Roy E. Weiss, M.D., Ph.D.

Clinical and Molecular Basis of Thyroid Hormone Action

Research Summary

My research is concerned with the molecular basis of thyroid hormone action. Thyroid hormone regulates gene expression by interacting with intranuclear thyroid hormone receptors alpha and beta as well as various cofactors that are either coactivators or repressors. In order to understand the biologic importance of these different receptors and cofactors we have studied humans with the syndrome of resistance to thyroid hormone (RTH). RTH in almost all cases reported is due to a mutation in the TR (thyroid hormone receptor) b (beta) and in one family a deletion of the TRb has been described. Transgenic mouse strains with complete deletion of either the TRb or TRa have allowed us to study the importance of these different TRs in the action in various tissues including the central nervous system, heart, liver, brown adipose tissue and bone. Manipulation of these animals in a manner that would be difficult to do in humans allows us the opportunity to dissect out the contribution of the TRb and TRa in each of these tissues. More specifically these mouse models will allow us to determine the role of maternal thyroid hormone levels in offspring with RTH. Future plans will be to determine the influence of other factors by cross mating these mice with "knockouts" of other cofactors.

A second line of investigation is a clinical study of the diagnostic tests of Cushing’s disease. Although there are several tests to aid in the differential diagnosis of hypercortisolism, there is not a single test that can be diagnostic in all individuals. This becomes most evident when the clinician is presented with the choice between subtle Cushings and pseudocushings. We have an active Clinical Research Center protocol and a Pituitary clinic jointly run with neurosurgery, neuroradiology, neuropathology and radiation oncology. Analysis of specific 24 hour profiles of cortisol and ACTH secretion have been observed that may be useful diagnostically. Currently we are in the process of determining the nature of the hypothalamic pituitary axis in morbidly obese subjects. Also we are determining the diagnostic specificity of the 1 m g ACTH stimulation test.

Selected Papers

Weiss RE, Korcarz C, Chassande O, Cua K, Sadow PM, Koo E, Samarut J, Lang R. (2002). Thyroid hormone and cardiac function in mice deficient in thyroid hormone receptor-alpha or -beta: an echocardiograph study. Am J Physiol Endocrinol Metab. 283(3):E428-35.

Cunningham JM, Buxton OM, Weiss RE. (2002). Circadian variation in Cushing's disease and pseudo-Cushing states by analysis of F and ACTH pulsatility. J Endocrinol Invest. 25(9):791-9.

Weiss RE. (2003). Empty sella following spontaneous resolution of a pituitary macroadenoma. Horm Res. 60(1):49-52.

Sadow PM, Chassande O, Gauthier K, Samarut J, Xu J, O'Malley BW, Weiss RE. (2003). Specificity of thyroid hormone receptor subtype and steroid receptor coactivator-1 on thyroid hormone action. Am J Physiol Endocrinol Metab. 284(1):E36-46. Epub 2002 Sep 17.

Sadow PM, Koo E, Chassande O, Gauthier K, Samarut J, Xu J, O'Malley BW, Seo H, Murata Y, Weiss RE. (2003).
Thyroid hormone receptor-specific interactions with steroid receptor coactivator-1 in the pituitary.
Mol Endocrinol. 17(5):882-94. Epub 2003 Feb 06.

Sadow PM, Chassande O, Koo EK, Gauthier K, Samarut J, Xu J, O'Malley BW, Weiss RE. (2003). Regulation of expression of thyroid hormone receptor isoforms and coactivators in liver and heart by thyroid hormone. Mol Cell Endocrinol. 203(1-2):65-75.

Weiss RE, Ramos HE. (2004). Thyroid hormone receptor subtypes and their interaction with steroid receptor coactivators.
Vitam Horm. 68:185-207. Review.

Mannavola D, Moeller LC, Beck-Peccoz P, Persani L, Weiss RE, Refetoff S. (2004). A novel splice variant involving the 5' untranslated region of thyroid hormone receptor beta1 (TRbeta1). J Endocrinol Invest. 27(4):318-22.

Suri D, Weiss RE. (2004). Effect of Pioglitazone on ACTH and Cortisol Secretion in Cushing's Disease.
J Clin Endocrinol Metab.

Lado-Abeal J, Dumitrescu AM, Liao XH, Cohen RN, Pohlenz J, Weiss RE, Lebrethon MC, Verloes A, Refetoff S. (2004). A de novo Mutation in an already mutant nucleotide of the thyroid hormone receptor beta gene perpetuates resistance to thyroid hormone. J Clin Endocrinol Metab. [Epub ahead of print]