title: The Nutrient and Energy Sensor Sirt1 Regulates the Hypothalamic-Pituitary-Adrenal (HPA) Axis by Altering the Production of the Prohormone Convertase 2 (PC2) Essential in the Maturation of Corticotropin-releasing Hormone (CRH) from Its Prohormone in Male Rats.
abstract: Understanding the role of hypothalamic neuropeptides and hormones in energy balance is paramount in the search for approaches to mitigate the obese state. Increased hypothalamic-pituitary-adrenal axis activity leads to increased levels of glucocorticoids (GC) that are known to regulate body weight. The axis initiates the production and release of corticotropin-releasing hormone (CRH) from the paraventricular nucleus (PVN) of the hypothalamus. Levels of active CRH peptide are dependent on the processing of its precursor pro-CRH by the action of two members of the family of prohormone convertases 1 and 2 (PC1 and PC2). Here, we propose that the nutrient sensor sirtuin 1 (Sirt1) regulates the production of CRH post-translationally by affecting PC2. Data suggest that Sirt1 may alter the preproPC2 gene directly or via deacetylation of the transcription factor Forkhead box protein O1 (FoxO1). Data also suggest that Sirt1 may alter PC2 via a post-translational mechanism. Our results show that Sirt1 levels in the PVN increase in rats fed a high fat diet for 12 weeks. Furthermore, elevated Sirt1 increased PC2 levels, which in turn increased the production of active CRH and GC. Collectively, this study provides the first evidence supporting the hypothesis that PVN Sirt1 activates the hypothalamic-pituitary-adrenal axis and basal GC levels by enhancing the production of CRH through an increase in the biosynthesis of PC2, which is essential in the maturation of CRH from its prohormone, pro-CRH.
authors.affiliation: From the Division of Endocrinology, Department of Medicine, The Warren Alpert Medical School of Brown University/Rhode Island Hospital, Providence, Rhode Island 02903,; the Graduate Program in Pathobiology and.
authors.forename: Anika M
authors.initials: AM
authors.lastname: Toorie
authors.affiliation: From the Division of Endocrinology, Department of Medicine, The Warren Alpert Medical School of Brown University/Rhode Island Hospital, Providence, Rhode Island 02903,; the Biology Department and Neuroscience Program, Stonehill College, Easton, Massachusetts 02357.
authors.forename: Nicole E
authors.initials: NE
authors.lastname: Cyr
authors.affiliation: From the Division of Endocrinology, Department of Medicine, The Warren Alpert Medical School of Brown University/Rhode Island Hospital, Providence, Rhode Island 02903.
authors.forename: Jennifer S
authors.initials: JS
authors.lastname: Steger
authors.affiliation: From the Division of Endocrinology, Department of Medicine, The Warren Alpert Medical School of Brown University/Rhode Island Hospital, Providence, Rhode Island 02903.
authors.forename: Ross
authors.initials: R
authors.lastname: Beckman
authors.affiliation: the Biology Department and Neuroscience Program, Stonehill College, Easton, Massachusetts 02357.
authors.forename: George
authors.initials: G
authors.lastname: Farah
authors.affiliation: From the Division of Endocrinology, Department of Medicine, The Warren Alpert Medical School of Brown University/Rhode Island Hospital, Providence, Rhode Island 02903,; Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, Rhode Island 02903, and. Electronic address: Eduardo_Nillni@Brown.edu.
authors.forename: Eduardo A
authors.initials: EA
authors.lastname: Nillni
mesh_terms: D000818:Animals; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism*; D004734:Energy Metabolism; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D008297:Male; D009765:Obesity / Q000378:metabolism; D010913:Pituitary-Adrenal System / Q000378:metabolism*; D045706:Proprotein Convertase 2 / Q000378:metabolism*; D011498:Protein Precursors / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D056564:Sirtuin 1 / Q000378:metabolism*
chemical_list: D011498:Protein Precursors; C041645:pro-corticotropin releasing hormone; D003346:Corticotropin-Releasing Hormone; D045706:Proprotein Convertase 2; C488368:Sirt1 protein, rat; D056564:Sirtuin 1
keywords: Sirt1 CRH; Sirt1 CRH hypothalamus; energy balance; hypothalamus; obesity; peptides; prohormone convertases; protein processing; sirtuin 1 (SIRT1)