characterized, and then ...

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Effect of TRH on TSH Glycosylation and Biological Action

Cited by 36 publications

References 38 publications

Leptin, nutrition, and the thyroid: the why, the wherefore, and the wiring

Leptin, nutrition, and the thyroid: the why, the wherefore, and the wiring

Coordination of hypothalamic and pituitary T3 production regulates TSH expression

60 YEARS OF NEUROENDOCRINOLOGY: TRH, the first hypophysiotropic releasing hormone isolated: control of the pituitary–thyroid axis

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