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Cold Exposure Increases the Biosynthesis and Proteolytic Processing of Prothyrotropin-Releasing Hormone in the Hypothalamic Paraventricular Nucleus via ß-Adrenoreceptors

Division of Endocrinology (M.P., R.C.S., C.A.V., E.A.N.), Department of Medicine, Brown University/Rhode Island Hospital, Department of Molecular Biology, Cell Biology, and Biochemistry (E.A.N.), and Department of Pathology and Laboratory Medicine (C.A.V.), Brown University, Providence, Rhode Island 02903

Address all correspondence and requests for reprints to: Dr. Eduardo A. Nillni, Division of Endocrinology, Brown Medical School/Rhode Island Hospital, 55 Claverick Street, Third Floor, Room 320, Providence, Rhode Island 02903. E-mail: eduardo_nillni{at}brown.edu.

Different physiological conditions affect the biosynthesis and processing of hypophysiotropic proTRH in the hypothalamic paraventricular nucleus, and consequently the output of TRH. Early studies suggest that norepinephrine (NE) mediates the cold-induced activation of the hypothalamic-pituitary-thyroid axis at a central level. However, the specific role of NE on the biosynthesis and processing of proTRH has not been fully investigated. In this study, we found that NE affects gene transcription, protein biosynthesis, and secretion in TRH neurons in vitro; these changes were coupled with an up-regulation of prohormone convertase enzymes (PC) 1/3 and PC2. In vivo, NE is the main mediator of the cold-induced activation of the hypothalamic-pituitary-thyroid axis at the hypothalamic level, in which it potently stimulates the biosynthesis and proteolytic processing of proTRH through a coordinated up-regulation of the PCs. This activation occurs via ß-adrenoreceptors and phosphorylated cAMP response element binding signaling. In contrast, -adrenoreceptors regulate TRH secretion but not proTRH biosynthesis and processing. Therefore, this study provides novel information on the molecular mechanisms of control of hypophysiotropic TRH biosynthesis.