Journal Article

Hepatic Sirt1 deficiency in mice impairs mTorc2/Akt signaling and results in hyperglycemia, oxidative damage, and insulin resistance

Wang, Rui-Hong, Xu, Xiaoling, Kim, Hyun-Seok, Deng, Chu-Xia, Xiao, Cuiying, Gavrilova, Oksana

2011

Overview

Insulin resistance is a major risk factor for type 2 diabetes mellitus. The protein encoded by the sirtuin 1 (Sirt1) gene, which is a mouse homolog of yeast Sir2, is implicated in the regulation of glucose metabolism and insulin sensitivity; however, the underlying mechanism remains elusive. Here, using mice with a liver-specific null mutation of Sirt1, we have identified a signaling pathway involving Sirt1, Rictor (a component of mTOR complex 2 [mTorc2]), Akt, and Foxo1 that regulates gluconeogenesis. We found that Sirt1 positively regulates transcription of the gene encoding Rictor, triggering a cascade of phosphorylation of Akt at S473 and Foxo1 at S253 and resulting in decreased transcription of the gluconeogenic genes glucose-6-phosphatase (G6pase) and phosphoenolpyruvate carboxykinase (Pepck). Liver-specific Sirt1 deficiency caused hepatic glucose overproduction, chronic hyperglycemia, and increased ROS production. This oxidative stress disrupted mTorc2 and impaired mTorc2/Akt signaling in other insulin-sensitive organs, leading to insulin resistance that could be largely reversed with antioxidant treatment. These data delineate a pathway through which Sirt1 maintains insulin sensitivity and suggest that treatment with antioxidants might provide protection against progressive insulin resistance in older human populations.

• Publisher: American Society for Clinical Investigation
• Subject: Animals / Biomedical research / Cellular signal transduction / Fasting / Female / Forkhead Box Protein O1 / Forkhead Transcription Factors - antagonists & inhibitors / Forkhead Transcription Factors - genetics / Forkhead Transcription Factors - metabolism / Gene expression / Gene Knockdown Techniques / Genes / Genetic aspects / Gluconeogenesis / Glucose / Glucose metabolism / Humans / Hyperglycemia / Hyperglycemia - etiology / Hyperglycemia - metabolism / Insulin resistance / Insulin Resistance - physiology / Liver / Liver - metabolism / Male / Mechanistic Target of Rapamycin Complex 2 / Metabolism / Mice / Mice, 129 Strain / Mice, Inbred C57BL / Mice, Knockout / Multiprotein Complexes - metabolism / Oxidative Stress / Phenotype / Phosphorylation / Proteins / Proto-Oncogene Proteins c-akt - metabolism / Risk factors / Signal Transduction / Sirtuin 1 - deficiency / Sirtuin 1 - genetics / Sirtuin 1 - metabolism / TOR Serine-Threonine Kinases - metabolism