Deletion of glycerol channel aquaporin‐9 ( Aqp9 ) impairs long‐term blood glucose control in C57BL/6 leptin receptor–deficient ( db/db ) obese mice

Abstract Deletion of the glycerol channel aquaporin‐9 ( Aqp9 ) reduces postprandial blood glucose levels in leptin receptor–deficient ( db/db ) obese mice on a C57 BL /6 × C57 BLKS mixed genetic background. Furthermore, sh RNA ‐mediated reduction of Aqp9 expression reduces liver triacylglycerol ( TAG ) accumulation in a diet‐induced rat model of obesity. The aim of this study was to investigate metabolic effects of Aqp9 deletion in coisogenic db/db mice of the C57 BL /6 background. Aqp9 wt db/db and Aqp9 −/− db/db mice did not differ in body weight and liver TAG contents. On the C57 BL /6 genetic background, we observed elevated plasma glucose in Aqp9 −/− db/db mice (+1.1 mmol/L, life‐time average), while plasma insulin concentration was reduced at the time of death. Glucose levels changed similarly in pentobarbital anesthetized, glucagon challenged Aqp9 wt db/db and Aqp9 −/− db/db mice. Liver transcriptional profiling did not detect differential gene expression between genotypes. Metabolite profiling revealed a sex independent increase in plasma glycerol (+55%) and glucose (+24%), and reduction in threonate (all at q  <   0.1) in Aqp9 −/− db/db mice compared to controls. Metabolite profiling thus confirms a role of AQP 9 in glycerol metabolism of obese C57 BL /6 db/db mice. In this animal model of obesity Aqp9 gene deletion elevates plasma glucose and does not alleviate hepatosteatosis.