Hypothalamic Sirt1 Regulates Food Intake in a Rodent Model System

Abstract

Sirt1 is an evolutionarily conserved NAD+ dependent deacetylase involved in a wide range of processes including cellular differentiation, apoptosis, as well as metabolism, and aging. In this study, we investigated the role of hypothalamic Sirt1 in energy balance. Pharmacological inhibition or siRNA mediated knock down of hypothalamic Sirt1 showed to decrease food intake and body weight gain. Central administration of a specific melanocortin antagonist, SHU9119, reversed the anorectic effect of hypothalamic Sirt1 inhibition, suggesting that Sirt1 regulates food intake through the central melanocortin signaling. We also showed that fasting increases hypothalamic Sirt1 expression and decreases FoxO1 (Forkhead transcription factor) acetylation suggesting that Sirt1 regulates the central melanocortin system in a FoxO1 dependent manner. In addition, hypothalamic Sirt1 showed to regulate S6K signaling such that inhibition of the fasting induced Sirt1 activity results in up-regulation of the S6K pathway. Thus, this is the first study providing a novel role for the hypothalamic Sirt1 in the regulation of food intake and body weight. Given the role of Sirt1 in several peripheral tissues and hypothalamus, potential therapies centered on Sirt1 regulation might provide promising therapies in the treatment of metabolic diseases including obesity.

Thyroid hormone regulation of Sirtuin 1 expression and implications to integrated responses in fasted mice

“…However, the mechanism underlying the regulation of SIRT1 protein content by TH is not clear, and the unchanged steady levels of Sirt1 mRNA do not support a transcriptional mechanism. Other reports had demonstrated altered levels of the protein in the presence of unchanged Sirt1 mRNA expression (Kanfi et al 2008, Cakir et al 2009, and post-transcriptional and post-translational mechanisms have been shown to be involved (Zschoernig & Mahlknecht 2008, Gao et al 2011. However, in our study, we are not able to exclude the possibility that Sirt1 mRNA level might have preceded the significant increase in SIRT1 protein, as we did the analysis just by the end of the hypo-and hyperthyroidism induction protocols.…”

<i>SIRT1</i> gene polymorphisms associated with carcass traits in Luxi cattle

“…No SNPs were found in the coding sequence from the set of animals used in this study. SNPs g.-382G > A and g.-274C > G were located in the promoter region and could cause disruption of several transcription factor binding sites, as predicted by MatInspector release 8.0 (Cakir et al, 2009). The other three SNPs were found in intron five.…”

Neuronal Sirt1 Deficiency Increases Insulin Sensitivity in Both Brain and Peripheral Tissues

“…In contrast, both intracerebroventricular (i.c.v.) injection of EX-527, a specific Sirt1 inhibitor, and deletion of Sirt1 in Agouti-related peptide (AgRP) neurons (situated adjacent to POMC cells in the hypothalamic arcuate nucleus (ARC), cause decreases of food intake and body weight in mice and rats (8,9). Thus, it appears that Sirt1 in different neuronal populations may play distinctive and sometimes even opposing roles in energy balance regulation.…”