Mechanisms of Hepatic Steatosis and Insulin Resistance Induced by Sleep Deprivation in Mice
Authors: SHIGIYAMA FUMIKA , KUMASHIRO NAOKI , YOSHIKAWA FUKUMI , TSUNEOKA YOUSUKE , FUNATO HIROMASA , HIROSE TAKAHISA 
Published: June 2018

Sleep is an important life style component and its deprivation is a risk for type 2 diabetes. However, the underlying mechanisms and the therapeutic target of sleep deprivation induced glucose intolerance are unclear. The aim of this study was to investigate the mechanisms of sleep deprivation induced glucose intolerance focusing on liver. We established a mouse model of sleep deprivation induced glucose intolerance using C57BL/6J male mice. Single 6 hours sleep deprivation by gentle handling method in fasted condition induced glucose intolerance. Interestingly, hepatic glucose production assessed by pyruvate challenge test was significantly increased, and hepatic triglyceride content was also increased in 67% in the sleep deprivation mice compared to freely sleeping control mice. To explore the molecular mechanisms of sleep deprivation induced hepatic steatosis, hepatic metabolites and gene expressions were comprehensively evaluated using metabolome and microarray analyses. Hepatic metabolites such as acetyl CoA, 3β-hydroxybutyric acid, and some acylcarnitines were significantly increased in sleep deprivation group, suggesting increased lipid oxidation in the liver. In contrast, hepatic gene expressions of Elovl3, Lpin1, Plin4, Plin5 and Acot1 that play a lipogenic role were significantly increased 2.7, 4.5, 3.7, 2.9, and 2.8 times respectively in sleep deprivation group compared to control group, confirmed by quantitative RT-PCR. The increased lipogenic gene expressions may partly explain the sleep deprivation induced hepatic steatosis.

Conclusion: Single 6 hours sleep deprivation caused hepatic steatosis and hepatic insulin resistance in fasted C57BL/6J mice. Increased hepatic lipogenic enzymes raised above may be potential therapeutic targets for the sleep deprivation induced hepatic steatosis and hepatic insulin resistance.

Disclosure

F. Shigiyama: None. N. Kumashiro: Speaker's Bureau; Self; Novo Nordisk Inc.. F. Yoshikawa: None. Y. Tsuneoka: None. H. Funato: None. T. Hirose: Research Support; Self; AstraZeneca. Speaker's Bureau; Self; AstraZeneca. Research Support; Self; Bayer Yakuhin, Ltd., Novartis Pharma K.K.. Speaker's Bureau; Self; Novartis Pharma K.K.. Research Support; Self; Takeda Development Center Asia, Pte. Ltd.. Speaker's Bureau; Self; Takeda Development Center Asia, Pte. Ltd.. Research Support; Self; Ono Pharmaceutical Co., Ltd., Eli Lilly and Company. Speaker's Bureau; Self; Eli Lilly and Company. Research Support; Self; MSD K.K.. Speaker's Bureau; Self; MSD K.K.. Research Support; Self; Sanofi K.K.. Speaker's Bureau; Self; Sanofi K.K.. Research Support; Self; Mitsubishi Tanabe Pharma Corporation. Speaker's Bureau; Self; Mitsubishi Tanabe Pharma Corporation. Research Support; Self; Daiichi Sankyo Company, Limited. Speaker's Bureau; Self; Daiichi Sankyo Company, Limited. Research Support; Self; Sumitomo Dainippon Pharma Co., Ltd.. Speaker's Bureau; Self; Sumitomo Dainippon Pharma Co., Ltd.. Research Support; Self; Novo Nordisk Inc.. Speaker's Bureau; Self; Novo Nordisk Inc.. Research Support; Self; Boehringer Ingelheim Pharmaceuticals, Inc.. Speaker's Bureau; Self; Boehringer Ingelheim Pharmaceuticals, Inc..