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Our findings show, for the first time, that insulin and leptin regulate the AQP through the phosphatidylinositol 3-kinase/Akt/mammalian target of rapamycin pathway in human visceral adipocytes and hepatocytes. AQP3 and AQP7 may facilitate glycerol efflux from adipose tissue while reducing the glycerol influx into hepatocytes via AQP9 to prevent the excessive lipid accumulation and the subsequent aggravation of hyperglycemia in human obesity.

Mitochondria are remarkably plastic organelles constantly changing their shape to fulfil their various functional activities. Although the osmotic movement of water into and out of the mitochondrion is central for its morphology and activity, the molecular mechanisms and the pathways for water transport across the inner mitochondrial membrane (IMM), the main barrier for molecules moving into and out of the organelle, are completely unknown. Here, we show the presence of a member of the aquaporin family of water channels, AQP8, and demonstrate the strikingly high water permeability (P f ) characterizing the rat liver IMM. Immunoblotting, electron microscopy, and biophysical studies show that the largest mitochondria feature the highest AQP8 expression and IMM P f . AQP8 was also found in the mitochondria of other organs, whereas no other known aquaporins were seen. The osmotic water transport of liver IMM was partially inhibited by the aquaporin blocker Hg 2؉ , while the related activation energy remained low, suggesting the presence of a Hg 2؉ -insensitive facilitated pathway in addition to AQP8. It is suggested that AQP8-mediated water transport may be particularly important for rapid expansions of mitochondrial volume such as those occurring during active oxidative phosphorylation and those following apoptotic signals.Mitochondrial volume is of pivotal importance for the activity of the electron transport chain (1) and a control point of apoptosis (2). Changes in mitochondrial volume occur in many other physiological and patho-physiological conditions, including intracellular signal transduction, liver regeneration, ischemia/reperfusion-induced damage, and anoxia (3-5). Mitochondria are well behaved osmometers, and swelling and contraction of the mitochondrial matrix and related changes to mitochondrial morphology are the consequence of the water movement that osmotically accompanies the net transport of solutes into and out of the mitochondrion (6), respectively. Mitochondrial volume changes are modulated by the net movement of solutes including K ϩ and Ca 2ϩ ions across the IMM 1 (7,8). The inner mitochondrial membrane acts as a major barrier for the solutes and water moving between the cytoplasm and the mitochondrial matrix, the outer membrane being freely permeable to molecules of up to 1.5 kDa due to the presence of the exceedingly large pores formed by VDAC, the voltage-dependent anion channel (9). However, although a number of IMM transport systems have been cloned and characterized for their ability to transport solutes across the IMM (10), the molecular pathway for the movement of water remains obscure. Important clues for understanding the molecular bases of the mitochondrial osmotic properties were recently provided by the identification of an aquaporin water channel (11), AQP8, in rat hepatocyte mitochondria (12). AQP8 was also found in intracellular vesicles that are shuttled to the hepatocyte apical membrane under choleretic stimuli such as those brought about by glucagon (13). This led us to hyp...

The aquaporin family of molecular water channels is widely expressed throughout the plant and animal kingdoms. No bacterial aquaporins are known; however, sequence-related bacterial genes have been identified that encode glycerol facilitators (glpF). By homology cloning, a novel aquaporin-related DNA (aqpZ) was identified that contained no surface N-glycosylation consensus. The aqpZ RNA was not identified in mammalian mRNA by Northern analysis and exhibited bacterial codon usage preferences. Southern analysis failed to demonstrate aqpZ in mammalian genomic DNA, whereas a strongly reactive DNA was present in chromosomal DNA from Escherichia coli and other bacterial species and did not correspond to glpF. The aqpZ DNA isolated from E. coli contained a 693-base pair open reading frame encoding a polypeptide 28 -38% identical to known aquaporins. When compared with other aquaporins, aqpZ encodes a 10-residue insert preceding exofacial loop C, truncated NH 2 and COOH termini, and no cysteines at known mercury-sensitive sites. Expression of aqpZ cRNA conferred Xenopus oocytes with a 15-fold increase in osmotic water permeability, which was maximal after 5 days of expression, was not inhibited with HgCl 2 , exhibited a low activation energy (E a ‫؍‬ 3.8 kcal/mol), and failed to transport nonionic solutes such as urea and glycerol. In contrast, oocytes expressing glpF transported glycerol but exhibited limited osmotic water permeability. Phylogenetic comparison of aquaporins and homologs revealed a large separation between aqpZ and glpF, consistent with an ancient gene divergence.

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