SirT1 Gain of Function Increases Energy Efficiency and Prevents Diabetes in Mice

Abstract

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.

Acetylation promotes TyrRS nuclear translocation to prevent oxidative damage

“…SIRT1, an NAD + -dependent deacetylase, is the best-studied member of the sirtuin family and has been implicated in signaling pathways in various diseases, including cancer (34), cardiovascular diseases (35), diabetes (36), and neurodegeneration (37). DNA damage due to oxidative stress is an important hallmark of many diseases, and SIRT1 plays several critical roles in the DNA damage response, as previously discussed (15,38).…”

Epigenetic regulation of aging stem cells

“…Understanding the role of Sirtuins in aging stem cells will likely provide insights into the mechanisms that regulate stem cell homeostasis, particularly in response to stress stimuli. In addition, the ability of Sirtuins to regulate both organismal energy metabolism (Banks et al, 2008;Feige et al, 2008;Kim et al, 2010;Ramadori et al, 2010;Zhong et al, 2010) and chromatin may be particularly important for the response of adult stem cells to environmental stimuli such as dietary restriction that are known to promote longevity and delay signs of aging.…”

Downregulation of miR-181a upregulates sirtuin-1 (SIRT1) and improves hepatic insulin sensitivity

“…Adenovirus-mediated overexpression of SIRT1 in the liver of insulin-resistant mice attenuates hepatic steatosis and ameliorates systemic insulin resistance [9]. Moderate transgenic overexpression of Sirt1 in db/db and high-fat diet-fed mice improves glucose tolerance and insulin sensitivity [10,11]. Aged mice orally administered resveratrol, which can enhance SIRT1 activity, display increased insulin sensitivity and survival [12].…”