HYPOTHALAMIC SIRT1 REGULATES THE HYPOTHALAMIC-PITUITARY-ADRENAL AXIS

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 649-659-Basic Mechanisms of Obesity
Basic
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-652
Anika M Toorie*1, Nicole E. Cyr1, Ross Beckman1, Ronald Stuart1 and Eduardo A. Nillni2
1The Warren Alpert Medical School of Brown University/Rhode Island Hospital, Providence, RI, 2The Warren Alpert Medical School of Brown University/Rhode Island Hospita, Providence, RI
Sirt1 is an evolutionarily conserved NAD+ -dependent deacetylase that regulates a myriad of cellular processes including cell differentiation, apoptosis, metabolism, and aging.  Regarding whole body metabolism, Sirt1 functions as a critical nutrient/energy sensor in both central and peripheral tissues. Recent studies from our laboratory have highlighted Sirt1’s orexigenic action in the arcuate nucleus (ARC) of the hypothalamus, specifically via its regulation of the central melanocortin system and reported higher hypothalamic Sirt1 levels in the diet-induced obese (DIO) condition (1). In the present study, we aimed to identify Sirt1’s function in the paraventricular nucleus (PVN) of the hypothalamus, specifically pertaining to its regulation of the hypothalamic-pituitary-adrenal (HPA) axis. The results show that diet-induced obese (DIO) rats exhibit elevated Sirt1 protein in PVN compared to their lean counterpart. We then manipulated Sirt1 pharmacologically in lean and DIO rats with a specific inhibitor, EX527. 

We found that Sirt1 inhibition significantly decreased the prohormone convertase 2 (PC2) protein levels in DIO rats. PC2 catalyzes the conversion of prohormones to their biologically active derivatives. In the PVN, PC2 acts to convert pro-corticotropin-releasing hormone (pro-CRH) to its bioactive form of CRH peptide (2). In-vitro manipulation of Sirt1 activity in hypothalamic N43/5 cells reveals that activation of Sirt1 increases PC2 promoter activity, while inhibition of Sirt1 results in decreased PC2 promoter activity, further validating Sirt1’s regulation of PC2. CRH is known to affect food intake acting as a neurotransmitter and via regulation of the HPA axis. Sustained, elevated levels of bioactive CRH in the PVN results in chronically increased levels of baseline (i.e. not stress induced) circulating glucocorticoids (GC), thereby altering metabolism and increasing food-intake in a diet-dependent manner (3). We show that pharmacological activation of Sirt1 in lean rats increases circulating glucocorticoids; further validating that Sirt1 regulates the HPA axis. We now provide evidence that Sirt1 activation within the PVN regulates a key enzyme that processes pro-CRH, which in turn regulates metabolism. Current studies are elucidating the mechanisms of Sirt1 action on the HPA axis by investigating Sirt1’s regulation of bioactive CRH in the hypothalamus, adrenocorticotropin (ACTH) in the anterior pituitary, and GC’s produced in the adrenal gland.

Nothing to Disclose: AMT, NEC, RB, RS, EAN

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Supported by NIDDK/NIH grant R01 DK085916-03; NIH 3R01 DK085916-03S1 to EAN.