Session: SAT 649-659-Basic Mechanisms of Obesity
Poster Board SAT-652
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
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