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.
Banks
Alexander S
AS
Naomi Berrie Diabetes Center, Department of Medicine, College of Physicians and Surgeons of Columbia University, New York, NY 10032, USA.
Kon
Ning
N
Knight
Colette
C
Matsumoto
Michihiro
M
Gutiérrez-Juárez
Roger
R
Rossetti
Luciano
L
Gu
Wei
W
Accili
Domenico
D
D000818:Animals; D000242:Cyclic AMP / Q000378:metabolism; D003920:Diabetes Mellitus / Q000378:metabolism / Q000517:prevention & control*; D004435:Eating; D004734:Energy Metabolism; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation; D018149:Glucose Intolerance / Q000378:metabolism; D006706:Homeostasis; D007333:Insulin Resistance; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D056564:Sirtuin 1; D037761:Sirtuins / Q000235:genetics / Q000378:metabolism*; D014018:Tissue Distribution
D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; C467200:Foxo1 protein, mouse; D000242:Cyclic AMP; C470545:Sirt1 protein, mouse; D056564:Sirtuin 1; D037761:Sirtuins