Background Sleep plays a key role in glucose homeostasis and is an essential component of metabolic health. Sleep deprivation can induce hepatic steatosis and insulin resistance in mice, and these effects are thought to involve disruption of circadian metabolic regulation and neuroendocrine pathways. Sleep deprivation has also been associated with increased hepatic expression of elongation of very long chain fatty acids-like 3 (Elovl3). Because Elovl3 is involved in very-long-chain fatty acid synthesis and exhibits circadian regulation in the liver, we hypothesized that hepatic Elovl3 upregulation may contribute to sleep deprivation-induced lipid accumulation. This study aimed to investigate whether downregulation of hepatic Elovl3 expression influences hepatic lipid accumulation and glucose metabolism under sleep deprivation conditions. Methods Eleven-week-old male C57BL/6J mice were fed a high-fat diet and high-sucrose water for two weeks, followed by a single 6-hour period of sleep deprivation. To suppress hepatic Elovl3 expression, Elovl3-specific small interfering RNA (siRNA) was administered via tail vein injection (Elovl3 siRNA group), whereas control mice received non-coding siRNA (negative siRNA group). Hepatic triglyceride content, gene expression, gluconeogenesis (pyruvate challenge test), insulin sensitivity (insulin tolerance test), and glucose tolerance (intraperitoneal glucose tolerance test (ipGTT)) were evaluated. The primary outcome of this study was hepatic triglyceride accumulation after acute sleep deprivation. Secondary outcomes included glucose tolerance, gluconeogenesis, and insulin sensitivity. Results A single 6-hour sleep deprivation increased hepatic Elovl3 mRNA expression by 2.7-fold; this increase was completely suppressed 48 hours after administration of Elovl3 siRNA. Hepatic triglyceride content was significantly lower in the Elovl3 siRNA group than in the negative siRNA group after sleep deprivation (3.1 ± 1.5 vs 10.4 ± 4.2 mg/g tissue, respectively), corresponding to an approximate 70.4% reduction, under fasting and movement-restriction conditions following sleep deprivation. Hepatic gluconeogenesis did not differ between groups, whereas blood glucose levels at 30 minutes during ipGTT were significantly lower in the Elovl3 siRNA group. Conclusions Suppression of hepatic Elovl3 expression attenuated sleep deprivation-induced hepatic steatosis in mice. However, although the blood glucose level at 30 minutes during ipGTT was significantly lower in the Elovl3 siRNA group, no significant differences were observed in glucose area under the curve during ipGTT, pyruvate challenge test, or insulin tolerance test, suggesting that additional interventions may be required to improve glucose intolerance associated with sleep deprivation. Hepatic Elovl3 may represent a potential therapeutic target for sleep deprivation-related metabolic dysfunction.
Shigiyama et al. (Fri,) studied this question.