Deiodinase Activity Research Articles

Altered thyroid feedback loop in Klinefelter syndrome: a cohort study from infancy through the transition into adulthood.

Thyroid dysfunction has been claimed contributing to the spectrum of Klinefelter syndrome (KS); however, studies are scarce. In a retrospective longitudinal study, we aimed at describing the hypothalamus-pituitary-thyroid (HPT) axis and thyroid ultrasonographic (US) appearance in patients with KS throughout the life span. 254 patients with KS (25.9±16.1 years) were classified according to their pubertal and gonadal status and compared with different groups of non-KS age-matched subjects with normal thyroid function, treated and untreated hypogonadism, or chronic lymphocytic thyroiditis. We assessed serum thyroid hormone levels, anti-thyroid antibodies, US thyroid parameters, in vitro pituitary type 2 deiodinase (D2) expression and activity. Thyroid autoimmunity was more prevalent among subjects with KS at all ages, although the Ab negative vs. positive cohorts were not different. Signs of thyroid dysfunction (reduced volume, lower echogenicity, and increased inhomogeneity) were more prominent in KS than in euthyroid controls. Free thyroid hormones were lower in pre-pubertal, pubertal, and adult subjects with KS, while TSH values were only lower in adults. Peripheral sensitivity to thyroid hormones was unaltered in KS, suggesting a dysfunctional HPT axis. Testosterone (T) was the only factor associated with thyroid function and appearance. In vitro testing demonstrated an inhibitory effect of T on pituitary D2 expression and activity, supporting enhanced central sensing of circulating thyroid hormones in hypogonadism. From infancy through adulthood, KS is characterized by increased morpho-functional abnormalities of the thyroid gland, combined with a central feedback dysregulation sustained by the effect of hypogonadism on D2 deiodinase.

Effect of the Fetal THRB Genotype on the Placenta.

Pregnant women with mutations in the thyroid hormone receptor beta (THRB) gene expose their fetuses to high TH levels shown to be detrimental to a normal fetus (NlFe) but not to an affected (AfFe) fetus. However, no information is available about differences in placental TH regulators. To investigate whether there are differences in placentas associated with a NlFe compared to an AfFe, we had the unique opportunity to study placentas from two pregnancies of the same woman with THRB mutation G307D. One placenta supported a NlFe while the other an AfFe. Sections of placentas were collected and frozen at -80°C after term delivery of NlFe and AfFe. Two placentas from healthy women of similar gestational age were also obtained. The fetal origin of the placental tissues was established by gDNA quantitation of genes on the X and Y chromosomes and THRB gene. Expression and enzymatic activity of deiodinases 2 and 3 were measured. The following genes expression was also quantitated: MCT10, MCT8, LAT1, LAT2, THRB, THRA. The placenta carrying the AfFe exhibited a significant reduction of deiodinase 2 and 3 activities as well as the expression of the thyroid hormone transporters MCT10, LAT1 and LAT2 and the THRA. Here, we present the first study of the effect of fetal THRB genotype on the placenta. Though limited by virtue of the rarity of THRB mutations and sample availability, we show that the fetal THRB genotype influences the levels of thyroid hormone regulators in the placenta.

Low Type 3 Deiodinase (DIO3) activity Post-Myocardial Infarction leads to a Greater Incidence of Heart Failure in Female Mice

Objective: Studies in male mice show that myocardial infarction (MI) leads to the upregulation of type 3 deiodinase (DIO3), the enzyme that inactivates thyroid hormones, which has been regarded as a predictor of poor outcomes after MI. Interestingly, a recent human study has shown a sex-specific regulation of DIO3 after an ischemic event, with women presenting a significant downregulation of this gene. Therefore, this study aims to investigate the biological importance of DIO3 activity on MI recovery in female mice. Methods: Female mice expressing a tamoxifen-inducible Cre-recombinase under the control of the cardiomyocyte-specific Myh6 promoter and carrying a floxed selenocysteine insertion sequence in the DIO3 gene were used to reduce heart DIO3 activity. Animals were treated with tamoxifen (1.5 mg, once daily, for 3 days). MI was induced via ligation of the left anterior descending coronary artery 4 weeks after tamoxifen treatment. Ejection fraction (EF) was measured at baseline, 2 weeks, and 4 weeks after MI induction using echocardiography. Animals were sacrificed 4 weeks post-MI, and heart mitochondrial respiration was measured using Oxygraph-2K. Results: Our data demonstrated that 4 weeks post-MI, females with low DIO3 heart activity show low EF compared to wild-type control mice. We also observed that the cardiac mitochondria of females with low DIO3 activity after MI had lower lipid-linked respiration compared to wild-type control mice. Discussion/Significance of Impact: Impaired cardiomyocyte mitochondrial function has been linked to a reduced ability to recover from MI. We found that lowering cardiac DIO3 activity in female mice caused a reduction in heart function and in cardiomyocyte mitochondrial respiration, suggesting these animals have a reduced ability to recover from MI. The data have important translational implications and clinical significance given that it challenges the current knowledge about DIO3 function after MI and will contribute to explaining why women face a 20% greater risk than men of developing heart failure after MI. Furthermore, it highlights the importance of DIO3 on female heart function since the human DIO3 gene is transcriptionally responsive to estrogen, and MI numbers are relatively low in premenopausal women but significantly increase after menopause. CTSA Grant UL1 TR002535, KL2 TR002534, & TL1 TR002533 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

MiR-24–3p/Dio3 axis is essential for BDE47 to induce local thyroid hormone disorder and neurotoxicity

BDE47 (2,2,4,4-tetrabromodiphenyl ether) is a member of the most important congeners of polybrominated diphenyl ethers (PBDEs) and has been identified as a developmental, reproductive and nervous system toxicant and endocrine system disruptor due to its frequent detection in human tissue and environmental samples. Our preliminary work suggested that high- and low-level of bromodiphenyl ethers have different effects on neuronal cells with differential targets of actions on neural tissues. In this study, we presented the underlying mechanism of BDE47 neurotoxicity from the perspective of thyroid hormone (TH) metabolism using in vitro model of human SK-N-AS neuronal cells. BDE47 could induce local TH metabolism disorder in neuronal cells by inhibiting the expression of the main enzyme, human type III iodothyronine deiodinase (Dio3). Further elucidation revealed that BDE47 effectively up-regulating miR-24–3p, which binds to the 3′-UTR of Dio3 and inhibits its expression. In addition, BDE47 could also inhibit the deiodinase activity of Dio3. Collectively, our study demonstrates the molecular mechanism of BDE47 regulating Dio3-induced TH metabolism disorder through inducing miR-24–3p, providing new clues for the role of miRNAs in neurodevelopmental toxicity mediated by environmental pollutants.

Effect of the obese phenotype on expression of hepatic T4–5’ deiodinase activity, T3 generation and thyroidal mediated actions in congenic LA/Ntul//–cprats

Parameters of thyroidal responses to diet and environment have long been shown to be impaired in the obese phenotype of the LA/Ntul//–cp rat. To characterize the effect of expression of the obese phenotype on activity of maximum T4–5’ deiodinase (T4–DI) activity on adiposity and aspects of metabolism, groups of lean and obese littermates were subjected to measures of resting metabolic rate (RMR, VO2) at thermal neutrality (30°C) after a brief fast, followed by dose response Norepinephrine (NE) stimulation. Hepatic T4–DI activity represents a major source of hormonally active T3 in plasma and is readily delivered to peripheral tissues. At 16 weeks of age animals were sacrificed by cervical dislocation, blood was collected, and liver tissue was dissected for measures of serum levels of T3 and T4, and measures of maximal tissue dithiolthreitol (DTT)–stimulated T4–DI activity determined. The retroperitoneal and dorsal white adipose (WAT) depots were also dissected to estimate the magnitude of adiposity present upon sacrifice in each phenotype. Measures of RMR and the VO2 response to NE were greater in lean than obese phenotype, and indicators of BW and adiposity were much greater in obese than lean (p=<0.01). Measures of serum T3 were greater in lean than obese, but T4 was similar in both phenotypes. Measures of the rate of hepatic T4 DI activity were greater in lean than obese (p=<0.05), and the T1/2 for T4 disappearance were also prolonged in the obese phenotype. These results are consistent with other studies of impaired nonshivering thermogenesis in this strain, and suggest that decreased activity of hepatic T4–5’ deiodinase activity may be a contributing factor in the impaired capacity for nonshivering thermogenesis and excess fat accretion in the obese phenotype of this strain.

Selenium Requirements of Rats for Normal Hepatic and Thyroidal 5′-Deiodinase (Type I) Activities

The nutritional requirement of selenium for type I 5'-deiodinase activity in thyroid compared with liver was assessed in rats. Male weanling Sprague-Dawley rats were fed a torula yeast-based diet for 20 wk. One group of rats was fed the Se-deficient basal diet (0.01 mg Se/kg). The other three groups were fed the basal diet plus sodium selenite at 0.05, 0.1 and 0.5 mg Se/kg diet. Liver 5'-deiodinase and glutathione peroxidase (GSH-Px) activities were depressed in the group fed the Se-deficient (basal) diet compared with the other groups. Liver 5'-deiodinase activity in the group fed 0.05 mg Se/kg diet was as high as in the groups fed 0.1 and 0.5 mg Se/kg diet, whereas GSH-Px activities in the groups fed 0.05 and 0.1 mg Se/kg diet were intermediate in value. Feeding the Se-deficient diet for 20 wk did not cause a suppression in 5'-deiodinase in the thyroid, and thyroid GSH-Px activity was approximately 40% of that in the other groups. In rats fed Se-supplemented diets, thyroid GSH-Px was approximately 20% or less of the activity found in liver. Plasma thyroxine was higher in the group fed the Se-deficient (basal) diet, but there were no differences in plasma 3,3',5-triiodothyronine among all groups. The results suggest that the nutritional Se requirement for 5'-deiodinase is less than that for GSH-Px and is approximately 0.05 mg Se/kg in the diet for normal activity in the liver and approximately 0.01 mg Se/kg for normal activity in the thyroid. Thyroid seems to be a priority organ over liver for Se when the intake of the element is limited.

Impaired sensitivity to thyroid hormone correlates to osteoporosis and fractures in euthyroid individuals.

There is growing evidence that thyroid function affects bone metabolism and even fractures risk. However, little is known about the relationship between thyroid sensitivity and osteoporosis and fractures. Therefore, we explored the relationship between thyroid sensitivity-related indices and bone mineral density (BMD) and fractures in euthyroid US adults. In this cross-sectional study, 20,686 subjects from National Health and Nutrition Examination Survey (NHANES) data were extracted and analyzed during 2007 to 2010. A total of 3403 men and postmenopausal women aged 50years or older with available data on diagnosis of osteoporosis and/or fragility fractures, bone mineral density (BMD) and thyroid function, were eligible. TSH index (TSHI), thyrotrophin T4/T3 resistance index (TT4RI/TT3RI), Thyroid feedback quantile-based index (TFQI), Parametric TFQI (PTFQI), free triiodothyronine to free thyroxine ratio (FT3/FT4), the secretory capacity of the thyroid gland (SPINA-GT) and the sum activity of peripheral deiodinases (SPINA-GD) were calculated. FT3/FT4, SPINA-GD, FT4, TSHI, TT4RI, TFQI and PTFQIFT4 were significantly correlated with BMD (P < 0.001). Multiple linear regression analysis showed that FT3/FT4 and SPINA-GD was significantly positively associated with BMD, while FT4, TSHI, TT4RI, TFQI and PTFQIFT4 were negatively associated with BMD (P < 0.05 or P < 0.001). In logistic regression analysis, the odds ratio (OR) for osteoporosis of TSHI, TFQI and PTFQIFT4 were 1.314(1.076, 1.605), 1.743(1.327, 2.288) and 1.827(1.359, 2.455) respectively, and were 0.746(0.620, 0.898) for FT3/FT4 (P < 0.05). In elderly euthyroid individuals, impaired sensitivity to thyroid hormones correlates to osteoporosis and fractures, independent of other conventional risk factors.

The association between thyroid homeostasis parameters and obesity in subjects with euthyroidism.

The relationship between thyroid homeostasis parameters and obesity remains poorly understood in subjects with euthyroidism. This retrospective study aimed to investigate the association between the thyroid homeostasis and obesity in a population with euthyroidism. A total of 201 adult participants with euthyroidism (age range: 27-85 years) were enrolled. Clinical measurements, including obesity indices and biochemical analyses, were conducted. Thyroid homeostasis parameters were calculated. Multiple linear regression analysis was used to analyze the associations between thyroid function, thyroid homeostasis parameters, and obesity measurements. There was a positive correlation between thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), Jostel's thyrotropin index (TSHI), standard TSH index (sTSHI), thyrotroph thyroid hormone sensitivity index (TTSI), sum activity of peripheral deiodinase (SPINA-GD), and body mass index (BMI) in participants with euthyroidism and a negative correlation between thyroid's secretory capacity (SPINA-GT) and BMI (all P<0.05). Only the fT3, TSHI, and sTSHI had a positive correlation with waist circumference (all P<0.05). We concluded that BMI was positively associated with pituitary thyrotropic function parameters and SPINA-GD, and negatively correlated with SPINA-GT in adults with euthyroidism.

The association between thyroid homeostasis parameters and obesity in subjects with euthyroidism.

The relationship between thyroid homeostasis parameters and obesity remains poorly understood in subjects with euthyroidism. This retrospective study aimed to investigate the association between the thyroid homeostasis and obesity in a population with euthyroidism. A total of 201 adult participants with euthyroidism (age range: 27-85 years) were enrolled. Clinical measurements, including obesity indices and biochemical analyses, were conducted. Thyroid homeostasis parameters were calculated. Multiple linear regression analysis was used to analyze the associations between thyroid function, thyroid homeostasis parameters, and obesity measurements. There was a positive correlation between thyroid-stimulating hormone (TSH), free triiodothyronine (fT3), Jostel's thyrotropin index (TSHI), standard TSH index (sTSHI), thyrotroph thyroid hormone sensitivity index (TTSI), sum activity of peripheral deiodinase (SPINA-GD), and body mass index (BMI) in participants with euthyroidism and a negative correlation between thyroid's secretory capacity (SPINA-GT) and BMI (all P<0.05). Only the fT3, TSHI, and sTSHI had a positive correlation with waist circumference (all P<0.05). We concluded that BMI was positively associated with pituitary thyrotropic function parameters and SPINA-GD, and negatively correlated with SPINA-GT in adults with euthyroidism.

Association of exposure to polycyclic aromatic hydrocarbons with thyroid hormones in adolescents and adults, and the influence of the iodine status.

Some studies of endocrine-disrupting polycyclic aromatic hydrocarbon (PAH) exposure and thyroid hormones (THs) are inconclusive. To assess the associations between PAHs and THs, and the influence of the iodine status on PAHs-THs, we employed 648 adolescents (12-19 years old) and 2691 adults from the National Health and Nutrition Examination Survey 2007-2008 and 2011-2012. PAH metabolites [1-hydroxynaphthalene (1-NAP), 2-NAP, 1-hydroxyphenanthrene (1-PHE), 2-PHE, 3-PHE, 2-hydroxyfluorene (2-FLU), 3-FLU, 9-FLU, and 1-hydroxypyrene (1-PYR)], THs [total and free thyroxine (TT4 and FT4), total and free triiodothyronine (TT3 and FT3), thyroid stimulating hormone (TSH), and thyroglobulin (Tg)], peripheral deiodinase activity (GD) and thyroid's secretory capacity (GT) were involved. Multiple linear regression and weighted quantile sum (WQS) regression models were used to assess PAH-TH associations and the interaction between PAHs and the iodine status. Stratification analyses were conducted based on sex, smoking and iodine status. For adolescents, in a multivariable-adjusted regression model (β; 95% CI), 1-PHE (4.08%; 1.01%, and 7.25%), 2-PHE (3.98%; 0.70%, and 7.25%) and 9-FLU (3.77%; 1.10%, 7.47%) were positively correlated with TT3; 3-PHE and 1-PYR interacted with the iodine status (P-int < 0.05); 9-FLU was positively correlated with GD in both sexes. Combined exposure to PAHs was positively associated with Tg (0.137; 0.030, and 0.243), and negatively correlated with TSH (-0.087; -0.166, and -0.008). For adults, 2-NAP was positively correlated with FT3 (0.90%; 0.20%, and 1.61%), FT4 (1.82%; 0.70%, and 2.94%), TT3 (1.31%; 0.10%, and 2.63%), TT4 (2.12%; 0.90%, and 3.36%) and GT (2.22%; 1.01%, and 3.46%), but negatively correlated with TSH (-4.97%; -8.33%, and -1.49%); 1-NAP interacted with the iodine status (P-int < 0.05); 1-PHE was inversely correlated with TT3 in males; 2-PHE was positively correlated with TT3 in females. Combined exposure to PAHs was positively associated with FT3 (0.008; 0.001, and 0.014). Combined exposure to PAHs was positively associated with FT3, TT3 and GD, and negatively correlated with FT4, TT4 and GT in non-smoking adults; but positively associated with Tg (β = 0.140; 95% CI: 0.042, 0.237) in smoking adults. Our results indicated that combined and individual PAH exposure might be related to THs, and the iodine status had an influence on PAH-TH associations. These associations were not identical between adolescents and adults, and there were sex and smoking status differences.

Roles of leptin on energy balance and thermoregulation in Eothenomys miletus.

Leptin is a hormone mainly synthesized and secreted by white adipose tissue (WAT), which regulates various physiological processes. To investigate the role of leptin in energy balance and thermoregulation in Eothenomys miletus, voles were randomly divided into leptin-injected and PBS-injected groups and placed at 25°C ± 1°C with a photoperiod of 12 L:12 D. They were housed under laboratory conditions for 28days and compared in terms of body mass, food intake, water intake, core body temperature, interscapular skin temperature, resting metabolic rate (RMR), nonshivering thermogenesis (NST), liver and brown adipose tissue (BAT) thermogenic activity, and serum hormone levels. The results showed that leptin injection decreased body mass, body fat, food intake, and water intake. But it had no significant effect on carcass protein. Leptin injection increased core body temperature, interscapular skin temperature, resting metabolic rate, non-shivering thermogenesis, mitochondrial protein content and cytochrome C oxidase (COX) activity in liver and brown adipose tissue, uncoupling protein 1 (UCP1) content and thyroxin 5'-deiodinase (T45'-DII) activity in brown adipose tissue significantly. Serum leptin, triiodothyronine (T3), thyrotropin-releasing hormone (TRH) and corticotropin-releasing hormone (CRH) concentrations were also increased significantly. Correlation analysis showed that serum leptin levels were positively correlated with core body temperature, body mass loss, uncoupling protein 1 content, thyroxin 5'-deiodinase activity, nonshivering thermogenesis, and negatively correlated with food intake; thyroxin 5'-deiodinase and triiodothyronine levels were positively correlated, suggesting that thyroxin 5'-deiodinase may play an important role in leptin-induced thermogenesis in brown adipose tissue. In conclusion, our study shows that exogenous leptin is involved in the regulation of energy metabolism and thermoregulation in E. miletus, and thyroid hormone may play an important role in the process of leptin regulating energy balance in E. miletus.

Effect of phenotype on thyroidal parameters and metabolic sequelae in Wistar fatty rats

To determine the effects of phenotype on parameters of peripheral thyroid hormone and actions, groups of adult male lean (LN) and obese (OB) Wistar Fatty Rats were fed a nutritionally adequate semisynthetic diet containing 54% carbohydrate, 16% mixed fats, 20% protein plus essential vitamins, minerals, and cellulose fiber for 8 weeks. Measures of weight gain (WG), feed efficiency ratio (FER), Resting (RMR) and norepinephrine (NE) stimulated VO2, serum triiodothyronine (T3), and in vitro T4-5’ deiodinase (5’DI) activity in liver (LVR), kidney (KID), gastrocnemius muscle (GNM) and interscapular brown adipose tissue (IBAT) were determined at baseline and after dithiothreitol (DTT) stimulation to optimize in vitro deiodination activity. The WG and FER of OB &gt;&gt; LN phenotype and FER increased over time in both phenotypes, with the greatest increase in the OB phenotype. The RMR of LN &gt; OB, and NE-stimulation (200 µg/kg BW, sc) increased VO2 by 180% in LN but only ~30% in OB phenotype. Serum T3 of LN &gt;&gt; OB. Baseline 5’DI of OB &gt; LN in LIV and KID and were of similar magnitude in both phenotypes in GNM and IBAT. After DTT stimulation, LIV increased ~200% in LN, ~30% in OB; In LN rats, KID +DTT increased ~200%, but only modest increases in OB phenotype, while in LN GNM, DTT resulted in 264% increase vs. +70% in OB rats. In IBAT, DTT resulted in ~ 30-fold increase in 5’DI in LN, and a 16-fold increase in 5’DI in the OB phenotype. These results indicate that parameters of thyroidal actions including circulating plasma levels of T3 and maximum capacity to generate T3 in peripheral tissues via 5’DI, although increased in the OB phenotype, were associated with decreases in RMR and NE-stimulated VO2. These observations occurred in association with an improved efficiency of FER and weight gain and dysregulation of intracellular T3 actions including parameters of T3 receptor affinity kinetics are likely to be among key contributors to the epigenetic expression of the OB+NIDDM phenotype in this strain and are consistent with a reduced affinity of T3- mediated cellular components of intermediary metabolism.

Biotransformation of Dec-604 and potential effect on thyroid deiodinase activity in highly flame retardant-exposed gulls

Several halogenated flame retardants (HFRs) have been identified as thyroid disruptors in birds including the polybrominated diphenyl ether (PBDE) mixtures, which have been replaced with other HFRs such as Dechlorane-604 (Dec-604). Dec-604 Component B (Dec-604 CB), a putative debrominated product of Dec-604, has been frequently reported in urban-adapted ring-billed gulls (Larus delawarensis) breeding in the Montreal area (QC, Canada). The metabolic pathways of Dec-604 are yet to be characterized, although the occurrence of Dec-604 CB in gulls may suggest that enzyme-mediated dehalogenation may occur, potentially involving the thyroid deiodinases. The objective of this study was to investigate the effect of Dec-604 on type 1 deiodinase (DIO1) in the presence of thyroxine (T4) in an in vitro DIO1 assay using liver microsomes of ring-billed gulls that are highly exposed to HFRs in the Montreal area, and to determine whether DIO1 is involved in the in vitro debromination of Dec-604. We tested the in vitro activity of DIO1 in gull liver microsomes in the presence of five concentrations of Dec-604 ranging from 0.86 to 86.21 nM. HFR concentrations (Σ40HFR) were also determined in liver samples of gulls. Results showed that total DIO1 activity in gull liver microsomes was increased by three of the five concentrations of Dec-604. No relationship between liver Σ40HFR concentrations and DIO1 activity was observed, except for T2 formation rates that significantly decreased with increasing liver HFR concentrations. Moreover, greater Dec-604 CB to Dec-604 concentration ratios in activated gull microsomes (with the DIO1 cofactor dithiothreitol) were found at the intermediate Dec-604 concentration compared to controls. These results suggested that liver microsome DIO1 activity may be perturbed in ring-billed gulls exposed to Dec-604, and be involved at least in part, in the debromination of Dec-604 leading to the formation of Dec-604 CB.

The dawning of deiodinases: an outer ring deiodinase activity in the social amoeba dictyostelium discoideum with high affinity for reverse t3

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Study of the Associations between Color Doppler Ultrasound Grading of Hyperthyroidism and Biochemical Data on Thyroid Function

Objective The main study objective was to investigate the correlation between the color Doppler ultrasound grading of hyperthyroidism and the biochemical data of thyroid function. Methods Seventy-six patients were diagnosed with hyperthyroidism based on clinical and laboratory data at our hospital. The patients were examined using color Doppler ultrasound and laboratory investigations before starting 131I treatment. First, patients were divided into two groups based on the blood flow distribution determined by ultrasound. If the blood flow signal in the parenchyma was scattered and thinned, with dispersive points and discontinuous streaky distribution, the blood flow distribution area in the sample frame was less than or equal to 1/2 of the sample frame area and was judged to be level 1. If the parenchyma was filled with diffuse blood flow signals or if most areas had depicted rich blood flow distribution when the area of blood flow distribution in the sampling frame was greater than 1/2 of the sampling frame area, it was judged to be level 2. Then, the correlations between color Doppler ultrasound grading and biochemical data of thyroid function were analyzed. The indices included FT3, FT4, TSH, anti-TG, anti-TPO, and TRAb. Parameters of thyroid homeostasis, including thyroid's secretory capacity (SPINA-GT), the total deiodinase activity (SPINA-GD), Jostel's TSH index, and the thyrotroph thyroid hormone sensitivity index (TTSI), were calculated and compared. Results Correlations were noted between color Doppler ultrasound grading and FT3, FT4, TRAb, SPINA-GT, TSHI, and TTSI. Moreover, FT3, FT4, TRAb, SPINA-GT, TSHI, and TTSI were higher in level 2 patients compared with level 1 patients. Conclusion Correlations were noted between color Doppler ultrasound grading and biochemical data of thyroid function.

Effects of Extreme Light Cycle and Density on Melatonin, Appetite, and Energy Metabolism of the Soft-Shelled Turtle (Pelodiscus sinensis).

Simple SummaryLight is an important factor that affects a variety of physiological functions of animals. Melatonin is known as the hormonal mediator of photoperiodic information to the central nervous system in vertebrates and plays a key role in food intake and energy balance regulation. The present work aimed to examine the effect of extreme light cycles (herein meaning constant darkness and constant light) that animals may encounter under dark culture situations or light pollution on melatonin secretion and melatonin-modulated appetite and energy metabolism of the soft-shelled turtle Pelodiscus sinensis. We measured melatonin level, appetite, and energy metabolism-related parameters under various photoperiods and stocking densities during daytime and nighttime. The results demonstrated that (1) melatonin secretion of the turtle was not only affected by light, but also likely to be regulated by unknown endogenous factors and density; and (2) altered plasma melatonin induced by constant darkness and density seemed to be involved in the modulation of energy metabolism (elevated thyroid activity and standard metabolic rate) rather than appetite (unchanged leptin and ghrelin contents, kisspeptin 1, cocaine amphetamine-regulated transcript, and neuropeptide Y mRNA) in Chinese soft-shelled turtles. Our results shed light on the physiological responses of freshwater turtles to extreme light cycles and also contribute important data for turtle culture.Constant darkness and constant light exposure often disturb the circadian rhythm in the behavior and energy metabolism of vertebrates. Melatonin is known as the hormonal mediator of photoperiodic information to the central nervous system and plays a key role in food intake and energy balance regulation in vertebrates. The popularly cultured soft-shelled turtle Pelodiscus sinensis has been reported to grow better under constant darkness; however, the underlying physiological mechanism by which darkness benefits turtle growth is not clear yet. We hypothesized that increased melatonin levels induced by darkness would increase appetite and energy metabolism and thus promote growth in P. sinensis. In addition, in order to elucidate the interaction of photoperiod and density, juvenile turtles were treated under three photoperiods (light/dark cycle: 24L:0D, 12L:12D, 0L:24D, light density 900 lux) and two stocking densities (high density: 38.10 ind./m2, low density: 6.35 ind./m2) for 4 weeks, and then the blood and brain tissues of turtles were collected during the day (11:00–13:00) and at night (23:00–1:00) after 2 days of fasting. We examined changes in plasma melatonin levels, food intake (FI), and appetite-related hormones (plasma ghrelin and leptin), as well as growth and energy metabolism parameters such as specific growth rate (SGR), standard metabolic rate (SMR), plasma growth hormone (GH), and thyroid hormone/enzyme activity (plasma triiodothyronine T3, thyroxine T4, and T45′-deiodinase activity). Moreover, we also assessed the responses of mRNA expression levels of food intake-related genes (kisspeptin 1 (Kiss1); cocaine amphetamine-regulated transcript (CART); neuropeptide Y (NPY)) in the brain. The results showed that under high density, SGR was the lowest in 24L:0D and the highest in 0L:24D. FI was the highest in 0L:24D regardless of density. Plasma melatonin was the highest in 0L:24D under high density at night. SMR increased with decreasing light time regardless of density. Most expressions of the measured appetite-related genes (Kiss1, CART, and NPY) were not affected by photoperiod, nor were the related hormone levels, such as plasma leptin, ghrelin, and GH. However, thyroid hormones were clearly affected by photoperiod. T3 level in 0L:24D under high density during the day was the highest among all treatment groups. T4 in 24L:0D under high density during the day and T45′-deiodinase activity in 24L:0D under low density at night were significantly reduced compared with the control. Furthermore, the energy metabolism-related hormone levels were higher under higher density, especially during the day. Together, melatonin secretion is not only modulated by light but also likely to be regulated by unknown endogenous factors and density. Altered plasma melatonin induced by constant darkness and density seems to be involved in the modulation of energy metabolism rather than appetite in the soft-shelled turtle.

In silico insights into the dimer structure and deiodinase activity of type III iodothyronine deiodinase from bioinformatics, molecular dynamics simulations, and QM/MM calculations

The homodimeric family of iodothyronine deiodinases (Dios) regioselectively remove iodine from thyroid hormones. Currently, structural data has only been reported for the monomer of the mus type III thioredoxin (Trx) fold catalytic domain (Dio3Trx), but the mode of dimerization has not yet been determined. Various groups have proposed dimer structures that are similar to the A-type and B-type dimerization modes of peroxiredoxins. Computational methods are used to compare the sequence of Dio3Trx to related proteins known to form A-type and B-type dimers. Sequence analysis and in silico protein-protein docking methods suggest that Dio3Trx is more consistent with proteins that adopt B-type dimerization. Molecular dynamics (MD) simulations of the refined Dio3Trx dimer constructed using the SymmDock and GalaxyRefineComplex databases indicate stable dimer formation along the β4α3 interface consistent with other Trx fold B-type dimers. Free energy calculations show that the dimer is stabilized by interdimer interactions between the β-sheets and α-helices. A comparison of MD simulations of the apo and thyroxine-bound dimers suggests that the active site binding pocket is not affected by dimerization. Determination of the transition state for deiodination of thyroxine from the monomer structure using QM/MM methods provides an activation barrier consistent with previous small model DFT studies. Communicated by Ramaswamy H. Sarma

Differential expression T4‐5’‐deiodinase activity in corpulent rats following cold exposure

Multiple studies indicate that the thermic responses to diet and cold exposure may be impaired in obese rodents and are likely secondary to the combined contributions of sympathetic and thyroidal components of nonshivering thermogenesis (NST). T4 is normally deiodinated via outer ring deiodinase activity by D‐1 and/or D‐2 deiodinase activity to form hormonaly active T3 during fed and cold environments, or inner ring deiodinase activity via D‐3 to form reverse T3 (rT3) during food or energy deprivation. The effect of 14 hours of 4°C cold exposure on the obese phenotype of the LA/Ntul//‐cp rats was determined in normally reared young female animals 8 to 9 weeks of age and fed the Purina Chow #5012 ad libitum throughout. Body weights and adipose tissue mass were greater in the obese than the lean phenotype (p=&lt;0.05). RMR and the dose related thermic responses to norepinephrine (NE, 200 ug., s.c.) were greater in lean than in obese. Cold exposure at 4°C resulted in decreases in rectal but not core temperature in obese rats, and the thermic responses to 45 minutes of 4°C cold exposure on VO2 were typical but were significantly greater in lean than obese animals at all time points measured. Circulating T4 concentrations were similar in lean and obese rats and serum T3 but not T4 concentrations increased dramatically in both phenotypes following the cold exposure, consistent with phenotype‐ and maximal IBAT‐linked changes in T4‐5’‐deiodinase activity / mg protein in kidney, liver and IBAT and in temperature linked increases in IBAT deiodinase activity / mg tissue protein in this strain. When D‐1 and D‐2 deiodinase activity was computed / tissue mass, further analysis indicated that D‐1 was the predominating deiodinase in liver, kidney, and gastrocnemius muscle, while in IBAT D‐2 &gt; D‐1 activity / IBAT depot and was greater in obese than lean rats. Cold exposure was associated with modest increases in net kidney deiodinase activity only in kidney. Thus, the cold induced increases in circulating T3 in lean and obese rats are likely attributed at least in part to modest increases in renal T4‐5’ D‐2 deiodinase activity, in addition to maximal rates of conversion in other tissues in possible combination with decreases in hormone clearance rates during cold induced stress.

Thermoregulatory dysfunction in post‐weaning congenic corpulent rats

To assess the capacity for cold induced thermoregulation in congenic corpulent rats, groups of normally fed post‐weaning lean and obese LA/Ntul//‐cp rats 6‐9 weeks of age were subjected to a 24°C vs. 4°C environment for &lt; 14 hours. Measures of resting VO2 (RMR) and the thermoregulatory responses to cold exposure, the thermic response to noradrenaline, thyroidal parameters, and measures of core and peripheral body temperatures following cold exposure were obtained. Body weights of obese were greater than in lean rats (p=&lt;0.01), and 14 hours of 4°C exposure demonstrated phenotype effects on both core and rectal temperatures (lean &gt; obese, rectal p=0.0012, core p= 0.0038). The RMR at thermal neutrality and the thermic response to 45 minutes of acute 4°C cold exposure was greater in lean than obese phenotype at all time points measured. The thermic responses to 100 vs 200 µg NE s.c. were greater in lean than in obese rats. Cold exposure induced a significant increase in circulating T3 and the T3:T4 ratios but T4 concentrations were unchanged by cold exposure challenge. Phenotype effects on outer ring T4‐5’ deiodinase activity/mg protein were present in Kidney and Liver (Lean &gt; Obese) while Interscapular brown adipose tissue (IBAT) demonstrated both phenotype and cold induced effects (Obese &gt; Lean). In contrast, T4‐5’deiodinase activity in gastrocnemius muscle tissue was similar in both phenotypes and lacked cold induced effects (p= n.s.). The results of this study indicate that an impaired capacity for thermoregulation occurs early in the lifespan of the corpulent rat, despite a robust increase in total IBAT 5’deiodinase activity and in circulating T3 concentrations following cold exposure in both lean and obese phenotypes. While the physiologic basis for the elevated T3 concentrations following cold exposure remains unclear and are likely secondary to the combined effects of optimizing peripheral T4 to T3 conversion rates in both phenotypes, and possible changes in kinetics of T3 receptor binding and clearance in IBAT and other tissues and which may contribute to a greater caloric efficiency and propensity for weight gain in the obese phenotype.

Comparison of selenium and deiodinase enzyme among healthy controls and hypothyroid patients

Background: Selenium an essential trace element plays an important role in human growth and development. Selenoproteins are involved in thyroid hormone metabolism and recent reports suggest there is increasing prevalence of subclinical hypothyroidism when compared to hypothyroidism. Objectives: In this paper, we aimed to analyse whether the altered thyroid profile observed in subclinical hypothyroidism is due to the deficiency of selenium or due to the defect in activity of deiodinase enzyme involved in thyroid hormone metabolism. Materials and methods: The study included the patients attending the outpatient department of General Medicine of VMKV Medical College and Hospitals, Salem. The study participants were classified into 3 groups based on their thyroid profile as Group 1- Control (n=20), Group 2: Patients with Subclinical hypothyroidism (n=20), Group 3: Patients with hypothyroidism (n=20). After obtaining informed consent from the study participants, blood sample was collected for Selenium and deiodinase assay. Selenium was performed in mass spectrophotometer using whole blood and deiodinase activity was measured in serum by ELISA method. Result: Our results showed a normal but statistically significant difference in the level of selenium and activity of deiodinase 2 enzyme in subclinical hypothyroidism and hypothyroidism when compared to healthy controls.