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. We previously discovered that a common polymorphism of the type 2 deiodianse gene (Thr92Ala) associates with decreased glucose disposal and, with a small but significant increase in body mass index. This was the first discovery in humans of clinically relevant effects of common genetic variants in the thyroid homeostasis pathways on substrate and energy metabolism. During this fiscal year we have focused our efforts in expanding, 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 double blind, cross over study is aimed to characterize in vivo the role of the peripheral metabolism of thyroid hormone with respect to end-organ targets of the thyroid hormone action. Fourteen patients have completed both phases of the study, and we are currently in the data analysis phase. The data obtained from this protocol have allowed us to characterize the pharmaco-equivalency of levothyroxine and liothyronine. 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 manuscript describing these findings has been extensively quoted in the literature. A secondary analysis of the data also indicates that the changes observed are entirely attributable to the peripheral effects of the two therapies, which reached near-identical pituitary response to escalating-dose of TRH. 06-DK-0183 Gene Expression and Release of Inflammatory Mediators in Overweight Subjects Before and After Weight Loss. The goal of this protocol is the assessment of the effects of moderate, sustained weight loss on inflammatory mediators and hormonal axes. This protocol is not currently active, but the analysis of the data has allowed us to demonstrate that moderate weight loss results in a significant perturbation of the pituitary-thyroid axis, and in a functional inhibition of the peripheral conversion of the thyroid hormone. A manuscript describing these findings has been recently been accepted for publication in THYROID. 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 whole room respiration chambers 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 have been collected, and through the collaboration with Dr. Kong Y. Chen, NIDDK-DEOB we have now validated a method to precisely measuring the brown adipose tissue activation. A manuscript describing the findings has been recently published. During the FY13 the dataset collection relative to obese and overweight volunteer has been completed, and the data are currently being analyzed. 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. We have developed 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. A secondary analysis of the original dataset was performed to study the -258A/G, a common genetic polymorphism of D2 which has been associated with increase D2 activity. After TRH injection carriers of the minor allele had a blunted rise in free T4 and a normal rise in T3. These data suggest an increase in intrathyroidal conversion with a shift of the substrate/product equilibrium, consistent with the study hypothesis and our previously published in vitro observations. Furthermore, haplotype analysis indicates an interaction of the two polymorphisms. The data have been published in the European Journal of Endocrinology. 11-DK-0256 Pharmacokinetic and Pharmacodynamic Studies of Liothyronine. A Study on the Metabolic Effects of Thyroid Hormone. We have developed a protocol aimed to characterize the pharmacokinetics and pharmacodynamic of T3 in the absence of endogenous or exogenous T4. During FY 13 the recruitment for the protocol has been robust and we have successfully completed the recruitment for the study population. 13-DK-0113 Impact of Chronic Cold Exposure on Energy Metabolism in Humans. This study is aimed to characterize the metabolic effects of long-term manipulation of environmental temperature in healthy individuals. The protocol has been recently implemented and currently the recruitment has reached the 20% of the accrual celiling. 13-DK-0058 Effects of Pharmacologic Block of Type-1 Deiodinase on Thyroid Hormone Action and on the Circulating Levels of T3 in Hypothyroid Patients. This protocol was designed to further characterize the role of peripheral metabolism of thyroid hormone in the tissue-specific delivery of the hormonal message. The protocol has been recently approved by the NIDDK-NIAMS IRB and is being implemented.

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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
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
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, 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
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
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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