The Nutrient and Energy Sensor Sirt1 Regulates the Hypothalamic-Pituitary-Adrenal (HPA) Axis by Altering the Production of the Prohormone Convertase 2 (PC2) Essential in the Maturation of Corticotropin-releasing Hormone (CRH) from Its Prohormone in Male Rats

Abstract

Understanding the role of hypothalamic neuropeptides and hormones in energy balance is paramount in the search for approaches to mitigate the obese state. Increased hypothalamicpituitary-adrenal axis activity leads to increased levels of glucocorticoids (GC) that are known to regulate body weight. The axis initiates the production and release of corticotropin-releasing hormone (CRH) from the paraventricular nucleus (PVN) of the hypothalamus. Levels of active CRH peptide are dependent on the processing of its precursor pro-CRH by the action of two members of the family of prohormone convertases 1 and 2 (PC1 and PC2). Here, we propose that the nutrient sensor sirtuin 1 (Sirt1) regulates the production of CRH post-translationally by affecting PC2. Data suggest that Sirt1 may alter the preproPC2 gene directly or via deacetylation of the transcription factor Forkhead box protein O1 (FoxO1). Data also suggest that Sirt1 may alter PC2 via a post-translational mechanism. Our results show that Sirt1 levels in the PVN increase in rats fed a high fat diet for 12 weeks. Furthermore, elevated Sirt1 increased PC2 levels, which in turn increased the production of active CRH and GC. Collectively, this study provides the first evidence supporting the hypothesis that PVN Sirt1 activates the hypothalamicpituitary-adrenal axis and basal GC levels by enhancing the production of CRH through an increase in the biosynthesis of PC2, which is essential in the maturation of CRH from its prohormone, pro-CRH.Since its discovery in 1981 (1), corticotropin-releasing hormone (CRH) 2 has been demonstrated to be involved in mediating various physiological processes, including those involved in organismal homeostasis. Renowned for its critical role in mediating the stress response (2), CRH functions to regulate metabolic, immunologic, and homeostatic changes both basally and under various pathologic conditions (3-5). CRH heterogeneously expresses in the periphery and the brain with high expression in the hypothalamic paraventricular nucleus (PVN) (6 -8). Arginine vasopressin (AVP) is also produced in the PVN and acts to synergize CRH actions. It is the CRH that is produced in the medial parvocellular division of the PVN that functions as the central regulator of the HPA axis (9). Levels of bioactive CRH are dependent on the post-translational processing of its precursor pro-CRH. Prohormone posttranslational processing is the mechanism by which all peptide hormones become biologically active (10, 11). In rodents and humans, aberrations in prohormone processing results in deleterious health consequences, including metabolic dysfunctions (12-17). CRH is initially produced as a large inactive precursor, preproCRH, that is made of 196 amino acids (18,19). After cleavage of the signal sequence, the prohormone (pro-CRH) enters the lumen of the rough endoplasmic reticulum and is routed to the trans-Golgi network where it undergoes enzymatic post-translational modifications to generate several intermediate forms as well as the bioactive CRH(1-41) peptid...

Role of sirtuins in bone biology: Potential implications for novel therapeutic strategies for osteoporosis

“…Interestingly, the phenotypic changes appear to be sex‐ and age‐specific, as indicated by the more pronounced alterations in female and young mice (1‐month‐old). Furthermore, it is evidenced that SIRT1 could influence bone remodeling via hormone and endocrine signaling pathways and the somatotropic axis (Cohen et al, 2009; Kolthur‐Seetharam et al, 2009; Toorie et al, 2016). The possible link between SIRT1 and steroid hormone signaling pathways is verified by the upregulation of SIRT1 expression upon estrogen treatment.…”

The Versatility of Sirtuin-1 in Endocrinology and Immunology

“…ACTH then triggers glucocorticoid production by the adrenal cortex responding to stress conditions (Yates et al, 2013;Yamamoto and Takahashi, 2018). Though researchers reported lack of connection between POMC specific SIRT1 induction/ablation with HPA axis activation during in vivo fasting conditions (Ramadori et al, 2010), SIRT1 increased PC2 levels in the PVN resulting in increased CRH production and HPA axis stimulation in high-fat diet fed mice (Toorie et al, 2016). Moreover, SIRT1 activator, resveratrol increased PC1 and PC2 levels while SIRT1 inhibitor, EX-527, decreased PC1 and PC2 levels in mouse corticotroph cell line (AtT20) suggesting indirect HPA axis modulating roles of SIRT1 via PC1 and PC2 (Toorie and Nillni, 2014;Toorie et al, 2016).…”

“…Though researchers reported lack of connection between POMC specific SIRT1 induction/ablation with HPA axis activation during in vivo fasting conditions (Ramadori et al, 2010), SIRT1 increased PC2 levels in the PVN resulting in increased CRH production and HPA axis stimulation in high-fat diet fed mice (Toorie et al, 2016). Moreover, SIRT1 activator, resveratrol increased PC1 and PC2 levels while SIRT1 inhibitor, EX-527, decreased PC1 and PC2 levels in mouse corticotroph cell line (AtT20) suggesting indirect HPA axis modulating roles of SIRT1 via PC1 and PC2 (Toorie and Nillni, 2014;Toorie et al, 2016). Further, SIRT1 overexpression reduced corticosterone (CORT) mediated autophagy and induced apoptosis while SIRT1 knockdown reversed the results during chronic cellular stress in vitro indicating SIRT1 involvement in stress management via HPA axis (Jiang et al, 2019).…”

The Essential Role of SIRT1 in Hypothalamic-Pituitary Axis

“…The precursor pro-CRH is post-translationally processed by the PC1 and PC2. SIRT1 increases the PC2 levels in the PVN that in turn increases the active-CRH production and results in the HPA axis activation ( 34 ). In mouse corticotroph cell line (AtT20 cells), treatment with resveratrol (a SIRT1 activating compound) increased the PC1 and PC2 levels.…”