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- Hoefig, CS, et al.
(författare)
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Biosynthesis of 3-Iodothyronamine From T4 in Murine Intestinal Tissue
- 2015
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Ingår i: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 156:11, s. 4356-4364
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Tidskriftsartikel (refereegranskat)abstract
- The endogenous metabolite 3-iodothyronamine (3-T1AM) induces strong hypothermia and bradycardia at pharmacological doses. Although its biosynthesis from thyroid hormone precursors appears likely, the sequence and sites of reactions are still controversial: studies in T4-substituted thyroid cancer patients lacking functional thyroid tissue suggested extrathyroidal 3-T1AM production, whereas studies using labeled T4 in mice indicated intrathyroidal formation. However, because the patients received T4 orally, whereas the mice were injected ip, we hypothesized that 3-T1AM synthesis requires the intestinal passage of T4. Using the everted gut sac model in combination with mass spectrometry, we demonstrate 3-T1AM production from T4 in mouse intestine via several deiodination and decarboxylation steps. Gene expression analysis confirmed the expression of all 3 deiodinases as well as ornithine decarboxylase (ODC) in intestine. Subsequent experiments employing purified human ODC revealed that this enzyme can in fact mediate decarboxylation of 3,5-T2 and T4 to the respective thyronamines (TAMs), demonstrating that the intestine expresses the entire molecular machinery required for 3-T1AM biosynthesis. Interestingly, TAM production was strongly affected by the antithyroid treatment methimazole and perchlorate independently of thyroid status, limiting the validity of the respective mouse models in this context. Taken together, our data demonstrate intestinal 3-T1AM biosynthesis from T4 involving decarboxylation through ODC with subsequent deiodination, and explain the apparent discrepancy between 3-T1AM serum levels in patients substituted orally and mice injected ip with T4. Identifying ODC as the first enzyme capable of decarboxylating thyroid hormone, our findings open the path to further investigations of TAM metabolism on molecular and cellular levels.
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- Hoefig, CS, et al.
(författare)
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Thermoregulatory and Cardiovascular Consequences of a Transient Thyrotoxicosis and Recovery in Male Mice
- 2016
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Ingår i: Endocrinology. - : The Endocrine Society. - 1945-7170 .- 0013-7227. ; 157:7, s. 2957-2967
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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.
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