Sirt1 inhibits the transcription factor CREB to regulate pituitary growth hormone synthesis

Abstract

Growth hormone (GH) is a major anabolic hormone and the primary regulator of organism growth. Its transcription is triggered by GH-releasing hormone (GHRH) through the transcription factor cAMP response element-binding protein (CREB) and by caloric intake. In contrast, the deacetylase Sirt1 is activated by caloric restriction. Therefore, the present study investigates how Sirt1 affects CREB function and GH synthesis. Sirt1 pharmacological activation with resveratrol (IC₅₀=87 μM) suppressed GHRH-induced GH secretion from rat anterior pituitary cells in vivo and in vitro, while vehicle controls showed no effect. Resveratrol's effects were abolished after knocking down Sirt1 with RNA interference, but not in control scrambled siRNA-transfected rat somatotrophs, confirming the Sirt1 specificity. Sirt1 activation and overexpression suppressed forskolin-induced CREB-Ser(133) phosphorylation, but no effect was seen with vehicle and empty plasmid controls. The deacetylase-dead mutant Sirt1 retained CREB-Ser(133) phosphorylation by keeping protein phosphatase protein phosphatase 1 activity low. Sirt1 activation suppressed glycogen synthase kinase 3 β acetylation, and a mutation on the GSK3β-Lys(205) residue mimicking a hypoacetylated form revealed increased activity. In summary, this is a novel mechanism through which Sirt1 intercepts the cAMP pathway by suppressing CREB transcriptional activation, resulting in decreased GH synthesis.

Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases

“…GSK3 has been reported to be cleaved to activated fragments by calpain (Goñi-Oliver et al, 2007; Goñi-Oliver et al, 2009) and by matrix metalloproteinase-2 (Kandasamy and Schulz, 2009), which may affect its selection of substrates to phosphorylate. A regulatory effect of acetylation on GSK3 activity was recently reported (Monteserin-Garcia et al, 2013). Furthermore, GSK3β was recently found to be inhibited by mono-ADP-ribosylation (Feijs et al, 2013; Rosenthal et al, 2013), and to be regulated by citrullination (Stadler et al, 2013).…”

“…There is also evidence that members of the sirtuin (Sirt) family of deacetylases regulate GSK3. Sirt2 activity is associated with inhibition of GSK3 (Dan et al, 2012; Si et al, 2013), whereas Sirt1 has been reported to either activate (Monteserin-Garcia et al, 2013) or inhibit (Li et al, 2013) GSK3. GSK3 also modulates post-translational modifications of histones by regulating several histone acetyltransferases (HATs).…”

Systemic regulation of mammalian ageing and longevity by brain sirtuins

“…Future investigations should address whether the reduction of Gnrh in the hypothalamus is a direct result of changes in hypothalamic Sirt1. Sirt1 is also abundantly expressed in the pituitary gland and regulates pituitary hormone secretion and/or synthesis, such as TSH 59 and GH 29,60 . A number of papers report that very complex changes occur in endocrine systems during the aging process in mammals 61 .…”

Effect of Nutrition on Statural Growth

“…SIRT1 has the same effect in the cytosol, as indicated by its ability to regulate autophagy upstream of mTOR by binding to the mTOR inhibitor TSC2 [163, 164]. It may also have a systemic effect on growth through its effect on GH secretion, as Resveratrol, a SIRT1 activator, significantly reduced growth hormone releasing hormone-induced GH secretion from rat anterior pituitary cells in vivo and in vitro [165]. …”