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

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.

Pubmed ID: 18840364

Authors

  • Banks AS
  • Kon N
  • Knight C
  • Matsumoto M
  • Gutiérrez-Juárez R
  • Rossetti L
  • Gu W
  • Accili D

Journal

Cell metabolism

Publication Data

October 8, 2008

Associated Grants

  • Agency: NIDDK NIH HHS, Id: DK07328
  • Agency: NIDDK NIH HHS, Id: DK079496
  • Agency: NIDDK NIH HHS, Id: DK20541
  • Agency: NIDDK NIH HHS, Id: DK63608
  • Agency: NIDDK NIH HHS, Id: DK64819
  • Agency: NIDDK NIH HHS, Id: F32 DK079496
  • Agency: NIDDK NIH HHS, Id: F32 DK079496-01
  • Agency: NIDDK NIH HHS, Id: F32 DK079496-02
  • Agency: NHLBI NIH HHS, Id: HL87123
  • Agency: NHLBI NIH HHS, Id: P01 HL087123
  • Agency: NHLBI NIH HHS, Id: P01 HL087123-020003
  • Agency: NIDDK NIH HHS, Id: P30 DK063608
  • Agency: NIDDK NIH HHS, Id: P30 DK063608-07
  • Agency: NCI NIH HHS, Id: R01 CA085533
  • Agency: NCI NIH HHS, Id: R01 CA098821
  • Agency: NCI NIH HHS, Id: R01 CA098821-06A1
  • Agency: NIDDK NIH HHS, Id: R01 DK057539
  • Agency: NIDDK NIH HHS, Id: R01 DK057539-09
  • Agency: NIDDK NIH HHS, Id: R01 DK064819

Mesh Terms

  • Animals
  • Cyclic AMP
  • Diabetes Mellitus
  • Eating
  • Energy Metabolism
  • Forkhead Transcription Factors
  • Gene Expression Regulation
  • Glucose Intolerance
  • Homeostasis
  • Insulin Resistance
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Sirtuin 1
  • Sirtuins
  • Tissue Distribution