| 1. |
|
|
| 2. |
|
|
| 3. |
|
|
| 4. |
|
|
| 5. |
|
|
| 6. |
|
|
| 7. |
|
|
| 8. |
|
|
| 9. |
|
|
| 10. |
- Mittag, J, et al.
(författare)
-
Adaptations of the autonomous nervous system controlling heart rate are impaired by a mutant thyroid hormone receptor-alpha1
- 2010
-
Ingår i: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 151:5, s. 2388-2395
-
Tidskriftsartikel (refereegranskat)abstract
- Thyroid hormone has profound direct effects on cardiac function, but the hormonal interactions with the autonomic control of heart rate are unclear. Because thyroid hormone receptor (TR)-α1 has been implicated in the autonomic control of brown adipose energy metabolism, it might also play an important role in the central autonomic control of heart rate. Thus, we aimed to analyze the role of TRα1 signaling in the autonomic control of heart rate using an implantable radio telemetry system. We identified that mice expressing the mutant TRα1R384C (TRα1+m mice) displayed a mild bradycardia, which becomes more pronounced during night activity or on stress and is accompanied by a reduced expression of nucleotide-gated potassium channel 2 mRNA in the heart. Pharmacological blockage with scopolamine and the β-adrenergic receptor antagonist timolol revealed that the autonomic control of cardiac activity was similar to that in wild-type mice at room temperature. However, at thermoneutrality, in which the regulation of heart rate switches from sympathetic to parasympathetic in wild-type mice, TRα1+m mice maintained sympathetic stimulation and failed to activate parasympathetic signaling. Our findings demonstrate a novel role for TRα1 in the adaptation of cardiac activity by the autonomic nervous system and suggest that human patients with a similar mutation in TRα1 might exhibit a deficit in cardiac adaptation to stress or physical activity and an increased sensitivity to β-blockers.
|
|
| 11. |
|
|
| 12. |
- Morte, B, et al.
(författare)
-
Deletion of the thyroid hormone receptor alpha 1 prevents the structural alterations of the cerebellum induced by hypothyroidism
- 2002
-
Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : Proceedings of the National Academy of Sciences. - 0027-8424. ; 99:6, s. 3985-3989
-
Tidskriftsartikel (refereegranskat)abstract
- Thyroid hormone (T3) controls critical aspects of cerebellar development, such as migration of postmitotic granule cells and terminal differentiation of Purkinje cells. T3 acts through nuclear receptors (TR) of two types, TRα1 and TRβ, that either repress or activate gene expression. We have analyzed the cerebellar structure of developing mice lacking the TRα1 isoform, which normally accounts for about 80% of T3 receptors in the cerebellum. Contrary to what was expected, granule cell migration and Purkinje cell differentiation were normal in the mutant mice. Even more striking was the fact that when neonatal hypothyroidism was induced, no alterations in cerebellar structure were observed in the mutant mice, whereas the wild-type mice showed delayed granule cell migration and arrested Purkinje cell growth. The results support the idea that repression by the TRα1 aporeceptor, and not the lack of thyroid hormone, is responsible for the hypothyroid phenotype. This conclusion was supported by experiments with the TRβ-selective compound GC-1. Treatment of hypothyroid animals with T3, which binds to TRα1 and TRβ, prevents any defect in cerebellar structure. In contrast, treatment with GC-1, which binds to TRβ but not TRα1, partially corrects Purkinje cell differentiation but has no effect on granule cell migration. Our data indicate that thyroid hormone has a permissive effect on cerebellar granule cell migration through derepression by the TRα1 isoform.
|
|
| 13. |
|
|
| 14. |
|
|
| 15. |
|
|
| 16. |
|
|
| 17. |
- Zandieh-Doulabi, B, et al.
(författare)
-
Zonal expression of the thyroid hormone receptor alpha isoforms in rodent liver
- 2003
-
Ingår i: The Journal of endocrinology. - : Bioscientifica. - 0022-0795 .- 1479-6805. ; 179:3, s. 379-385
-
Tidskriftsartikel (refereegranskat)abstract
- Many metabolic processes occur simultaneously in the liver in different locations along the porto-central axis of the liver units. These processes are often regulated by hormones, one of which is thyroid hormone which for its action depends on the presence of the different isoforms of the thyroid hormone receptor (TR). These are encoded by two genes: c-erbA-alpha encoding TRalpha1 and TRalpha2 and their respective Delta isoforms, and c-erbA-beta which encodes TRbeta1, TRbeta2 and TRbeta3. We recently found a zonal (pericentral) expression of and a diurnal variation in the TRbeta1 isoform in rat liver. We were therefore also interested to see whether TRalpha1 and TRalpha2 expression showed similar characteristics. For this reason we raised both polyclonal and monoclonal antibodies against TRalpha1 and TRalpha2 isoforms and characterised these. Antibody specificity was tested using Western blots and immunohistochemistry in liver of TR isoform-specific knockout animals. Using these antibodies we found that the TRalpha1 and TRalpha2 isoforms are zonally expressed around the central vein in rat liver. The experiments show that the portal to central gradient of TRalpha1 is broader than that of TRbeta1. Moreover, the expression of the TRalpha2 protein showed a diurnal variation with a peak in the afternoon when the animals are least active whereas no such variation was found for the TRalpha1 protein.From our data it appears that both the TRalpha1 and TRalpha2 isoforms show a zonal distribution in liver. This finding, together with the observed diurnal rhythm, has major implications for interpreting and timing experiments concerning the TR and its downstream actions in liver.
|
|
| 18. |
|
|
| 19. |
- Amma, LL, et al.
(författare)
-
Distinct tissue-specific roles for thyroid hormone receptors beta and alpha1 in regulation of type 1 deiodinase expression
- 2001
-
Ingår i: Molecular endocrinology (Baltimore, Md.). - : The Endocrine Society. - 0888-8809 .- 1944-9917. ; 15:3, s. 467-475
-
Tidskriftsartikel (refereegranskat)abstract
- Type 1 deiodinase (D1) metabolizes different forms of thyroid hormones to control levels of T3, the active ligand for thyroid hormone receptors (TR). The D1 gene is itself T3-inducible and here, the regulation of D1 expression by TRα1 and TRβ, which act as T3-dependent transcription factors, was investigated in receptor-deficient mice. Liver and kidney D1 mRNA and activity levels were reduced in TRβ−/− but not TRα1−/− mice. Liver D1 remained weakly T3 inducible in TRβ–/– mice whereas induction was abolished in double mutant TRα1–/–TRβ–/– mice. This indicates that TRβ is primarily responsible for regulating D1 expression whereas TRα1 has only a minor role. In kidney, despite the expression of both TRα1 and TRβ, regulation relied solely on TRβ, thus revealing a marked tissue restriction in TR isotype utilization. Although TRβ and TRα1 mediate similar functions in vitro, these results demonstrate differential roles in regulating D1 expression in vivo and suggest that tissue-specific factors and structural distinctions between TR isotypes contribute to functional specificity. Remarkably, there was an obligatory requirement for a TR, whether TRβ or TRα1, for any detectable D1 expression in liver. This suggests a novel paradigm of gene regulation in which the TR sets both basal expression and the spectrum of induced states. Physiologically, these findings suggest a critical role for TRβ in regulating the thyroid hormone status through D1-mediated metabolism.
|
|
| 20. |
|
|
| 21. |
|
|
| 22. |
|
|
| 23. |
|
|
| 24. |
|
|
| 25. |
|
|
| 26. |
|
|
| 27. |
|
|
| 28. |
|
|
| 29. |
|
|
| 30. |
|
|
| 31. |
|
|
| 32. |
- Forrest, D, et al.
(författare)
-
Functions of thyroid hormone receptors in mice
- 2000
-
Ingår i: Thyroid : official journal of the American Thyroid Association. - : Mary Ann Liebert Inc. - 1050-7256. ; 10:1, s. 41-52
-
Tidskriftsartikel (refereegranskat)
|
|
| 33. |
|
|
| 34. |
|
|
| 35. |
|
|
| 36. |
|
|
| 37. |
|
|
| 38. |
|
|
| 39. |
|
|
| 40. |
- Hoefig, CS, et al.
(författare)
-
Thermoregulatory and Cardiovascular Consequences of a Transient Thyrotoxicosis and Recovery in Male Mice
- 2016
-
Ingår i: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 157:7, s. 2957-2967
-
Tidskriftsartikel (refereegranskat)abstract
- Thyroid hormones play a major role in body homeostasis, regulating energy expenditure and cardiovascular function. Given that obese people or athletes might consider rapid weight loss as beneficial, voluntary intoxication with T4 preparations is a growing cause for thyrotoxicosis. However, the long-lasting effects of transient thyrotoxicosis are poorly understood. Here we examined metabolic, thermoregulatory, and cardiovascular function upon induction and recovery from a 2-week thyrotoxicosis in male C57BL/6J mice. Our results showed that T4 treatment caused tachycardia, decreased hepatic glycogen stores, and higher body temperature as expected; however, we did not observe an increase in brown fat thermogenesis or decreased tail heat loss, suggesting that these tissues do not contribute to the hyperthermia induced by thyroid hormone. Most interestingly, when the T4 treatment was ended, a pronounced bradycardia was observed in the animals, which was likely caused by a rapid decline of T3 even below baseline levels. On the molecular level, this was accompanied by an overexpression of cardiac phospholamban and Serca2a mRNA, supporting the hypothesis that the heart depends more on T3 than T4. Our findings therefore demonstrate that a transient thyrotoxicosis can have pathological effects that even persist beyond the recovery of serum T4 levels, and in particular the observed bradycardia could be of clinical relevance when treating hyperthyroid patients.
|
|
| 41. |
|
|
| 42. |
|
|
| 43. |
|
|
| 44. |
|
|
| 45. |
|
|
| 46. |
|
|
| 47. |
|
|
| 48. |
|
|
| 49. |
|
|
| 50. |
|
|
