Thyroid hormone plays an important regulatory role in the development and function of virtually all organs and its homeostasis is maintained by a highly regulated, multi-step redundant system that allows a time-and tissue-specific modulation of the hormonal message. The peripheral metabolism of thyroid hormone, by regulating the circulating and intracellular levels of the active hormone T3, represents an important tissue-specific pre-receptor modulator of the hormonal action. The deiodinases are selenoenzymes which convert the pro-hormone T4 into its active hormone T3 or into the metabolically inactive rT3. We previously discovered that a common polymorphism of the type 2 deiodianse gene (Thr92Ala) associates with decreased glucose disposal and, in the presence of a previously described inactivating beta-3 adrenergic receptor polymorphism, with a small but significant increase in body mass index. This polymorphism does not affect indices of insulin resistance in a physically active founder population, the Old Order Amish, suggesting a gene-environment interaction. We speculated that the Thr92Ala polymorphism generates a defective enzyme thus leading to a decrease intracellular conversion of T4 to T3, ultimately leading to reduced energy expenditure and impaired transcription of the insulin-dependent glucose transporter-4, whose gene is thyroid hormone-regulated. During this year we have focused our efforts in developing and implementing a portfolio of clinical protocols aimed to characterize in vivo the role of the peripheral metabolism of thyroid hormone and its role in modulating the energy and glucose metabolism. Specifically, the following protocols have been implemented: 05-DK-0119 Peripheral Thyroid Hormone Conversion and Glucose and Energy Metabolism. This clinical protocol aimed to characterize in vivo the role of the peripheral metabolism of thyroid hormone with respect to glucose and energy metabolism is designed as a double blind, cross over study in which hypothyroid patients are treated either with T4 or T3 and after reaching a stable replacement dose, are admitted to the Metabolic Unit of the Clinical Center for a detailed evaluation of the energy and glucose homeostasis. Presently twelve patients have completed both phases of the study. The data obtained from this protocol have allowed us to characterize the pharmaco-equivalency of levothyroxine and liothyronine. This information is of clinical relevance since the preparation for the treatment of differentiated thyroid cancer is based on the substitution of liothyronine for levothyroxine. The data obtained form this protocol allow an accurate substitution of the thyroid hormone replacement, thus minimizing the discomfort and the potential risks associated with over- or under-replacement. The data have been presented in a manuscript entitled: """"""""The pharmacodynamic equivalence of levothyroxine and liothyronine. A randomized, double blind, cross-over study in thyroidectomized patients"""""""" recently accepted for publication in Clinical Endocrinology. The analysis of the differences between the two thyroid hormone formulations at the target-organ level indicates that the substitution therapy with liothyronine produces substantial changes in lipid and energy metabolism parameters. The data have been recently published in the Journal of Clinical Endocrinology and Metabolism. 06-DK-0133 Thyroid hormone-induced lipolysis: an in vivo microdialysis study. This clinical protocol is aimed to study, by exploiting the microdialysis technique, the pharmacological action of thyroid hormone on the adipose tissue and to study in vivo the action of the deiodinases. The study is subdivided in four phases. The recruitment of healthy volunteers has been halted during FY10 in order to redirect the efforts to different protocols. It is expected that the collection of the data will be completed by FY 12. 07-DK-0202 Thyroid hormones homeostasis and energy metabolism changes during exposure to cold temperature in humans. This clinical protocol is aimed to study in vivo, by taking advantage of the newly opened respiratory chamber in the Metabolic Unit of the Clinical Center, the changes of circulating thyroid hormones during exposure to mild changes in environmental temperature. The first phase of the study has been completed and 25 volunteers have successfully completed the study. A manuscript published in the European Journal of Endocrinology describes the changes in energy expenditure, substrate utilization and hormonal changes. The results obtained thus far have prompted us to request an amendment to the protocol in order to extend the recruitment to obese and elderly individuals, and to perform PET studies in order to analyze the physiological role of brown adipose tissue in the cold-induced thermogenesis. The dataset relative to the PET studies has been collected and the data are currently being analyzed. 07-DK-0219 A Nutrigenomics Intervention for the Study of the Role of Dietary Sitosterol on Lipid, Glucose and Energy Metabolism. This is a nutrigenomics intervention on ABCG8 mutation carriers and sex-matched unaffected siblings aimed to study the effects of the interaction between modifications of ABCG8 gene mutations and plant sterol dietary content. We hypothesize that carriers of the ABCG8 gene mutation will further improve metabolic syndrome indices when challenged with a high-sitosterol diet, and will regress toward the non-carrier controls when treated with a low-sitosterol diet. This study is conducted in the Old Order Amish population of Lancaster Co. PA, a founder population with a high prevalence of ABCG8 mutations. Currently three sib-pairs have completed the first phase of the study. The patient recruitment has been completed and the data are presently being analyzed. 08-DK-0165 Thyroid hormones homeostasis and energy metabolism changes during stimulation of endogenously secreted bile acids (BAs). In vitro and animal data indicate that the bile acids activate in a endocrine fashion the conversion of T4 to T3 ultimately leading to an increase in energy expenditure. This translational protocol is aimed to study in healthy volunteers the role of macronutrients and bile acids in the thermic effects of food. Thirty healthy volunteers have successfully completed the study, achieving the recruitment goal. We are currently analyzing the data. 08-DK-0058 Pharmacogenomic Response to Thyrotropin-Releasing Hormone Stimulation in Healthy Volunteers: The Influence of a Common Type 2 Deiodinase Genetic Polymorphism on Serum T3. Our data obtained form McCune-Albright Syndrome patients clearly indicate that intra-thyroidal conversion of T4 in T3 occurs upon activation of the cAMP pathway. We are thus exploiting this pathway using a pharmacogenomic study design to assess in vivo the effects of a common polymorphism of the D2 (Thr92Ala) by analyzing the differences in T3 levels upon TRH-stimulated raise in TSH in individuals carriers of the three genotypes (Thr/Thr, Thr/Ala, and Ala/Ala). 45 study volunteers have successfully completed the study and the data, consistent with the study hypothesis, demonstrate that subjects homozygous for the Ala92 variant have a delayed rise in circulating T3 levels after TRH-induced TSH stimulation. The data have been published in the journal THYROID.

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Agnihothri, Ritesh V; Courville, Amber B; Linderman, Joyce D et al. (2014) Moderate weight loss is sufficient to affect thyroid hormone homeostasis and inhibit its peripheral conversion. Thyroid 24:19-26
Yavuz, Sahzene; Linderman, Joyce D; Smith, Sheila et al. (2013) The dynamic pituitary response to escalating-dose TRH stimulation test in hypothyroid patients treated with liothyronine or levothyroxine replacement therapy. J Clin Endocrinol Metab 98:E862-6
Chen, Kong Y; Brychta, Robert J; Linderman, Joyce D et al. (2013) Brown fat activation mediates cold-induced thermogenesis in adult humans in response to a mild decrease in ambient temperature. J Clin Endocrinol Metab 98:E1218-23
Lee, Paul; Brychta, Robert J; Linderman, Joyce et al. (2013) Mild cold exposure modulates fibroblast growth factor 21 (FGF21) diurnal rhythm in humans: relationship between FGF21 levels, lipolysis, and cold-induced thermogenesis. J Clin Endocrinol Metab 98:E98-102
Lee, P; Linderman, J; Smith, S et al. (2013) Fibroblast growth factor 21 (FGF21) and bone: is there a relationship in humans? Osteoporos Int 24:3053-7
Lee, P; Brychta, R J; Collins, M T et al. (2013) Cold-activated brown adipose tissue is an independent predictor of higher bone mineral density in women. Osteoporos Int 24:1513-8
Peltsverger, Maya Y; Butler, Peter W; Alberobello, Anna Teresa et al. (2012) The -258A/G (SNP rs12885300) polymorphism of the human type 2 deiodinase gene is associated with a shift in the pattern of secretion of thyroid hormones following a TRH-induced acute rise in TSH. Eur J Endocrinol 166:839-45
Celi, Francesco S; Zemskova, Marina; Linderman, Joyce D et al. (2011) Metabolic effects of liothyronine therapy in hypothyroidism: a randomized, double-blind, crossover trial of liothyronine versus levothyroxine. J Clin Endocrinol Metab 96:3466-74
Alberobello, Anna Teresa; Congedo, Valentina; Liu, Hong et al. (2011) An intronic SNP in the thyroid hormone receptor ýý gene is associated with pituitary cell-specific over-expression of a mutant thyroid hormone receptor ýý2 (R338W) in the index case of pituitary-selective resistance to thyroid hormone. J Transl Med 9:144
Celi, Francesco S; Brychta, Robert J; Linderman, Joyce D et al. (2010) Minimal changes in environmental temperature result in a significant increase in energy expenditure and changes in the hormonal homeostasis in healthy adults. Eur J Endocrinol 163:863-72

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