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Tesi etd-08302009-052433


Thesis type
Tesi di dottorato di ricerca
Author
MARSILI, ALESSANDRO
URN
etd-08302009-052433
Title
Studies on peripheral metabolism of thyroid hormones-the role of type 2 iodothyronine deiodinase in mediating tissue-specific effects of thyroxine
Settore scientifico disciplinare
MED/13
Corso di studi
SCIENZE ENDOCRINE E METABOLICHE
Commissione
tutor Prof. Santini, Ferruccio
Parole chiave
  • stem cells
  • skeletal muscle
  • regeneration
  • feedback
  • thyroid
  • type 2 deiodinase
Data inizio appello
22/09/2009;
Consultabilità
parziale
Data di rilascio
22/09/2049
Riassunto analitico
The iodothyronine deiodinases initiate or terminate thyroid hormone action and therefore are critical for the biological effects mediated by thyroid hormone.<br>During the course of the studies reported in this thesis, different aspects of the role of deiodinases, in particular of type-2 deiodinase (D2), which catalyzes T4-to-T3 conversion, has been studied.<br>The importance of this enzyme in the hypothalamic pituitary thyroid axis feedback and in preserving tissue levels of the biologically active molecule T(3) has been known for a long time. In the first section, in light of recent findings that have rejuvenated the interest in the field, our aim was to clarify which center (pituitary or medio-basal-hypothalamus, both expressing D2) is the most critical in regulating the TSH response to an acute increase in T4 or T3. We demonstrate that the pituitary is dominant for this purpose, being capable of determine a dramatic change in serum TSH levels with no change in TRH message after acute increase of thyroid hormones levels. <br>We found also that deiodinases can also locally increase or decrease thyroid hormone signaling in a tissue- and temporal-specific fashion, independent of or with minimal changes in thyroid hormone serum concentrations. <br>The consequences of the local activation of thyroid hormone signaling can be either confined to the tissue or systemic. A paradigm for the latter is the induction of D2 expression by bile acids conferring resistance to diet-induced obesity in mice. <br>Given that skeletal muscle and thyroid status are two major determinants of resting energy expenditure in humans, the demonstration that type 2 deiodinase mRNA in skeletal muscle has raised the possibility of a finely tuned control of metabolism mediated by local T3 production, with the potential for pharmacological modulation of energy expenditure. <br>The extremely controversial data reported in terms of D2 activity and the importance of this issue, led us, in the second chapter, to use the unique tools genetically modified mice, one strain overexpressing D2 in cardiac muscle, the second lacking D2 (D2KO) to develop a sensitive method for accurate and reliable measurement of D2 activity in skeletal muscle. <br>In contrast to previous data, we found the presence of D2 activity in both adult murine and in human skeletal muscle, especially in oxidative fibers, namely soleus, with enzymatic characteristics (such as an increase in response to hypothyroidism) analogous to other tissues like brain.<br>Moreover, the observation of high levels of this enzyme in neonatal skeletal muscle or in immature cells, has been the trigger to further studies on the role of thyroid hormone signaling in skeletal muscle development and regeneration. <br>In the third and final chapter, we show that the presence of a time and cell type-dependent amplification of thyroid hormone signaling in muscle stem cells is critical for proper muscle differentiation and for muscle repair. Furthermore, by influencing thyroid hormone action at the intracellular level, the proliferation potential of muscle stem cells may be easily and reversibly manipulated, which could have important clinical implications for patients with muscle disease.<br>
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