FP03-6 ATF6 Association With CRTC2 As A Possible Mechanism Through Which Glucocorticoids Controls Hypothalamic Crh Expression and FOOD Intake

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: FP03-Glucocorticoids & Glucocorticoid Actions
Basic/Translational
Saturday, June 15, 2013: 11:00 AM-11:30 AM
Presentation Start Time: 11:25 AM
Room 130 (Moscone Center)

Poster Board SAT-6
Caroline Costa Mesquita*1, Danilo Silva Ferreira1, Ana Paula Lima Barbosa1, Joseane Morari1, Licio Augusto Velloso2 and Gabriel Forato Anhe3
1State University of Campinas, 2University of Campinas, Campinas, Brazil, 3State Univeristy of Campinas, Campinas, SP, Brazil
Rodents produce corticosterone in a circadian fashion with peaking values approximately 2 hours before lights off. Among the myriad of functions attributed to corticosterone, this hormone is known to stimulate food intake by reducing hypothalamic Corticotrophin-Releasing Hormone (CRH) expression. Apart from this, the precise mechanism leading to downregulation of CRH still remains to be described. Recent publications show that the Unfolded Protein Response (UPR) established in the hypothalamus is able to stimulate food intake and body weight gain. Dexamethasone (DEX), a synthetic glucocorticoid, was described to specifically activate the ATF6 branch of the UPR in different cell types. The aim of this study was to investigate if glucocorticoids regulate CRH expression and food intake through a mechanism dependent on ATF6. Male Wistar rats were kept under a light/dark cycle (12h/12h) with standard chow ad libitum. Rats were sacrificed in different moments of the light dark cycle (ZT0, ZT4, ZT8, ZT12, ZT16 or ZT20). Different set of animals were adrenalectomized (ADX) or subjected to sham surgery (SHAM). Intraperitoneal injections with DEX were performed at ZT1 (2, 20 or 200 mg/kg). Hypothalami removed from the rats were used for western blot detection of Activating transcription factor 6 (ATF6), cAMP response element-binding protein 1 (CREB1) and CREB co-activator (CRTC2). Tissues were also processed for quantification of CRH mRNA by Real Time PCR. CRTC2 association with CREB1 or ATF6 was determined by co-immunoprecipitation. ATF6 expression was maximal at ZT12 and minimal at ZT0. This was paralleled by increased ATF6/CRTC2 association at ZT16 (higher than ZT4). In contrast, CRTC2/CREB1 association was higher in ZT4 than in ZT16. Hypothalamic CRH expression peaked at ZT16. ADX rats have reduced ATF6 content and association with CRTC2. Moreover, ADX rats displayed increased CRTC2/CREB1 association, higher CRH expression at the end of the dark phase and reduced food intake. Acute exposition to DEX in vivo increased food intake, ATF6 expression and association with CRTC2 and decreased CRTC2/CREB1 association. Our data suggest that physiological levels of glucocorticoids might repress CRH expression and stimulate food intake through an ATF6-dependent pathway. We propose that ATF6 may associate with CRTC2 thus decreasing the formation of the CRTC2/CREB1 complex. These events, by extension, would decrease CREB1 transcriptional activity over CRH.­

Nothing to Disclose: CCM, DSF, APLB, JM, LAV, GFA

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

Sources of Research Support: Sao Paulo State Foundation for Research Support (FAPESP)
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