Coordinated Regulation of Fat-Specific and Liver-Specific Glycerol Channels, Aquaporin Adipose and Aquaporin 9

Coordinated Regulation of Fat-Specific and Liver-Specific Glycerol Channels, Aquaporin Adipose and Aquaporin 9 Hiroshi Kuriyama , Iichiro Shimomura , Ken Kishida , Hidehiko Kondo , Naoki Furuyama , Hitoshi Nishizawa , Norikazu Maeda , Morihiro Matsuda , Hiroyuki Nagaretani , Shinji Kihara , Tadashi Nakamura , Yoshihiro Tochino , Tohru Funahashi and Yuji Matsuzawa From the Department of Internal Medicine and Molecular Science, Graduate School of Medicine, Osaka University, Osaka, Japan Abstract Plasma glycerol is a major substrate for hepatic gluconeogenesis. Aquaporin adipose (AQPap/7), an adipose-specific glycerol channel, provides fat-derived glycerol into plasma. In the present study, we cloned the coding and promoter regions of mouse aquaporin 9 (AQP9), a liver-specific glycerol channel. Fasting and refeeding of mice increased and decreased hepatic AQP9 mRNA levels, respectively. Insulin deficiency induced by streptozotocin resulted in increased hepatic AQP9 mRNA. These changes in hepatic AQP9 mRNA were accompanied by those of hepatic gluconeogenic mRNAs and plasma glycerol levels. In cultured hepatocytes, insulin downregulated AQP9 mRNA. The AQP9 promoter contained the negative insulin response element TGTTTTC at −496/−502, similar to the promoter of the AQPap/7 gene. In contrast, in insulin-resistant db +/ db + mice, AQPap/7 mRNA in fat and AQP9 mRNA in liver were increased, despite hyperinsulinemia, with high plasma glycerol and glucose levels. Glycerol infusion in the db +/ db + mice augmented hepatic glucose output. Our results indicate that coordinated regulations of fat-specific AQPap/7 and liver-specific AQP9 should be crucial to determine glucose metabolism in physiology and insulin resistance. Footnotes Address correspondence and reprint requests to Iichiro Shimomura Department of Organismal Biosystems, Graduate School of Frontier Bioscience, Department of Medicine and Pathophysiology, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan. E-mail: ichi{at}imed2.med.osaka-u.ac.jp . Received for publication 15 March 2002 and accepted in revised form 26 June 2002. AQP, aquaporin; AQPap/7, aquaporin adipose; DMEM, Dulbecco’s modified Eagle’s medium; FFA, free fatty acid; GlyK, glycerokinase; HSL, hormone-sensitive lipase; IRE, insulin response element; IRS, insulin receptor substrate; PEPCK, phosphoenolpyruvate carboxykinase; RACE, rapid amplification of cDNA ends; STZ, streptozotocin. DIABETES