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  • Author: Denise P Carvalho x
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Rodrigo S Fortunato, Andrea C F Ferreira, Fabio Hecht, Corinne Dupuy and Denise P Carvalho

Thyroid diseases, such as autoimmune disease and benign and malignant nodules, are more prevalent in women than in men, but the mechanisms involved in this sex difference is still poorly defined. H2O2 is produced at high levels in the thyroid gland and regulates parameters such as cell proliferation, migration, survival, and death; an imbalance in the cellular oxidant–antioxidant system in the thyroid may contribute to the greater incidence of thyroid disease among women. Recently, we demonstrated the existence of a sexual dimorphism in the thyrocyte redox balance, characterized by higher H2O2 production, due to higher NOX4 and Poldip2 expression, and weakened enzymatic antioxidant defense in the thyroid of adult female rats compared with male rats. In addition, 17β-estradiol administration increased NOX4 mRNA expression and H2O2 production in thyroid PCCL3 cells. In this review, we discuss the possible involvement of oxidative stress in estrogen-related thyroid pathophysiology. Our current hypothesis suggests that a redox imbalance elicited by estrogen could be involved in the sex differences found in the prevalence of thyroid dysfunctions.

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Andrea C F Ferreira, Lívia P Lima, Renata L Araújo, Glaucia Müller, Renata P Rocha, Doris Rosenthal and Denise P Carvalho

Transport of iodide into thyrocytes, a fundamental step in thyroid hormone biosynthesis, depends on the presence of the sodium–iodide symporter (NIS). The importance of the NIS for diagnosis and treatment of diseases has raised several questions about its physiological control. The goal of this study was to evaluate the influence of thyroid iodine content on NIS regulation by thyrotrophin (TSH) in vivo. We showed that 15-min thyroid radioiodine uptake can be a reliable measurement of NIS activity in vivo. The effect of TSH on the NIS was evaluated in rats treated with 1-methyl-2-mercaptoimidazole (MMI; hypothyroid with high serum TSH concentrations) for 21 days, and after 1 (R1d), 2 (R2d), or 5 (R5d) days of withdrawal of MMI. NIS activity was significantly greater in both MMI and R1d rats. In R2d and R5d groups, thyroid iodide uptake returned to normal values, despite continuing high serum TSH, possibly as a result of the re-establishment of iodine organification after withdrawal of MMI. Excess iodine (0.05% NaI for 6 days) promoted a significant reduction in thyroid radioiodide uptake, an effect that was blocked by concomitant administration of MMI, confirming previous findings that iodine organification is essential for the iodide transport blockade seen during iodine overload. Therefore, our data show that modulation of the thyroid NIS by TSH depends primarily on thyroid iodine content and, further, that the regulation of NIS activity is rapid.

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Michelle P Marassi, Rodrigo S Fortunato, Alba C Matos da Silva, Valmara S Pereira, Denise P Carvalho, Doris Rosenthal and Vânia M Corrêa da Costa

Iodothyronine deiodinase activities are regulated by sex steroids; however, the mechanisms underlying the reported sexual dimorphism are poorly defined. In the present report, we aimed to investigate whether type 1 deiodinase (D1) sexual dimorphism exists early in sexual development by studying pre-pubertal male (Pm) and female (Pf) rats, as well as adult controls (C) and gonadectomized male and females rats. Adult male Wistar rats were studied 21 days after orchiectomy (Tex), and adult females were studied 21 days after ovariectomy (Ovx), and after estradiol benzoate (Eb) replacement. Serum total triiodothyronine (T3) was higher in pre-pubertal (P) rats than in the matching adults, with no difference between genders, although in adult males T3 was significantly lower than in females. There were no sex or age differences in serum total T4. Serum TSH in pre-pubertal (P) rats was within the adult female range, and both were significantly lower than in adult males. D1 activity in liver was greater in Pm than in Pf. In adult females, liver D1 activity was lower, while in adult males it was higher than in P rats. The same pattern of D1 activity was found in kidney. In thyroid and pituitary, D1 activity was similar in Pm, Pf, and adult females, which were all significantly lower than in the adult male. There were no differences in serum T3 and T4 between C and Tex males, but serum TSH was significantly decreased in Tex rats. Hepatic and renal D1 activities were lower in Tex than in C, but no changes were detected in thyroid and pituitary. In Ovx females, T3 was significantly lower than in the C group. Serum T4 was significantly decreased by estradiol replacement therapy in Ovx rats, in both doses used, whereas TSH was unchanged. Eb replacement increased liver and thyroid D1 activity, but in the kidney, only the highest estradiol dose promoted a significant D1 increase. In conclusion, in males, hepatic and renal D1 activity appears to be significantly influenced by gonadal hormones, in contrast to females, in which only exogenous Eb treatment stimulated D1 activity. The comparison between pre-pubertal and adult rats suggests that serum T3 is not the main regulator of D1 activity, and other factors, besides T3 and gonadal hormones, can modulate D1 activity during murine maturation.

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Renata Lopes Araujo, Bruno Moulin de Andrade, Álvaro Souto Padron de Figueiredo, Monique Leandro da Silva, Michelle Porto Marassi, Valmara dos Santos Pereira, Eliete Bouskela and Denise P Carvalho

During food restriction, decreased basal metabolic rate secondary to reduced serum thyroid hormones levels contributes to weight loss resistance. Thyroxine (T4) and 3,3′,5-tri-iodothyronine (T3) administration during caloric restriction produce deleterious side effects; however, the administration of physiological doses of T4 during food restriction has never been evaluated. The aim of this study was to analyze the effects of low replacement doses of T4 in Wistar rats subjected to 40% food restriction. Food restriction for 30 days led to significantly reduced liver type 1 deiodinase activity, serum TSH, leptin, T4, T3, metabolic rate, and body mass. The significant reduction in hepatic deiodinase activity found during food restriction was normalized in a dose-dependent manner by T4 replacement, showing that decreased type 1 deiodinase (D1) activity is secondary to decreased serum thyroid hormone levels during caloric restriction. The lowest replacement dose of T4 did not normalize resting metabolic rate, but was able to potentiate the effects of food restriction on carcass fat loss and did not spare body protein. The highest dose of T4 produced a normalization of daily oxygen consumption and determined a significant reduction in both carcass fat and protein content. Our results show that serum T4 normalization during food restriction restores serum T3 and liver D1 activity, while body protein is not spared. Thus, decreased serum T4 during caloric restriction corresponds to a protective mechanism to avoid body protein loss, highlighting the importance of other strategies to reduce body mass without lean mass loss.

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Rodrigo Soares Fortunato, Daniele Leão Ignácio, Álvaro Souto Padron, Ramon Peçanha, Michelle Porto Marassi, Doris Rosenthal, João Pedro Saar Werneck-de-Castro and Denise P Carvalho

The hypothalamic–pituitary–thyroid axis is affected by acute exercise, but the mechanisms underlying thyroid function changes after exercise remain to be defined. The aim of this study was to elucidate the effects of a session of acute exercise on the treadmill at 75% of maximum oxygen consumption on thyroid function of rats. Male Wistar rats were divided into five groups: control (without exercise), and killed immediately after (0 min) or 30, 60, and 120 min after the end of the exercise session. A significant increase in serum tri-iodothyronine (T3) occurred immediately after the exercise, with a gradual decrease thereafter, so that 120 min after the end of the exercise, serum T3 was significantly lower than that in controls. Total thyroxine (T4) increased progressively reaching values significantly higher than that in the control group at 120 min. T3/T4 ratio was significantly decreased 60 and 120 min after the exercise, indicating impaired T4-to-T3 conversion. Liver type 1 deiodinase activity (D1) significantly decreased at 60 and 120 min, while pituitary D1 increased progressively from 30 to 120 min after the exercise, and thyroid D1 was increased only immediately after the end of the exercise. Brown adipose tissue (BAT) type 2 deiodinase activity (D2) was significantly lower at 30 min, but pituitary D2 remained unchanged. No change in serum thyrotropin was detected, while serum corticosterone was significantly higher 30 min after the exercise. Our results demonstrate that decreased liver D1 and BAT D2 might be involved in the decreased T4-to-T3 conversion detected after an exercise session on the treadmill.

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Nicolás Gigena, Vanina A Alamino, María del Mar Montesinos, Magalí Nazar, Ruy A Louzada, Simone M Wajner, Ana L Maia, Ana M Masini-Repiso, Denise P Carvalho, Graciela A Cremaschi and Claudia G Pellizas

We reported thyroid hormone (TH) receptor expression in murine dendritic cells (DCs) and 3,5,3′-triiodothyronine (T3)-dependent stimulation of DC maturation and ability to develop a Th1-type adaptive response. Moreover, an increased DC capacity to promote antigen-specific cytotoxic T-cell activity, exploited in a DC-based antitumor vaccination protocol, was revealed. However, putative effects of the main circulating TH, l-thyroxine (T4) and the mechanisms of TH transport and metabolism at DC level, crucial events for TH action at target cell level, were not known. Herein, we show that T4 did not reproduce those registered T3-dependent effects, finding that may reflect a homoeostatic control to prevent unspecific systemic activation of DCs. Besides, DCs express MCT10 and LAT2 TH transporters, and these cells mainly transport T3 with a favored involvement of MCT10 as its inhibition almost prevented T3 saturable uptake mechanism and reduced T3-induced IL-12 production. In turn, DCs express iodothyronine deiodonases type 2 and 3 (D2, D3) and exhibit both enzymatic activities with a prevalence towards TH inactivation. Moreover, T3 increased MCT10 and LAT2 expression and T3 efflux from DCs but not T3 uptake, whereas it induced a robust induction of D3 with a parallel slight reduction in D2. These findings disclose pivotal events involved in the mechanism of action of THs on DCs, providing valuable tools for manipulating the immunogenic potential of these cells. Furthermore, they broaden the knowledge of the TH mechanism of action at the immune system network.