Thyroid hormone (TH) is a key regulator of metabolic homeostasis in humans. It also plays a fundamental role in human development. Thus, an elegant feedback system has developed to tightly control circulating TH levels within a tight range. Central to this control is the negative regulation of thyrotropin-releasing hormone (TRH) gene expression in the paraventricular nucleus of the hypothalamus (PVH) by TH. In addition to TH, TRH is also regulated by leptin and melanocortin signaling pathways such that fasting represses TRH expression. However, the molecular mechanism by which TRH is negatively regulated by both TH and fasting is not known. On positively regulated genes TH interacts with thyroid hormone receptor isoforms (TRs) on TH response elements (TREs) to initially relieve repression caused by the unliganded receptor's ability to recruit a corepressor complex. In addition to relieving repression, TH further activates gene expression by allowing the TR to recruit a cast of coactivators which act as histone-modifying enzymes and enhance transcription. While corepressors and coactivators are presumed to play a role in negative regulation no in vivo model system has been developed to test there role. Furthermore, the identification of true negative TREs has remained elusive. Thus, understanding the regulation of TRH gene expression provides an ideal model to discern the mechanisms governing negative regulation by TH. In addition, new insight will be garnered in the cross-talk that must exist between leptin and TH signaling in the TH neuron. In this proposal we will use a number of new genetic models to allow us to determine the molecular mechanism governing the regulation of TRH gene expression.
Aim 1 will employ novel mouse models to discern the role of coregulators in negative regulation of TRH by TH.
Aim 2 will utilize a novel transgenic mouse which contains a TRH BAG that the targets the PVN and is regulated by TH. Manipulation of this BAG will allow for the identification for the first time of a negative TRE.
Aim 3 will focus on both cross-talk between the leptin and TH pathways within the TRH neuron and also understanding the exact mechanism by which leptin and/or downstream pathways regulate TRH expression. Completion of these Aims will shed new light on how metabolic pathwys target gene expression to preserve metabolic homeostasis. This should allow for a better understanding of physiologic adaptation to disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Project (R01)
Project #
5R01DK078090-03
Application #
7585204
Study Section
Molecular and Cellular Endocrinology Study Section (MCE)
Program Officer
Margolis, Ronald N
Project Start
2007-04-10
Project End
2011-03-31
Budget Start
2009-04-01
Budget End
2010-03-31
Support Year
3
Fiscal Year
2009
Total Cost
$333,200
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Astapova, Inna; Ramadoss, Preeti; Costa-e-Sousa, Ricardo H et al. (2014) Hepatic nuclear corepressor 1 regulates cholesterol absorption through a TR?1-governed pathway. J Clin Invest 124:1976-86
Vella, Kristen R; Ramadoss, Preeti; Costa-E-Sousa, Ricardo H et al. (2014) Thyroid hormone signaling in vivo requires a balance between coactivators and corepressors. Mol Cell Biol 34:1564-75
Chiappini, Franck; Ramadoss, Preeti; Vella, Kristen R et al. (2013) Family members CREB and CREM control thyrotropin-releasing hormone (TRH) expression in the hypothalamus. Mol Cell Endocrinol 365:84-94
Costa-e-Sousa, Ricardo H; Hollenberg, Anthony N (2012) Minireview: The neural regulation of the hypothalamic-pituitary-thyroid axis. Endocrinology 153:4128-35
Costa-e-Sousa, Ricardo H; Astapova, Inna; Ye, Felix et al. (2012) The thyroid axis is regulated by NCoR1 via its actions in the pituitary. Endocrinology 153:5049-57
Astapova, Inna; Vella, Kristen R; Ramadoss, Preeti et al. (2011) The nuclear receptor corepressor (NCoR) controls thyroid hormone sensitivity and the set point of the hypothalamic-pituitary-thyroid axis. Mol Endocrinol 25:212-24
Fozzatti, Laura; Lu, Changxue; Kim, Dong Wook et al. (2011) Resistance to thyroid hormone is modulated in vivo by the nuclear receptor corepressor (NCOR1). Proc Natl Acad Sci U S A 108:17462-7
Vella, Kristen R; Ramadoss, Preeti; Lam, Francis S et al. (2011) NPY and MC4R signaling regulate thyroid hormone levels during fasting through both central and peripheral pathways. Cell Metab 14:780-90
Chiappini, Franck; Cunha, Lucas L; Harris, Jamie C et al. (2011) Lack of cAMP-response element-binding protein 1 in the hypothalamus causes obesity. J Biol Chem 286:8094-105
Ghamari-Langroudi, Masoud; Vella, Kristen R; Srisai, Dollada et al. (2010) Regulation of thyrotropin-releasing hormone-expressing neurons in paraventricular nucleus of the hypothalamus by signals of adiposity. Mol Endocrinol 24:2366-81

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