SirT1 gain-of-function increases energy efficiency and prevents diabetes in mice

By Alexander S. Banks, N. Kon, Colette M. Knight, M. Matsumoto, R. Gutiérrez-Juárez, L. Rossetti, W. Gu, D. Accili. Cell Metabolism, 2008

659 citations recorded by the source corpus.

Summary In yeast, worms and flies, an extra copy of the gene encoding the Sirtuin Sir2 increases metabolic efficiency, as does administration of polyphenols like resveratrol, thought to act through Sirtuins. But evidence that Sirtuin gain-of-function results in increased metabolic efficiency in mammals is limited. We generated transgenic mice with moderate overexpression of SirT1, designed to mimic the Sirtuin gain-of-function that improves metabolism in C.elegans. These mice exhibit normal insulin sensitivity, but decreased food intake and locomotor activity, resulting in decreased energy expenditure. However, in various models of insulin resistance and diabetes, SirT1 transgenics display improved glucose tolerance due to decreased hepatic glucose production and increased adiponectin levels, without changes in body weight or composition. We conclude that SirT1 gain-of-function primes the organism for metabolic adaptation to insulin resistance, increasing hepatic insulin sensitivity and decreasing whole-body energy requirements. These findings have important implications for Sirtuin-based therapies in humans.

Subfields: Epidemiology, Geriatrics and Gerontology, Physiology

View Paper: https://www.semanticscholar.org/paper/f70ed3f53bce486c9918b29675f47b4585a6a54a

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In Epidemiology

1. Joseph A. Baur
2. Johan Auwerx
3. D. Sinclair
4. S. Imai

In Geriatrics and Gerontology

1. Johan Auwerx
2. D. Sinclair
3. C. Cantó
4. Joseph A. Baur
5. R. Houtkooper
6. S. Imai
7. Brian J. North
8. R. Wanders

In Physiology

1. Johan Auwerx
2. D. Sinclair
3. C. Cantó
4. Joseph A. Baur
5. S. Imai
6. R. Houtkooper
7. C. Palmeira
8. Brian J. North

Citations in the corpus

• Sirt1 extends life span and delays aging in mice through the regulation of Nk2 homeobox 1 in the DMH and LH. (2013, background): “, 2007) or preventive effects on metabolic complications caused by high-fat diet and aging (Banks et al., 2008; Pfluger et al., 2008).”
• Resveratrol Ameliorates Aging-Related Metabolic Phenotypes by Inhibiting cAMP Phosphodiesterases (2012, positive): “, 2004), overexpression of Sirt1, the mammalian homolog of Sir2, has been reported to protect mice from aging-related phenotypes that are similar to type 2 diabetes (Banks et al., 2008; Bordone et al., 2007; Pfluger et al., 2008), cancer (Herranz et al.”
• The secret life of NAD+: an old metabolite controlling new metabolic signaling pathways. (2010, background): “This observation was consolidated recently in a mouse model of mild SIRT1 overexpression (197).”
• SIRT1 is required for AMPK activation and the beneficial effects of resveratrol on mitochondrial function (2012, background): “Treatment of rodents with resveratrol, SRT1720, or overexpression of SIRT1 has been shown to activate PGC-1a and prevent diseases commonly associated with mitochondrial dysfunction and aging (Banks et al., 2008; Baur et al., 2006; Bordone and Guarente, 2005; Herranz et al., 2010; Lagouge et al., 200”
• SIRTUIN 1 AND SIRTUIN 3: PHYSIOLOGICAL MODULATORS OF METABOLISM (2012, background): “Concomitant overexpression of SIRT1 in environmental and genetic models of insulin resistance and diabetes improved glucose tolerance due to decreased hepatic glucose production and increased adiponectin levels; however, body weight and body composition remained unchanged (28).”
• Hepatocyte-specific Deletion of SIRT1 Alters Fatty Acid Metabolism and Results in Hepatic Steatosis and Inflammation (2009, background): “Additionally, recent studies demonstrated that modest overexpression of SIRT1 resulted in a protective effect against high-fat induced hepatic steatosis and glucose intolerance (Banks et al., 2008; Pfluger et al., 2008).”
• Brown Remodeling of White Adipose Tissue by SirT1-Dependent Deacetylation of Pparγ (2012, neutral): “insulin-sensitizing function of Pparg ligands in vivo (Banks et al., 2008).”
• AMP-Activated Protein Kinase–Deficient Mice Are Resistant to the Metabolic Effects of Resveratrol (2009, background): “(35), which are congenic in C57BL6/J background, have reduced metabolic rate and body temperature and have the same amount of fat despite eating less.”