Thyrotropin-releasing hormone (TRH) produced by neurons in the hypothalamic paraventricular nucleus (PVN) has an important role in the regulation of energy homeostasis by establishing circulating levels of thyroid hormone under normal conditions and during special circumstances when metabolic adaptation is necessary such as fasting, infection and chronic illnesses. Mechanisms whereby metabolic signals regulate TRH neurons in the PVN will be explored, facilitated by the use of the Cre/loxP recombinase system in transgenic mice in which Cre-recombinase is expressed selectively in TRH cells. Attention will be given to the importance of direct vs indirect leptin signaling during fasting and in association with diet-induced obesity, the role of AGRP as an inverse agonist at MC-4 receptors, participation of CREB, ERK and AMPK signaling pathways as mediators of leptin's diverse actions on hypophysiotropic TRH neurons, and cannabinoid/glutamate interactions as a novel mechanism involved in fasting-induced suppression the HPT axis. The importance of the hypothalamic dorsomedial nucleus (DMN) as a relay station between the arcuate nucleus and TRH neurons in the PVN will be explored and the hypothesis tested that the DMN integrates signals from leptin- responsive arcuate nucleus neurons and the subparaventricular zone to give rise to the circadian periodicity of the HPT axis. Mechanisms by which endotoxin suppress hypophysiotropic TRH neurons will also be studied, focusing on effects mediated by cAMP-response element modulator (CREM), inducible cAMP early repressor (ICER), corticotropin-releasing hormone (CRH) and the role of increased T3 levels in the mediobasal hypothalamus as a result of endotoxin-induced increased type 2 iodothyronine deiodinase levels in tanycytes. Thyrotropin-releasing hormone (TRH) plays a major role in energy homeostasis by establishing circulating levels of thyroid hormone under normal conditions and during special circumstances such as fasting and critical illness when changes in thyroid status are required for adaptation. The proposed studies will elucidate how this specialized group of neurons in the hypothalamic paraventricular nucleus is regulated by metabolic signals and the neuroanatomical pathways and modulators involved, providing insight into disorders commonly referred to as the nonthyroidal illness syndrome.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Molecular and Cellular Endocrinology Study Section (MCE)
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Hyde, James F
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Tufts University
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Wittmann, Gábor; Szabon, Judit; Mohácsik, Petra et al. (2015) Parallel regulation of thyroid hormone transporters OATP1c1 and MCT8 during and after endotoxemia at the blood-brain barrier of male rodents. Endocrinology 156:1552-64
Wittmann, Gábor; Harney, John W; Singru, Praful S et al. (2014) Inflammation-inducible type 2 deiodinase expression in the leptomeninges, choroid plexus, and at brain blood vessels in male rodents. Endocrinology 155:2009-19
Fekete, Csaba; Lechan, Ronald M (2014) Central regulation of hypothalamic-pituitary-thyroid axis under physiological and pathophysiological conditions. Endocr Rev 35:159-94
Wittmann, Gabor; Hrabovszky, Erik; Lechan, Ronald M (2013) Distinct glutamatergic and GABAergic subsets of hypothalamic pro-opiomelanocortin neurons revealed by in situ hybridization in male rats and mice. J Comp Neurol 521:3287-302
Fekete, C; Zseli, G; Singru, P S et al. (2012) Activation of anorexigenic pro-opiomelanocortin neurones during refeeding is independent of vagal and brainstem inputs. J Neuroendocrinol 24:1423-31
Singru, Praful S; Wittmann, Gabor; Farkas, Erzsebet et al. (2012) Refeeding-activated glutamatergic neurons in the hypothalamic paraventricular nucleus (PVN) mediate effects of melanocortin signaling in the nucleus tractus solitarius (NTS). Endocrinology 153:3804-14
Marsili, Alessandro; Sanchez, Edith; Singru, Praful et al. (2011) Thyroxine-induced expression of pyroglutamyl peptidase II and inhibition of TSH release precedes suppression of TRH mRNA and requires type 2 deiodinase. J Endocrinol 211:73-8
Rosene, Matthew L; Wittmann, Gabor; Arrojo e Drigo, Rafael et al. (2010) Inhibition of the type 2 iodothyronine deiodinase underlies the elevated plasma TSH associated with amiodarone treatment. Endocrinology 151:5961-70
Sanchez, Edith; Singru, Praful S; Wittmann, Gabor et al. (2010) Contribution of TNF-alpha and nuclear factor-kappaB signaling to type 2 iodothyronine deiodinase activation in the mediobasal hypothalamus after lipopolysaccharide administration. Endocrinology 151:3827-35
Freitas, Beatriz C G; Gereben, Balazs; Castillo, Melany et al. (2010) Paracrine signaling by glial cell-derived triiodothyronine activates neuronal gene expression in the rodent brain and human cells. J Clin Invest 120:2206-17

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