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How Do Thyroid Hormones Enter Target Cells

Role Of Feedback Loops

Thyroid Gland: Thyroid Hormone Function

The contribution of feedback loops to homeostasis will only be briefly reviewed here. Positive feedback loops are characterized by the release of additional hormone in response to an original hormone release. The release of oxytocin during childbirth is a positive feedback loop. The initial release of oxytocin begins to signal the uterine muscles to contract, which pushes the fetus toward the cervix, causing it to stretch. This, in turn, signals the pituitary gland to release more oxytocin, causing labor contractions to intensify. The release of oxytocin decreases after the birth of the child.

The more common method of hormone regulation is the negative feedback loop. Negative feedback is characterized by the inhibition of further secretion of a hormone in response to adequate levels of that hormone. This allows blood levels of the hormone to be regulated within a narrow range. An example of a negative feedback loop is the release of glucocorticoid hormones from the adrenal glands, as directed by the hypothalamus and pituitary gland. As glucocorticoid concentrations in the blood rise, the hypothalamus and pituitary gland reduce their signaling to the adrenal glands to prevent additional glucocorticoid secretion .

Figure 4. Negative Feedback Loop

The Thyroid Hormone Receptors Antagonize Transformation And Tumorigenesis By Oncogenic Ras

TRs also inhibit Ras-mediated cellular transformation and tumor growth. Formation of transformation foci in NIH-3T3 fibroblasts by oncogenic Ras is strongly decreased in TR-expressing cells, although TR1 appears to have a stronger anti-transforming activity than TR1. Furthermore, the inhibition of transformation by TR1 is lost after cyclin D1 over-expression, indicating that downregulation of this cyclin is also involved in the anti- transforming effects of the receptor. To analyze whether TRs could act as suppressors of tumor formation by ras, NIH-3T3 cells expressing in a stable manner oncogenic Ras alone or in combination with TR1 or TR1 were injected into the flanks of immunodeficient nude mice. Whereas large tumors developed in mice injected with fibroblasts expressing Ras alone, tumor formation was blocked in mice injected with fibroblasts co-expressing the oncoprotein and TR1. Co-expression of oncogenic Ras with TR1 did not abolish tumor formation but delayed the appearance of tumors.23 Therefore, TRs could play a relevant role as suppressors of ras-dependent tumors although TR1 appears to exert a stronger anti-tumorigenic effect in vivo.

T. Parry, … M.A. Portman, in, 2017

How Do Endocrine Hormones Work

Endocrine hormones like estrogen are messenger molecules that are secreted by endocrine glands into the bloodstream. They travel throughout the body in the circulation. Although they reach virtually every cell in the body in this way, each hormone affects only certain cells, called target cells. A target cell is the type of cell on which a hormone has an effect. A target cell is affected by a particular hormone because it has receptor proteins either on the cell surface or within the cell that are specific to that hormone. An endocrine hormone travels through the bloodstream until it finds a target cell with a matching receptor to which it can bind. When the hormone binds to the receptor, it causes changes within the cell. The manner in which it changes the cell depends on whether the hormone is a steroid hormone or a non-steroid hormone.

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Factors Affecting Target Cell Response

You will recall that target cells must have receptors specific to a given hormone if that hormone is to trigger a response. But several other factors influence the target cell response. For example, the presence of a significant level of a hormone circulating in the bloodstream can cause its target cells to decrease their number of receptors for that hormone. This process is called downregulation, and it allows cells to become less reactive to the excessive hormone levels. When the level of a hormone is chronically reduced, target cells engage in upregulation to increase their number of receptors. This process allows cells to be more sensitive to the hormone that is present. Cells can also alter the sensitivity of the receptors themselves to various hormones.

Two or more hormones can interact to affect the response of cells in a variety of ways. The three most common types of interaction are as follows:

Effects Of T3 In Bone Cells In Vitro

PPT

Chondrocytes

TRa1 and TR1 are expressed in resting and proliferating chondrocytes in the growth plate, suggesting these cells are direct targets for T3 actions . T3 stimulates clonal expansion of resting chondrocyte progenitor cells but inhibits subsequent chondrocyte proliferation, while stimulating hypertrophic differentiation . Accordingly, T3 induces markers of hypertrophic chondrocyte differentiation, including alkaline phosphatase and collagen X expression in primary growth-plate chondrocyte cultures, and enhances cartilage matrix mineralization . T3 also stimulates the expression of proteoglycan and collagen-degrading enzymes including aggrecanase-2 and matrix metalloproteinase 13 . T3 regulation of growth plate chondrocyte proliferation and differentiation in vitro has been shown to involve a number of growth factor signaling pathways including IGF-1, Wnt, the Ihh/PTHrP feedback loop and FGFR3 . In conclusion, TH stimulates maturation of chondrocytes and the progression of endochondral ossification and is essential for linear growth.

Figure 2

Mechanisms for T3 regulation of chondrocyte differentiation. T3 can modulate local actions of growth factors such as IGF-I, FGFs, Wnts, Ihh and PTHrp to regulate proliferation and differentiation of cells of chondrocytic lineage. The differentiating promoting actions of T3 on chondrocytes are known to be mediated via inhibition of Sox9 and stimulation of Runx2 expression.

Osteoblasts

Figure 3

Osteoclasts

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Skeletal Phenotype Of Th Signaling Related Mutant Mice

Mouse mutants with altered TSH or TH levels

Pax8/ mice lack the thyroid specific transcription factor Pax8 required for thyroid follicular cell formation and hyt/hyt mice have a loss-of-function mutation in the TSH receptor . Both mutants have a 2000-fold elevation of TSH and undetectable THs, but the TSHR is functional in Pax8/ mice whereas it is non-functional in hyt/hyt mice. Thus, the reciprocal relationship between THs and TSH remains intact in Pax8/ mice but is disrupted in hyt/hyt mice . Both mutants exhibited a similar skeletal phenotype of impaired linear growth, delayed endochondral ossification, impaired chondrocyte differentiation, reduced cortical bone, impaired trabecular bone remodeling and reduced bone mineralization . These data indicate that any action of TSH in bone is likely to be minor when compared to the effects of T3.

Table 1 Skeletal phenotype of TH signaling related mutant mice

TRa mutants

Mice harboring dominant-negative mutations of TRa1 in different genetic backgrounds have mild and transient systemic hypothyroidism but they also exhibit a more severe phenotype of delayed skeletal development than TRa0/0 mice. TRa1PV/+ mice are most severely affected, displaying persistent post-natal growth retardation and markedly delayed endochondral ossification and decreased mineralization .

TR mutants

Thyroxine Iodine And Apoptosis

Thyroxine and iodine stimulate the spectacular apoptosis of the cells of the larval gills, tail and fins in amphibian metamorphosis, and stimulate the evolution of their nervous system transforming the aquatic, vegetarian tadpole into the terrestrial, carnivorous frog. In fact, amphibian frog Xenopus laevis serves as an ideal model system for the study of the mechanisms of apoptosis.

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Module : The Endocrine System

  • Identify the three major classes of hormones on the basis of chemical structure
  • Compare and contrast intracellular and cell membrane hormone receptors
  • Describe signaling pathways that involve cAMP and IP3
  • Identify several factors that influence a target cells response
  • Discuss the role of feedback loops and humoral, hormonal, and neural stimuli in hormone control

Although a given hormone may travel throughout the body in the bloodstream, it will affect the activity only of its target cells that is, cells with receptors for that particular hormone. Once the hormone binds to the receptor, a chain of events is initiated that leads to the target cells response. Hormones play a critical role in the regulation of physiological processes because of the target cell responses they regulate. These responses contribute to human reproduction, growth and development of body tissues, metabolism, fluid, and electrolyte balance, sleep, and many other body functions. The major hormones of the human body and their effects are identified in Table 1.

Table 1. Endocrine Glands and Their Major Hormones
Endocrine gland
Stimulate development of female secondary sex characteristics and prepare the body for childbirth

How Does A Hormone Affect A Target Cell

Follicular Cells & the Synthesis of Thyroid Hormones

A target cell responds to a hormone because it bears receptors for the hormone. In very basic terms, binding of hormone to receptor triggers a cascade of reactions within the cell that affects function. Additional details about receptor structure and function are provided in the section on hormone mechanism of action.

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C Thyroid Status And Diabetes

The interaction of thyroid status and diabetes is complex. Patients with type 1 diabetes have an increase in prevalence rates of autoimmune thyroid disorders compared with the nondiabetic population, especially among women . This is thought to be due to similar genetic susceptibility to both autoimmune conditions . Studies investigating the interaction of type 2 diabetes and thyroid dysfunction, however, have not shown a consistent association . Abnormal serum TSH concentrations were seen in 30% of poorly controlled type 2 diabetic patients . Among those patients with an abnormal low or high TSH levels, who were negative for thyroid autoantibodies, serum TSH normalized in all but one patient when their glucose level was controlled for 2 mo . Conversely, in severely thyrotoxic patients, the calculated metabolic clearance rate of insulin is markedly higher than control patients, contributing to hyperglycemia in the thyrotoxic state . In a recent case report, a patient with severe insulin resistance improved dramatically after suppressive dose levothyroxine for thyroid cancer . Imaging of the patient when hypothyroid and then after replacement was restored showed induction of BAT, highlighting the role of TH in insulin sensitivity and energy expenditure.

Everyday Connections Bisphenol A And Endocrine Disruption

You may have heard news reports about the effects of a chemical called bisphenol A in various types of food packaging. BPA is used in the manufacturing of hard plastics and epoxy resins. Common food-related items that may contain BPA include the lining of aluminum cans, plastic food-storage containers, drinking cups, as well as baby bottles and sippy cups. Other uses of BPA include medical equipment, dental fillings, and the lining of water pipes.

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Health Consequences Of Disturbed Thyroid Hormone Action

Thyroid hormones are of significant importance for regular functioning of almost all body organs. Thyroxine is the main hormone released from the thyroid gland and it is transformed into biologically active 3′,3,5-triiodothyronine via 5′-deiodinases of thyroid hormone target cells . For thyroid hormone synthesis, sufficient supply of the thyroid gland with essential micronutrients such as iodine and selenium is crucial.

The most important target tissues of thyroid hormones are the central nervous system, the cardiovascular system and the skeleton. Moreover, due to the increasing incidence of obesity worldwide, thyroid hormone action in adipose tissue has re-gained increasing interest for understanding energy homeostasis .

Health-economical dimensions of thyroid disorders are shown most plainly by the example of latent hypothyroidism which is evident in about 20% of all individuals at the age of 60-79 years, with higher incidences in women than in men . On top of this, an increase in the number of patients with thyroid disorders is expected in the future. Possible causes are anthropogenic in origin and are represented by a variety of environmental substances, so-called endocrine disruptors such as estrogen-derivates and PBCBs, that affect the endocrine system at large including the thyroid gland and thyroid hormone actions .

Th/thr Signaling Pathways And Mechanisms

Endocrine System

THR/TH-mediated signaling pathways: TH signaling is primarily by genomic action through nuclear THR-mediated genes expression , referred to as type 1 TH action . TH production is regulated by the HPT axis. T4 provides negative feedback to the hypothalamus and pituitary. Local Dio2 converts T4 to T3, which then downregulates thyroid releasing hormone in the hypothalamus and thyroid stimulating hormone in the pituitary . When T4 levels are low and feedback is reduced, TRH is increased in the hypothalamus and stimulates the pituitary to secrete TSH TSH then stimulates the thyroid gland to concentrate iodide and synthesize TH.

Figure 21.7. Hypothalamic-pituitary-thyroid axis and thyroid hormone action.

Thyroid releasing hormone is secreted in the hypothalamus and stimulates thyroid stimulating hormone secretion from the pituitary gland. TSH acts on thyroid follicular cells to stimulate thyroid hormone secretion. T4 and T3 subsequently inhibit secretion of TRH and TSH. Thyroid hormones enter target cells via specific membrane transporters, such as Mct9. The intracellular concentration of T3 is determined by the relative activities of the deiodinases, Dio 1 and Dio 2. T3 enters the nucleus and binds to nuclear thyroid hormone receptors to regulate expression of T3 target genes. T3 and T4 have also a nongenomic action through TRs and other membrane receptors. CoA, coactivator RXR, retinoic X receptor TRE, thyroid response element v3, plasma membrane integrin receptor.

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Clinical Manifestation Of Th Signaling Related Mutations In Humans

The developing skeleton is sensitive to thyroid status and childhood hypothyroidism is characterized by growth retardation, delayed bone age and short stature, whereas juvenile thyrotoxicosis accelerates growth and advances bone age but results in persistent short stature due to premature fusion of the epiphyses . A loss of function mutation of the TSH -subunit results in TSH deficiency and congenital hypothyroidism. Two affected siblings received TH replacement from birth but despite the lifelong absence of TSH, their skeletal development and bone mineral density were normal . These findings suggest that TSH is not required for normal skeletal development and growth. TSHR mutations result in wide spectrum of clinical manifestations ranging from mild to severe hypothyroidism and hyperthyroidism . Up to this date more than 40 kinds of loss of function mutations in the TSHR gene have been reported as the causative defect in congenital hypothyroidism . By contrast, gain of function mutations in the TSHR gene were identified in familial non-autoimmune hyperthyroidism or sporadic non-autoimmune hyperthyroidism .

Table 2 Clinical manifestation of TH signaling related mutations in humans

Endocrinesystems And Feedback Cycles

The endocrine system uses cyclesand to regulate physiologicalfunctions. Negative feedback regulates the secretion of almost everyhormone. Cycles of secretionmaintain physiological and homeostatic control. These cycles canrange from hours to months in duration.

Negative feedback in the thyroxine releasereflex. Image from Purves et al., Life: The Science ofBiology, 4th Edition, by Sinauer Associates and WH Freeman ,used with permission.

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Clinical Relevance Of Mct8

Worldwide, over 100 families have been reported where males are affected by severe psychomotor retardation associated with a particular combination of abnormal serum TH levels. A large family with this X-linked mental retardation syndrome was first reported in 1944 by Allan, Herndon and Dudley . Since then, this disorder is usually referred to as the Allan-Herndon-Dudley syndrome . Only 60 years later it was realized that patients with AHDS also have abnormal TH levels .

Usually, patients with AHDS are born at term following an uncomplicated pregnancy with a normal birthweight, body length and head circumference. During the first 6 months a general hypotonia is noticed. During development the truncal hypotonia remains, whereas the distal hypotonia progresses into dystonia and spasticity. The truncal hypotonia results in poor head control. Growth is relatively normal, but final body length is reduced and body weight is usually extremely low with obvious signs of muscle wasting. There is also progressive microcephaly. In the first 2 years of life, brain MRI shows clearly delayed myelination. Although myelination improves in subsequent years, it never really normalizes. This is supported by a recent study of post-mortem brains from a fetal and a 11-year old AHDS patient . Based on observations of delayed myelination, AHDS has also been referred to as a Pelizaeus-Merzbacher-like disorder .

D Factors Contributing To Diabetes

Mechanism of STEROID HORMONE action

TH induces HIF-1 via the PI3K/ERK pathways, as well as by direct induction. The known HIF-1 target genes include the glucose transporter 1 , phosphofructokinase , and monocarboxylate transporter 4 , which regulate cellular glucose metabolism by controlling glucose uptake, glycolysis, and lactate transport, respectively . These genes are induced by physiological doses of T3, and pretreatment with a PI3K inhibitor abolishes this effect . HIF-1 also induces expression of D3 gene leading to reduced T3 and increased rT3 production .

Systemic administration of T1AM rapidly increases endogenous glucose production, glucagon, and corticosterone but does not increase plasma insulin . Central administration of T1AM resulted in a much more profound effect on endogenous glucose production and hyperglucagonemia and reduced plasma insulin . The effects of T1AM on glucose and insulin, like the effects of TH, likely vary with the mode and duration of exposure.

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D Fatty Acid Metabolism

TH stimulates both lipolysis and lipogenesis, although the direct action is lipolysis with lipogenesis thought to be stimulated to restore fat stores . A time course study in rats carefully measured whole body lipid content and thermogenesis after T3 treatment and concluded that the TH-induced lipogenesis is primarily to maintain fat loss that occurs with TH-induced lipolysis . Fatty acids produced from TH-induced lipolysis are the substrate for the increase in thermogenesis . T3 regulation of these divergent metabolic pathways is subject to nuclear receptor crosstalk, ligand-binding, nutritional status, and competition for RXR heterodimers . TH plays a significant role in the conversion of preadipocytes to adipocytes .

Malonyl CoA production in the liver promotes lipogenesis and directly inhibits carnitine palmitoyl transferase -I, which converts long-chain fatty acyl-CoAs to acylcarnitines for translocation from the cytosol into inner mitochondrial matrix where -oxidation occurs . T3 also induces the transcription of acetyl CoA carboxylase -1, which generates malonyl CoA from acetyl CoA. ACC-1 is regulated by TR, LXR, and SREBP-1 . While LXR can directly stimulate ACC-1 , TR and SREBP1 must form a complex that stabilizes SREBP-1 on the binding site . SREBP-1 action is also enhanced by a PPAR agonist, which can potentiate SREBP-1c nuclear activity .

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