Hypothyroidism induces type 2 iodothyronine deiodinase expression in mouse heart and testis

Wagner, Verena; Morimoto, Ryo; Dora, José Miguel; Benneman, A; Pavan, Renata Bigatti Bellizzotti; Maia, Ana Luiza

doi:10.1677/jme.0.0310541

Cited by 44 publications

(31 citation statements)

References 49 publications

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“…Although we detected D1, D2, and D3 mRNA in the lungs of SB animals, in agreement with previous reports (11,12), expression of D1 was lower than expression of D2 [cycle threshold (Ct) for D1, 31.3 ± 0.2; Ct for D2, 28.3 ± 0.4]. No differences in D1 and D3 mRNA levels were observed between VILI and SB WT animals ( Fig.…”

Section: Resultssupporting

confidence: 92%

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Role of type 2 deiodinase in response to acute lung injury (ALI) in mice

Barca-Mayo

Liao

DiCosmo

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Thyroid hormone (TH) metabolism, mediated by deiodinase types 1, 2, and 3 (D1, D2, and D3) is profoundly affected by acute illness. We examined the role of TH metabolism during ventilator-induced lung injury (VILI) in mice. Mice exposed to VILI recapitulated the serum TH findings of acute illness, namely a decrease in 3,5,3′-triiodothyronine (T 3 ) and thyroid-stimulating hormone and an increase in reverse T 3 . Both D2 immunoreactivity and D2 enzymatic activity were increased significantly. D1 and D3 activity did not change. Using D2 knockout (D2KO) mice, we determined whether the increase in D2 was an adaptive response. Although similar changes in serum TH levels were observed in D2KO and WT mice, D2KO mice exhibited greater susceptibility to VILI than WT mice, as evidenced by poorer alveoli integrity and quantified by lung chemokine and cytokine mRNA induction. These data suggest that an increase in lung D2 is protective against VILI. Similar findings of increased inflammatory markers were found in hypothyroid WT mice exposed to VILI compared with euthyroid mice, indicating that the lungs were functionally hypothyroid. Treatment of D2KO mice with T 3 reversed many of the lung chemokine and cytokine profiles seen in response to VILI, demonstrating a role for T 3 in the treatment of lung injury. We conclude that TH metabolism in the lung is linked to the response to inflammatory injury and speculate that D2 exerts its protective effect by making more TH available to the injured lung tissue.nonthyroidal illness | euthyroid sick | reverse triiodothyronine | bronchial alveolar lavage | sepsis T hyroid hormone [TH, here denoting the active hormone 3,5,3′-triiodothyronine (T 3 ) and its precursor thyroxine (T 4 )] is necessary for the normal development and function of virtually every vertebrate tissue. Although the thyroid gland is predominantly responsible for the production and release of T 4 , the cellular bioavailability of the active T 3 depends on TH-specific transporters and tissue TH metabolism. Metabolism of TH is regulated by three iodothyronine deiodinases. Both type 1 (D1) and type 2 (D2) deiodinases serve to generate bioactive T 3 by outer-ring deiodination of T 4 . D2 has a major role in the intracellular generation of the active TH in mouse; the role of the D1, with its broad substrate specificity and ability to carry out both outer-and inner-ring deiodination, is less well understood. In contrast, type 3 iodothyronine deiodinase (D3) inactivates TH by inner-ring deiodination of T 4 to reverse T 3 (3′,5,3-triiodothyronine; rT 3 ) and T 3 to 3,3′-diiodothyronine (T 2 ), both biologically inactive compounds (1).Studies have elucidated the dynamic effects of TH action on brain, bone, liver (2-5), and maturation of the fetal lung (6, 7), but little is known regarding the role of TH in adult lung physiology. Until now, evidence suggesting that TH influences adult lung physiology has been indirect and based on the presence of TH receptors (8), deiodinases (9-12), and measured TH concentrations (10,13,14) i...

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Section: Resultssupporting

confidence: 92%

“…Until now, evidence suggesting that TH influences adult lung physiology has been indirect and based on the presence of TH receptors (8), deiodinases (9)(10)(11)(12), and measured TH concentrations (10,13,14) in the lung.…”

mentioning

confidence: 99%

Role of type 2 deiodinase in response to acute lung injury (ALI) in mice

Barca-Mayo

Liao

DiCosmo

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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“…Type 2 deiodinase expression in rodent heart is much lower than in human heart (Croteau et at., 1996), therefore rodents are not considered a suitable model for human D2 regulation. Cardiac D2 mRNA and activity in mouse and rats has, however, been demonstrated to respond to changes in thyroid hormone levels induced by hypothyroidism provoked by methimazol treatment (Wagner et al, 2003) or iodine deficiency (Lavado-Autric et al, 2013) and attenuated by T3 administration (Wagner et al, 2003). This could indicate that in our study, local changes in thyroid hormone evoked by CR were not sufficient to alter D2 expression.…”

Section: Discussioncontrasting

confidence: 55%

The effects of caloric restriction and age on thyroid hormone signalling in the heart of rats

Lachowicz¹,

Fürstenberg²,

Pałkowska³

et al. 2014

J. Anim. Feed Sci.

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“…Type 2 deiodinase (D2) catalyzes T 4 to T 3 conversion, and plays a critical role in maintaining intracellular T 3 levels in specialized tissues, such as the anterior pituitary, CN, and brown adipose tissue (BAT) (1). D2 gene (DIO2) expression has also been reported in pituitary, thyroid, placenta, heart and skeletal muscle, and testis (2)(3)(4)(5)(6)(7)(8). Recently, it has been suggested that D2 also contributes for a fraction of the serum T 3 levels in euthyroid and hypothyroid individuals (9).…”

Section: Introductionmentioning

confidence: 99%

Association of the type 2 deiodinase Thr92Ala polymorphism with type 2 diabetes: case–control study and meta-analysis

Dora¹,

Machado²,

Rheinheimer³

et al. 2010

European Journal of Endocrinology

122

103

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Objective: The type 2 deiodinase (D2) is a key enzyme for intracellular triiodothyronine (T 3 ) generation. A single-nucleotide polymorphism in D2 (Thr92Ala) has been associated with increased insulin resistance in nondiabetic and type 2 diabetes (DM2) subjects. Our aim was to evaluate whether the D2 Thr92Ala polymorphism is associated with increased risk for DM2. Design and methods: A case-control study with 1057 DM2 and 516 nondiabetic subjects was performed. All participants underwent genotyping of the D2 Thr92Ala polymorphism. Additionally, systematic review and meta-analysis of the literature for genetic association studies of D2 Thr92Ala polymorphism and DM2 were performed in Medline, Embase, LiLacs, and SciELO, and major meeting databases using the terms 'rs225014' odds ratio (OR) 'thr92ala' OR 'T92A' OR 'dio2 a/g'. Results: In the case-control study, the frequencies of D2 Ala92Ala homozygous were 16.4% (nZ173) versus 12.0% (nZ62) in DM2 versus controls respectively resulting in an adjusted OR of 1.41 (95% confidence intervals (CI) 1.03-1.94, PZ0.03). The literature search identified three studies that analyzed the association of the D2 Thr92Ala polymorphism with DM2, with the following effect estimates: Mentuccia (OR 1.40 (95% CI 0.78-2.51)), Grarup (OR 1.09 (95% CI 0.92-1.29)), and Maia (OR 1.22 (95% CI 0.78-1.92)). The pooled effect of the four studies resulted in an OR 1.18 (95% CI 1.03-1.36, PZ0.02). Conclusions: Our results indicate that in a case-control study, the homozygosity for D2 Thr92Ala polymorphism is associated with increased risk for DM2. These results were confirmed by a metaanalysis including 11 033 individuals, and support a role for intracellular T 3 concentration in skeletal muscle on DM2 pathogenesis.

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Hypothyroidism induces type 2 iodothyronine deiodinase expression in mouse heart and testis

Cited by 44 publications

References 49 publications

Role of type 2 deiodinase in response to acute lung injury (ALI) in mice

Role of type 2 deiodinase in response to acute lung injury (ALI) in mice

The effects of caloric restriction and age on thyroid hormone signalling in the heart of rats

Association of the type 2 deiodinase Thr92Ala polymorphism with type 2 diabetes: case–control study and meta-analysis

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