Sex-specific effect of AQP9 deficiency on hepatic triglyceride metabolism in mice with diet-induced obesity.

Studies in obese rats and human cell models of non-alcoholic fatty liver disease have indicated that knockdown of the hepatic glycerol channel aquaporin 9 (AQP9) leads to decreased hepatic steatosis. However, a study in leptin receptor-deficient mice did not find that knockout of AQP9 alleviated hepatic steatosis. The aim of this study was to investigate the effect of high-fat diet (HFD) on hepatic glycerol and triglyceride metabolism in male and female AQP9 knockout (KO) mice. Male and female AQP9 KO mice and wild type (WT) littermates were fed a HFD for 12 weeks. Weight, food intake and blood glucose were monitored throughout the study and tissue analysis included determination of hepatic triglyceride content and triglyceride secretion. The expression of key molecules for hepatic, glycerol and triglyceride metabolism was evaluated using qPCR and western blotting. AQP9 KO and WT mice demonstrated a similar weight gain throughout the study period, and we found no evidence for AQP9 deficiency being associated with a reduced hepatic accumulation of triglyceride or a reduced blood glucose level. Instead, we show that the effect of AQP9 deficiency on hepatic lipid metabolism is sex-specific, with only male AQP9 KO mice having a reduced hepatic secretion of triglycerides and an elevated expression of PPARα. Male AQP9 KO had an elevated blood glucose level after 12 weeks of HFD when compared to baseline levels. Thus, we found no evidence for AQP9 inhibition being a target for alleviating the development of hepatic steatosis in mice with diet-induced obesity. KEY POINTS: This study investigates the effect of AQP9 deficiency on hepatic triglyceride metabolism in both male and female mice fed a high-fat diet for 12 weeks. No evidence for AQP9 deficiency being associated with a reduced hepatic accumulation of triglyceride or a reduced blood glucose level was found. The effect of AQP9 deficiency on hepatic triglyceride metabolism is sex-specific. Male AQP9 KO mice had a reduced hepatic secretion of triglycerides and an elevated expression of PPARα that likely promotes an increased hepatic fatty acid oxidation. Male AQP9 KO had an elevated blood glucose level after 12 weeks of HFD when compared to baseline levels. Abstract figure legend Hepatic glycerol uptake is facilitated by the glycerol channel aquaporin 9 (AQP9) Schematic overview of the effect of 12 weeks of high-fat diet (HFD) in female and male wildtype (WT) and AQP9 knockout (KO) mice. A sex-specific effect of AQP9 deficiency was observed, with only male AQP9 KO mice having a reduced hepatic secretion of triglyceride (TG) and an increased expression of PPARα. Both male and female AQP9 KO mice demonstrated an increased serum glycerol level. AQP9 deficiency had no significant effect on the development of hepatic steatosis as compared to WT mice. Glycerol-3-phosphate (G3P), fatty acids (FA), brown arrows indicate significant changes. This article is protected by copyright. All rights reserved.