Fig. 2.

Aquaporins network in the induction of metabolic disease. Schematic representation of the likely interaction of AQPs between adipocytes and hepatocytes in the context of insulin resistance and type-2 diabetes. The black arrows highlight the major interaction between adipocytes and hepatocytes during lipolysis of TG stores. Glycerol is trafficked between adipocytes and hepatocytes with the help of AQP7 and AQP9, respectively. Hepatic glycerol of adipose tissue origin can enter gluconeogenesis or de novo lipogenesis together with FFA to yield hepatic MAG, DAG and TAG. Obesity leads to mitochondrial dysfunction with the subsequent oxidative stress accumulation in form of H₂O₂. This is likely driven into the ER through AQP11, promoting the creation of a stress-promoting-stress circle (Red arrows). Conversely, AQP11 displays beneficial effects in adipocytes, where its overexpression leads to a decrease of the ER stress caused by lipid overload by promoting the efflux of H₂O₂ from the ER itself. We hypothesize that a similar protective mechanism could be mirrored in hepatocytes (Green arrow). The light blue arrows denote the novel branch of the insulin signaling pathway in hepatocytes, which involves AQP3 for its modulation. The insulin signaling from the PI3K/AKT branch brings to the inhibition of the gluconeogenesis in physiologic conditions. Accumulation of DAG in the cytoplasm of hepatocytes due to increased uptake of glycerol and FFA inhibits the signaling cascade at the level of PI3K/AKT with the subsequent up-regulation of the gluconeogenesis, increasing blood glucose levels. (For interpretation of the references to colour in this figure legend, the reader is referred to the Web version of this article.)