Peripheral Thyroid Hormone Metabolism Research Articles

Induction of type 1 iodothyronine deiodinase expression inhibits proliferation and migration of renal cancer cells

Type 1 iodothyronine deiodinase (DIO1) regulates peripheral metabolism of thyroid hormones that control cellular proliferation, differentiation and metabolism. The significance of DIO1 in cancer is unknown. In this study we hypothesized that diminished expression of DIO1, observed in renal cancer, contributes to the carcinogenic process in the kidney.Here, we demonstrate that ectopic expression of DIO1 in renal cancer cells changes the expression of genes controlling cell cycle, including cyclin E1 and E2F5, and results in inhibition of proliferation. The expression of genes encoding collagens (COL1A1, COL4A2, COL5A1), integrins (ITGA4, ITGA5, ITGB3) and transforming growth factor-β-induced (TGFBI) is significantly altered in renal cancer cells with induced expression of DIO1. Finally, we show that overexpression of DIO1 inhibits migration of renal cancer cells.In conclusion, we demonstrate for the first time that loss of DIO1 contributes to renal carcinogenesis and that its induced expression protects cells against cancerous proliferation and migration.

Thyrostimulin deficiency does not alter peripheral responses to acute inflammation-induced nonthyroidal illness.

Thyrostimulin, a putative glycoprotein hormone, comprises the subunits GPA2 and GPB5 and activates the TSH receptor (TSHR). The observation that proinflammatory cytokines stimulate GPB5 transcription suggested a role for thyrostimulin in the pathogenesis of nonthyroidal illness syndrome (NTIS). In the present study, we induced acute inflammation by LPS administration to GPB5(-/-) and WT mice to evaluate the role of thyrostimulin in peripheral thyroid hormone metabolism during NTIS. In addition to serum thyroid hormone concentrations, we studied mRNA expression and activity of deiodinase types I, II, and III (D1, D2, and D3) in peripheral T3 target tissues, including liver, muscle, and white and brown adipose tissue (WAT and BAT), of which the latter three express the TSHR. LPS decreased serum free (f)T4 and fT3 indexes to a similar extent in GPB5(-/-) and WT mice. Serum reverse (r)T3 did not change following LPS administration. LPS also induced significant alterations in tissue D1, D2, and D3 mRNA and activity levels, but only the LPS-induced increase in WAT D2 mRNA expression differed between GPB5(-/-) and WT mice. In conclusion, lacking GPB5 during acute illness does not affect the LPS-induced decrease of serum thyroid hormones while resulting in subtle changes in tissue D2 expression that are unlikely to be mediated via the TSHR.

Interdependence of the peripheral metabolism of glucocorticoids and thyroid hormones under calorie deficit in rats at different ages

Interdependence of the peripheral metabolism of glucocorticoids and thyroid hormones under calorie deficit in rats at different ages

The Sonic Hedgehog-Induced Type 3 Deiodinase Facilitates Tumorigenesis of Basal Cell Carcinoma by Reducing Gli2 Inactivation

Thyroid hormone (TH) is an important regulator of growth, development, and metabolism. Most of the active TH T3 is generated by peripheral TH metabolism mediated by the iodothyronine deiodinases. Type 3 deiodinase (D3) inactivates T3 via specific deiodination reactions. It is an oncofetal protein frequently expressed in neoplastic tissues and is a direct target of the sonic hedgehog (Shh) pathway in basal cell carcinomas (BCCs). However, the molecular mechanisms triggered by T3 in BCC are still mostly unrevealed. Here, we demonstrate that D3 action is critical in the proliferation and survival of BCC cells. D3 depletion or T3 treatment induce apoptosis of BCC cells and attenuate Shh signaling. This is achieved through a direct impairment of Gli2 protein stability by T3. T3 induces protein kinase A, which in turn destabilizes Gli2 protein via its C-terminal degron. Finally, in a mouse model of BCC, T3-topical treatment significantly reduces tumor growth. These results demonstrate the existence of a previously unrecognized cross talk between TH and Gli2 oncogene, providing functional and mechanistic evidence of the involvement of TH metabolism in Shh-induced cancer. TH-mediated Gli2 inactivation would be beneficial for therapeutically purposes, because the inhibition of Shh-Gli2 signaling is an attractive target for several anticancer drugs, currently in clinical trials.

Thyroid disorders and chronic kidney disease.

Thyroid hormones play a very important role regulating metabolism, development, protein synthesis, and influencing other hormone functions. The two main hormones produced by the thyroid are triiodothyronine (T3) and thyroxine (T4). These hormones can also have significant impact on kidney disease so it is important to consider the physiological association of thyroid dysfunction in relation to chronic kidney disease (CKD). CKD has been known to affect the pituitary-thyroid axis and the peripheral metabolism of thyroid hormones. Low T3 levels are the most common laboratory finding followed by subclinical hypothyroidism in CKD patients. Hyperthyroidism is usually not associated with CKD but has been known to accelerate it. One of the most important links between thyroid disorders and CKD is uremia. Patients who are appropriately treated for thyroid disease have a less chance of developing renal dysfunction. Clinicians need to be very careful in treating patients with low T3 levels who also have an elevation in TSH, as this can lead to a negative nitrogen balance. Thus, clinicians should be well educated on the role of thyroid hormones in relation to CKD so that proper treatment can be delivered to the patient.

RTHα, a Newly Recognized Phenotype of the Resistance to Thyroid Hormone (RTH) Syndrome in Patients With THRA Gene Mutations

RTHα, a Newly Recognized Phenotype of the Resistance to Thyroid Hormone (RTH) Syndrome in Patients With THRA Gene Mutations

Roux-en-Y gastric bypass and calorie restriction induce comparable time-dependent effects on thyroid hormone function tests in obese female subjects

Obesity and weight loss influence thyroid hormone physiology. The effects of weight loss by calorie restriction vs Roux-en-Y gastric bypass (RYGB) in obese subjects have not been studied in parallel. We hypothesized that differences in transient systemic inflammation and catabolic state between the intervention types could lead to differential effects on thyroid hormone physiology. We recruited 12 lean and 27 obese females with normal fasting glucose (normal glucose tolerant (NGT)) and 27 obese females with type 2 diabetes mellitus (T2DM) for this study. Weight loss was achieved by restrictive treatment (gastric banding or high-protein-low-calorie diet) or by RYGB. Fasting serum leptin, TSH, triiodothyronine (T₃), reverse T₃ (rT₃), and free thyroxine (fT₄) concentrations were measured at baseline and 3 weeks and 3 months after the start of the interventions. Obesity was associated with higher TSH, T₃, and rT₃ levels and normal fT₄ levels in all the subjects when compared with the controls. After 3 weeks, calorie restriction and RYGB induced a decline in TSH levels and a rise in rT₃ and fT₄ levels. The increase in rT₃ levels correlated with serum interleukin 8 (IL8) and IL6 levels. After 3 months, fT₄ and rT₃ levels returned to baseline levels, whereas TSH and T₃ levels were persistently decreased when compared with baseline levels. No differences in the effects on thyroid hormone parameters between the interventions or between NGT and T2DM subjects were observed at any time point. In summary, weight loss directly influences thyroid hormone regulation, independently of the weight loss strategy used. The effects may be explained by a combination of decreased leptin levels and transient changes in peripheral thyroid hormone metabolism.

PECULIARITIES OF LIPID METABOLISM IN INDIVIDUALS WITH METABOLIC SYNDROME AGAINST A BACKGROUND OF THYROID HOMEOSTASIS VIOLATIONS

Background. Metabolic syndrome (MS) affects about aquarter of the world’s population and is accompanied by abdominal obesity and insulin resistance, which are the factors ofdyslipidemia, hypertension and hyperglycemia.Nonthyroidal illness syndrome (NTIS) affects about 75% ofhospitalized patients and is accompanied by peripheral hypothyroidism due to inhibition of peripheral conversion of thyroid hormones. Due to the fact that about 80% of thyroid hormones are produced in peripheral organs, and that thyroid hormones regulate almost all processes in the body including lipidmetabolism, the pathological changes that accompany NTIS canbe regardered significant.The aim of the study. To study the dependence of the parameters of thyroid homeostasis in the patients with metabolicsyndrome on lipid, carbohydrate metabolism, the degree andtype of obesity.Materials and methods. 74 patients with MS were enrolled in the study. To investigate the functional status of pituitary-thyroid axis we calculated fT3/fT4, TSH/fT4, TSH/fT3indices, thyroid index (TI). Peripheral activity of thyroid hormones was estimated by total thyroid index (TTI). We madeanalysis of correlations between the parameters of thyroid homeostasis and lipid, carbohydrate metabolism and anthropometric characteristics of the patients with MS.Results. Negative correlation between the body mass indexand leptin levels with indices of pituitary-thyroid axis functioning has been determined. It has been found out that the atherogenic coefficient, cholesterol and triglycerides levels negativelycorrelated with indices of peripheral metabolism of thyroid hormones. Positive correlation between low density lipoproteinsand indices of pituitary-thyroid axis functioning and negativecorrelation of high density lipoproteins with these indices havebeen determined.Conclusions: 1. In patients with metabolic syndrome thenonthyroidal illness syndrome develops.2. Violation of thyroid homeostasis which indicators are related to the parameters of lipid metabolism, plays a role in themechanism of dyslipidemia at metabolic syndrome.

Smoking and Early Pregnancy Thyroid Hormone and Anti-Thyroid Antibody Levels in Euthyroid Mothers of the Northern Finland Birth Cohort 1986

Smokers in the general population have lower thyrotropin (TSH) and higher free triiodothyronine (fT3) and free thyroxine (fT4) concentrations, but the results in pregnant population vary from no effect to a decrease in TSH and fT4 concentrations and an increase in fT3 levels. Our objective was to further evaluate the question of whether there is an association between smoking, before and during pregnancy, with maternal thyroid function during pregnancy and with the risk for subsequent hypothyroidism. Our study population was a prospective population-based cohort (N=9362), the Northern Finland Birth Cohort 1986, with extensive data throughout gestation. The mothers underwent serum sampling in early pregnancy. The samples were assayed for TSH, fT3, fT4, thyroid-peroxidase antibodies (TPO-Ab), and thyroglobulin antibodies (TG-Abs) (n=5805). Mothers with thyroid dysfunction diagnosed before or during pregnancy were excluded, leaving 4837 euthyroid mothers. The smoking status of mothers and fathers were requested by questionnaires during pregnancy. Subsequent maternal morbidity relating to hypothyroidism 20 years after the index pregnancy was evaluated using national registers. Euthyroid mothers who smoked before, or continued smoking during first trimester of pregnancy, had higher serum fT3 (p<0.001) and lower fT4 (p=0.023) concentrations than nonsmokers. Smoking in the second trimester was associated with higher fT3 (p<0.001) concentrations, but no difference in fT4 concentrations compared with nonsmokers. TG-Abs were less common among smoking than nonsmoking mothers (2.5% vs. 4.7%, p<0.001), but the prevalence of TPO-Ab was similar. Paternal smoking had no independent effect on maternal early pregnancy thyroid hormone or antibody concentrations. The risk of subsequent maternal hypothyroidism after follow-up of 20 years was similar among prepregnancy smokers and nonsmokers. In euthyroid women, smoking during pregnancy was associated with higher fT3 levels and lower fT4 levels; possibly reflecting smoking-induced changes in peripheral metabolism of thyroid hormones. No differences were found in TSH concentrations between smokers and nonsmokers. Our results differ from those of the general population, which usually have shown smoking-induced thyroidal stimulation. This is possibly due to pregnancy-induced changes in thyroid function. Decreases in fT4 levels among smokers might predispose to hypothyroidism or hypothyroxinemia during pregnancy. Despite these changes in thyroid function, smoking did not increase the woman's risk of subsequent hypothyroidism.

New Insights toward the Acute Non-Thyroidal Illness Syndrome

The non-thyroidal illness syndrome (NTIS) refers to changes in serum thyroid hormone levels observed in critically ill patients in the absence of hypothalamic–pituitary–thyroid primary dysfunction. Affected individuals have low T3, elevated rT3, and inappropriately normal TSH levels. The pathophysiological mechanisms are poorly understood but the acute and chronic changes in pituitary–thyroid function are probably the consequence of the action of multiple factors. The early phase seems to reflect changes occurring primarily in the peripheral thyroid hormone metabolism, best seen in humans since 80–90% of the circulating T3 are derived from the pro-hormone T4. The conversion of T4 to T3 is catalyzed by type 1 (D1) and type 2 (D2) deiodinases via outer-ring deiodination. In contrast, type 3 deiodinase (D3) catalyzes the inactivation of both T4 and T3. Over the last decades, several studies have attempted to elucidate the mechanisms underlying the changes on circulating thyroid hormones in NTIS. Increased inflammatory cytokines, which occurs in response to virtually any illness, has long been speculated to play a role in derangements of deiodinase expression. On the other hand, oxidative stress due to augmented reactive oxygen species (ROS) generation is characteristic of many diseases that are associated with NTIS. Changes in the intracellular redox state may disrupt deiodinase function by independent mechanisms, which might include depletion of the as yet unidentified endogenous thiol cofactor. Here we aim to present an updated picture of the advances in understanding the mechanisms that result in the fall of thyroid hormone levels in the acute phase of NTIS.

Leptin Administration Restores the Fasting-Induced Increase of Hepatic Type 3 Deiodinase Expression in Mice

Decreased serum leptin has been proposed as a critical signal initiating the neuroendocrine response to fasting. Leptin administration partially reverses the fasting-induced suppression of the hypothalamus-pituitary-thyroid axis at the central level. It is, however, unknown to what extent leptin affects peripheral thyroid hormone metabolism. The aim of this study was to evaluate the effect of leptin administration on starvation-induced alterations of peripheral thyroid hormone metabolism in mice. Three types of experiments were performed: (i) mice were fasted for 24 hours while leptin was administered twice (at 0 and 8 hours, 1 μg/g body weight [BW]), (ii) mice were fasted for 24 hours and, subsequently, leptin was given once at 24 hours (killed at 28 and 32 hours), and (iii) mice were fasted for 48 hours. All groups had appropriate controls. Serum triiodothyronine and thyroxine, liver type 1 deiodinase (D1), type 3 deiodinase (D3), thyroid hormone receptor (TR)β1, TRα1 and α2 mRNA expression, and liver D1 and D3 activity were measured. Twenty-four hours of fasting decreased liver TRβ1 mRNA expression, while liver TRα1, TRα2, and D1 mRNA expression and activity did not change. In contrast, 24 hours of fasting increased liver D3 mRNA. Leptin administration after fasting restored liver D3 expression, while serum thyroid hormone levels and liver TRβ1 expression remained low. Leptin administration selectively restores starvation-induced increased hepatic D3 expression independently of serum thyroid hormone concentrations. The present study shows that fasting-induced changes in mRNA expression of genes involved in hepatic hormone metabolism are influenced not only by decreased serum thyroid hormone levels but also by serum leptin.

Stress and the thyroid gland

The review highlights the effects of acute and chronic stress on thyroid metabolism. Special attention is paid to the influence of stress and the direct effects of glucocorticoids on the thyroid status, the activities of thyrocyte iodine uptake, oxidation and organification as well as peripheral metabolism of thyroid hormones (deposition and transport of thyroid hormones, deiodinase activities in different tissues). The role of stress in the development of thyroid pathology is analysed and characteristic features of thyroid function alterations during impaired functioning of the pitiutary-adrenal system are established. The mechanisms of the stress-induced impairments in thyroid functions are of interest for further research, taking into consideration serious consequences of thyroid deficiency for the body, even in subclinical thyroid insufficiency.

T3/rT3-Ratio is Associated with Insulin Resistance Independent of TSH

Thyroid dysfunction has been shown to be associated with insulin resistance (IR). This may involve peripheral thyroid hormone metabolism, which is assumed to be reflected by the ratio triiodothyronine/reverse triiodothyronine (T3/rT3-ratio). To explore a potential association between the T3/rT3-ratio and IR we investigated pairs which differed in IR, but were matched by sex, age, body mass index (BMI), and thyroid stimulating hormone (TSH). For this purpose, matched pair analyses were embedded into a cross sectional study group. 22 pairs were matched from either the first or the third tertile of HOMA%S of a cohort of 353 euthyroid subjects with normal glucose metabolism who did not take any medication. The T3/rT3-ratio was compared in the matched pairs. The T3/rT3-ratio was significantly increased in the insulin resistant subjects compared to their insulin sensitive partners (8.78 ± 0.47 vs. 7.33 ± 0.33, p=0.019). Furthermore the T3/rT3-ratio was lower in men compared to women (p for the within-subject effect=0.046) both in the insulin sensitive and the insulin resistant subjects. Here we show that the T3/rT3-ratio, which is supposed to reflect the tissue thyroid hormone metabolism, is significantly increased in insulin resistant subjects. This further supports a link between thyroid function and IR.

Sorafenib enhances the peripheral metabolism of thyroid hormones, likely by activity of type 3 deiodinase, which may contribute to hypothyroidism

Sorafenib enhances the peripheral metabolism of thyroid hormones, likely by activity of type 3 deiodinase, which may contribute to hypothyroidism

Thyroid Hormone Receptor α Modulates Lipopolysaccharide-Induced Changes in Peripheral Thyroid Hormone Metabolism

Acute inflammation is characterized by low serum T(3) and T(4) levels accompanied by changes in liver type 1 deiodinase (D1), liver D3, muscle D2, and muscle D3 expression. It is unknown at present whether thyroid hormone receptor alpha (TRalpha) plays a role in altered peripheral thyroid hormone metabolism during acute illness in vivo. We induced acute illness in TRalpha-deficient (TRalpha(0/0)) mice by administration of a sublethal dose of LPS. Compared with wild-type, TRalpha(0/0) mice have lower basal serum T(4) and lower liver D1 activity and muscle D3 mRNA expression, whereas liver D3 activity is higher. These changes are gender specific. The inflammatory response to LPS was similar in WT and TRalpha(0/0) mice. The decrease in serum thyroid hormones and liver D1 was attenuated in TRalpha(0/0) mice, whereas the LPS induced fall in liver D3 mRNA was more pronounced in TRalpha(0/0) mice. Muscle D2 mRNA increased similarly in both strains, whereas muscle D3 mRNA decreased less pronounced in TRalpha(0/0) mice. We conclude that alterations in peripheral thyroid hormone metabolism induced by LPS administration are partly regulated via TRalpha.

Thyroid Hormone Receptor α Modulates Lipopolysaccharide-Induced Changes in Peripheral Thyroid Hormone Metabolism

Thyroid Hormone Receptor α Modulates Lipopolysaccharide-Induced Changes in Peripheral Thyroid Hormone Metabolism

Stress and thyroid gland

The review highlights the effects of acute and chronic stress on thyroid metabolism. Special attention is paid to the influence of stress and the direct effects of glucocorticoids on the thyroid status, the activities of thyrocyte iodine uptake, oxidation and organification as well as peripheral metabolism of thyroid hormones (deposition and transport of thyroid hormones, deiodinase activities in different tissues). The role of stress in the development of thyroid pathology is analysed and charestiristic features of thyroid function alterations during impaired functioning of the pitiutary-adrenal system are established. The mechanisms of the stress-induced impairments in thyroid functions are of interest for further research, taking into consideration serious consequences of thyroid deficiency for the body, even in subclinical thyroid insufficiency.

Thyroid Function and Exposure to Styrene

Many natural substances and drugs have long been known to cause goiter or thyroid dysfunction. More recently, several environmental pollutants, such as pesticides and industrial compounds, have been investigated for their thyroid-disrupting activity and related adverse effects on human health. The aim of this study was to evaluate the effects of styrene on the thyroid axis in occupationally exposed workers. Thirty-eight exposed (E) and 123 nonexposed (NE) male workers (controls) were assessed. Serum concentrations of thyrotropin (TSH; basal and after thyrotropin-releasing hormone [TRH] administration.), free thyroxine (FT(4)), free triiodothyronine (FT(3)), anti-thyroglobulin, thyroid peroxidase antibody, and calcitonin were measured. Thyroid ultrasound examination was also performed. In E workers, urinary creatinine, mandelic acid (MA), and phenylglyoxylic acid (PGA) were also measured. No significant differences between E and NE workers were demonstrated, as far as thyroid volume, nodularity, serum thyroid antibodies, and calcitonin were analyzed. However, in the E group a positive correlation between duration of exposure and thyroid volume was detected. After exclusion of subjects with nodular or autoimmune thyroid diseases, serum concentrations of FT(4), FT(3), and TSH did not differ between the two groups. In E workers there was a positive correlation between the urinary concentrations of styrene metabolites (MA plus PGA) and FT(4) or FT(4)/FT(3) ratio (p < 0.05; r = 0.45 and p < 0.005; r = 0.61, respectively), while no correlation was observed between urinary concentrations of MA plus PGA and serum TSH (either basal and stimulated). Chronic exposure to styrene is not associated with an increase in nodular or autoimmune thyroid diseases. However, styrene could interfere with peripheral metabolism of thyroid hormones by inhibiting T(4) to T(3) conversion. Whether this is a direct effect on iodothyronine deiodinases or a consequence of a general distress, such as in nonthyroidal illnesses, remains to be established. Further studies in a larger population of exposed workers are needed to confirm these preliminary observations.

Lacking thyroid hormone receptor β gene does not influence alterations in peripheral thyroid hormone metabolism during acute illness

The downregulation of liver deiodinase type 1 (D1) is supposed to be one of the mechanisms behind the decrease in serum tri-iodothyronine (T3) observed during non-thyroidal illness (NTI). Liver D1 mRNA expression is positively regulated by T3, mainly via the thyroid hormone receptor (TR)beta1. One might thus expect that lacking the TRbeta gene would result in diminished downregulation of liver D1 expression and a smaller decrease in serum T3 during illness. In this study, we used TRbeta-/- mice to evaluate the role of TRbeta in lipopolysaccharide (LPS, a bacterial endotoxin)-induced changes in thyroid hormone metabolism. Our results show that the LPS-induced serum T3 and thyroxine and liver D1 decrease takes place despite the absence of TRbeta. Furthermore, we observed basal differences in liver D1 mRNA and activity between TRbeta-/- and wild-type mice and TRbeta-/- males and females, which did not result in differences in serum T3. Serum T3 decreased rapidly after LPS administration, followed by decreased liver D1, indicating that the contribution of liver D1 during NTI may be limited with respect to decreased serum T3 levels. Muscle D2 mRNA did not compensate for the low basal liver D1 observed in TRbeta-/- mice and increased in response to LPS in TRbeta-/- and WT mice. Other (TRbeta independent) mechanisms like decreased thyroidal secretion and decreased binding to thyroid hormone-binding proteins probably play a role in the early decrease in serum T3 observed in this study.

Guía clínica de las modificaciones hipotalamohipofisarias en el embarazo y en el período posparto

During pregnancy, the body undergoes a major adaptation process as a result of the interaction between mother, placenta and fetus. Major anatomical and histological changes are produced in the pituitary, with an increase of up to 40% in the size of the gland. There are wide variations in the function of the hypothalamus-pituitary-thyroid axis that effect iodine balance, the overall activity of the gland, as well as transport of thyroid hormones in plasma and peripheral metabolism of thyroid hormones. The incidence of goiter and thyroid nodules increases throughout pregnancy. The management of differentiated thyroid carcinoma should be individually tailored according to tumoral type and pregnancy stage. Given the effects of hypothyroidism on fetal development, both the diagnosis and appropriate therapeutic management of thyroid hypofunction are essential. The most important modification to the hypothalamus-pituitary-adrenal axis during pregnancy is the rise in serum cortisol levels due to an increase in cortisol-binding proteins. Although Cushing's syndrome during pregnancy is infrequent, both diagnosis and treatment of this disorder are especially difficult. Adrenal insufficiency during pregnancy does not substantially differ from that occurring outside pregnancy. However, postpartum pituitary necrosis (Sheehan's syndrome) is a well-known complication that occurs after delivery and, together with lymphocytic hypophysitis, constitutes the most frequent cause of adrenal insufficiency. The management of prolactinoma during pregnancy requires suppression of dopaminergic agonists and their reintroduction if there is tumoral growth. Notable among the neuropituitary disorders that can occur throughout pregnancy is diabetes insipidus, which occurs as a consequence of increased vasopressinase activity.