Adipose and hepatic aquaglyceroporins in energy metabolism: physio-pathology and translational relevance

Glycerol is an important intermediate in energy metabolism, being a key substrate for de novo synthesis of glucose (gluconeogenesis) during fasting and direct source of glycerol-3-phosphate for triglycerides synthesis (lipogenesis). Aquaglyceroporins (AQP3, AQP7, AQP9 and AQP10) are a group of aquaporin membrane channels that facilitate the movement of glycerol and some other neutral solutes in addition to water into or out of cells. Adipose tissue is a major source of glycerol released by adipocyte through AQP7 and AQP3. Through the bloodstream, lipolytic glycerol flows to the liver where it is imported by hepatocytes mostly by means of AQP9. The functional significance of AQP10 in fat tissue and liver is still debated. Although with distinctions between rodents and human, adipocyte and hepatocyte aquaglyceroporins are controlled by insulin and leptin via the PI3K/Akt/ mTOR signaling cascade. Negative regulation is exerted by estrogens on fat and hepatic aquaglyceroporins likely explaining the sexual dimorphism that characterizes these AQPs in energy homeostasis. Adipose and liver AQP7 and AQP9 have been shown to play roles in energy balance disorders. AQP7 deficiency has been linked to abnormal triglycerides accumulation in fat tissue and adult onset of obesity and dysregulated expression of hepatic AQP9 is seen in animal models and patients with diabetes, obesity and/or fatty liver disease. Hepatocyte AQP9 is involved in the lipid-lowering activity exerted by the nutraceutical silybin through modulation of autophagy. Potent and isoform-specific blockers of AQP3, AQP7 and AQP9 are available and preclinical work is going on to investigate their relevance as drug targets in energy dyshomeostasis and other clinical disorders.