Sirt1 Regulates Insulin Secretion by Repressing UCP2 in Pancreatic β Cells

By Laura Bordone, Maria Carla Motta, F. Picard, Ashley S. Robinson, U. Jhala, Javier Apfeld, Thomas McDonagh, M. Lemieux, M. McBurney, A. Szilvasi and 3 more. PLoS Biology, 2005

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Sir2 and insulin/IGF-1 are the major pathways that impinge upon aging in lower organisms. In Caenorhabditis elegans a possible genetic link between Sir2 and the insulin/IGF-1 pathway has been reported. Here we investigate such a link in mammals. We show that Sirt1 positively regulates insulin secretion in pancreatic β cells. Sirt1 represses the uncoupling protein (UCP) gene UCP2 by binding directly to the UCP2 promoter. In β cell lines in which Sirt1 is reduced by SiRNA, UCP2 levels are elevated and insulin secretion is blunted. The up-regulation of UCP2 is associated with a failure of cells to increase ATP levels after glucose stimulation. Knockdown of UCP2 restores the ability to secrete insulin in cells with reduced Sirt1, showing that UCP2 causes the defect in glucose-stimulated insulin secretion. Food deprivation induces UCP2 in mouse pancreas, which may occur via a reduction in NAD (a derivative of niacin) levels in the pancreas and down-regulation of Sirt1. Sirt1 knockout mice display constitutively high UCP2 expression. Our findings show that Sirt1 regulates UCP2 in β cells to affect insulin secretion.

Subfields: Aging, Geriatrics and Gerontology, Physiology

View Paper: https://www.semanticscholar.org/paper/c385a9e2cf49e285d82ba8da8e35523bf3c059ba

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Citations in the corpus

Sirtuins in aging and age-related disease. (2006, background): “Bordone et al. reported that an siRNA-enforced reduction of Sirt1 expression in β cell lines leads to an increase in the expression of uncoupling protein 2 (UCP2) and a reduc- 264 Cell 126, July 28, 2006 ©2006 Elsevier Inc. tion in insulin secretion (Bordone et al., 2006).”
The NAD+ precursor nicotinamide riboside enhances oxidative metabolism and protects against high-fat diet induced obesity (2012, positive): “Consistent with SIRT1 being a negative regulator of Ucp2 expression (Bordone et al., 2006), NR decreased Ucp2 mRNA levels (Fig.2B).”
SIRTUIN 1 AND SIRTUIN 3: PHYSIOLOGICAL MODULATORS OF METABOLISM (2012, positive): “This NAMPT-SIRT1 loop acts to fine-tune the circadian oscillation of the CLOCKBMAL1 complex, linking metabolism variances to the circadian rhythm (40, 47).”
Mammalian sirtuins--emerging roles in physiology, aging, and calorie restriction. (2006, background): “Indeed, BESTO islets demonstrate higher ATP levels (Moynihan et al. 2005), while islets from SIRT1 knockout (KO) mice do not elevate ATP production in response to glucose (Bordone et al. 2006).”
SIRT4 inhibits glutamate dehydrogenase and opposes the effects of calorie restriction in pancreatic beta cells. (2006, background): “, 2003b) and in pancreas during overnight starvation (Bordone et al., 2005).”
Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC‐1α (2007, background): “For example, the ability of SIRT1 to repress PPARg confers increases of lipolytic rates in white adipose tissue (Picard et al, 2004) and insulin secretion in b-pancreatic cells (Bordone et al, 2006).”
A Low Dose of Dietary Resveratrol Partially Mimics Caloric Restriction and Retards Aging Parameters in Mice (2008, positive): “Given that overexpression of SIRT1 in mice does induce physiological alterations consistent with CR [32], it is possible that CR impacts the levels of SIRT1 and other sirtuins in other tissues that play a central role in regulating metabolism, such the pancreas [33,34].”
SIRT1 regulates circadian clock gene expression through PER2 deacetylation. (2008, positive): “SIRT1 was found to deacetylate not only histones but also several transcriptional regulatory proteins involved in the control of metabolism, including members of the FOXO protein family (Bordone et al., 2006; Brunet et al., 2004; Motta et al., 2004), peroxisome proliferator-activated receptor gamma ”
The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. (2010, background): “, SIRT1 and SIRT4 seem have contrary actions on insulin secretion (110).”
Glucose restriction inhibits skeletal myoblast differentiation by activating SIRT1 through AMPK-mediated regulation of Nampt. (2008, background): “…angiogenesis (Potente et al., 2007), survival of neurons (Araki et al., 2004) and pancreatic β-cells (Kitamura et al., 2005), insulin secretion (Bordone et al., 2006) (Moynihan et al., 2005), lipid (Li et al., 2007) and liver metabolism (Rodgers et al., 2005), and increased physical activity…”