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Am J Physiol Endocrinol Metab. 2018 Jul 10. doi: 10.1152/ajpendo.00072.2018. [Epub ahead of print]

Mechanisms of sleep deprivation-induced hepatic steatosis and insulin resistance in mice.

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Toho University Graduate School of Medicine, Japan.
Metabolism & Endocrinology, Juntendo University Graduate School of Medicine.
Division of Diabetes, Metabolism and Endocrinology, Department of Internal Medicine, Toho University School of Medicine.


Sleep deprivation is associated with increased risk for type 2 diabetes mellitus. However, the underlying mechanisms of sleep deprivation-induced glucose intolerance remain elusive. The aim of this study was to investigate the mechanisms of sleep deprivation-induced glucose intolerance in mice with a special focus on the liver. We established a mouse model of sleep deprivation-induced glucose intolerance using C57BL/6J male mice. A single 6-hr sleep deprivation by the gentle handling method under fasting condition induced glucose intolerance. Hepatic glucose production assessed by pyruvate challenge test was significantly increased, as was hepatic triglyceride content (by 67.9%) in the sleep deprivation group, compared with freely sleeping control mice. Metabolome and microarray analyses were used to evaluate hepatic metabolites and gene expression levels and determine the molecular mechanisms of sleep deprivation-induced hepatic steatosis. Hepatic metabolites, such as acetyl CoA, 3β-hydroxybutyric acid, and certain acylcarnitines were significantly increased in the sleep deprivation group, suggesting increased lipid oxidation in the liver. In contrast, fasted sleep-deprived mice showed that hepatic gene expression levels of Elovl3, Lpin1, Plin4, Plin5 and Acot1, which are known to play lipogenic roles, were 2.7, 4.5, 3.7, 2.9, and 2.8 times, respectively, those of the fasted sleeping control group, as assessed by quantitative RT-PCR. Sleep deprivation-induced hepatic steatosis and hepatic insulin resistance seem to be mediated through upregulation of hepatic lipogenic enzymes.


Hepatic insulin resistance; Hepatic steatosis; Sleep deprivation


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