The NAD-dependent protein deacetylase Sirt1 regulates POMC transcription and ACTH synthesis

One of the most well known experimental procedures that extend lifespan and resistance to aging-related diseases is caloric restriction. Recently Sir2/Sirt1, which is NAD-dependent protein deacetylase, and therefore sensitive to changes in cellular energy levels, was shown to mediate the lifespan extending effect of caloric restriction. Sirt1 transcript and protein was found in the mouse corticotrophinoma AtT-20 cells. Treatment with the red wine polyphenol resveratrol, which is known to activate Sirt1, decreased ACTH secretion in these cells. In order to investigate Sirt1 action on POMC expression, AtT-20 cells were transfected with a reporter vector bearing the POMC promoter upstream the luciferase gene. Knocking down Sirt1 by RNA interference increased POMC relative luciferase activity, as did treatment with the Sirt1 inhibitor nicotinamide. On the other hand, Sirt1 overexpression decreased POMC transcriptional activity. Very important transcription factors in POMC transcriptional regulation are the orphan receptors Nurr1 and Nur77. Knocking down Sirt1 and treatment with NAM increased Nur transcriptional activity. These preliminary data suggest a mechanism in which nutrient availability regulates POMC transcription through Sirt1.