title: Insulin- and leptin-mediated control of aquaglyceroporins in human adipocytes and hepatocytes is mediated via the PI3K/Akt/mTOR signaling cascade.
abstract: OBJECTIVE
  Glycerol constitutes an important metabolite for the control of lipid accumulation and glucose homeostasis. The impact of obesity and obesity-associated type 2 diabetes as well as the potential regulatory role of insulin and leptin on aquaglyceroporins (AQP) 3, 7, and 9 were analyzed.
  
  
  METHODS
  The tissue distribution and expression of AQP in biopsies of omental and sc adipose tissue as well as liver were analyzed in lean and obese Caucasian volunteers (n = 63). The effect of insulin (1, 10, and 100 nmol/liter) and leptin (0.1, 1, and 10 nmol/liter) on the expression of the glycerol channels was determined in vitro in human omental adipocytes and HepG2 hepatocytes. The translocation of AQP in response to insulin and isoproterenol was analyzed by immunocytochemistry.
  
  
  RESULTS
  In addition to the well-known expression of AQP7 in adipose tissue, AQP3 and AQP9 were also expressed in both omental and sc adipose tissue. Obese type 2 diabetes patients showed higher expression of AQP in visceral adipose tissue and lower expression of AQP7 in sc adipose tissue and hepatic AQP9. The staining of AQP9 in the plasma membrane of adipocytes was reinforced by insulin, whereas isoproterenol induced the translocation of AQP3 and AQP7 from the lipid droplets to the plasma membrane. Insulin up-regulated all AQP, whereas leptin up-regulated AQP3 and down-regulated AQP7 and AQP9 in adipocytes and hepatocytes. These effects were abrogated by both the phosphatidylinositol 3-kinase inhibitor wortmannin and the mammalian target of rapamycin inhibitor rapamycin.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Metabolic Research Laboratory, University of Navarra, 31080 Pamplona, Spain.
authors.forename: Amaia
authors.initials: A
authors.lastname: Rodríguez
authors.forename: Victoria
authors.initials: V
authors.lastname: Catalán
authors.forename: Javier
authors.initials: J
authors.lastname: Gómez-Ambrosi
authors.forename: Socorro
authors.initials: S
authors.lastname: García-Navarro
authors.forename: Fernando
authors.initials: F
authors.lastname: Rotellar
authors.forename: Víctor
authors.initials: V
authors.lastname: Valentí
authors.forename: Camilo
authors.initials: C
authors.lastname: Silva
authors.forename: María J
authors.initials: MJ
authors.lastname: Gil
authors.forename: Javier
authors.initials: J
authors.lastname: Salvador
authors.forename: María A
authors.initials: MA
authors.lastname: Burrell
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Calamita
authors.forename: María M
authors.initials: MM
authors.lastname: Malagón
authors.forename: Gema
authors.initials: G
authors.lastname: Frühbeck
mesh_terms: D041721:3T3-L1 Cells; D017667:Adipocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D000818:Animals; D051397:Aquaglyceroporins / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D005786:Gene Expression Regulation / Q000187:drug effects; D056945:Hep G2 Cells; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007328:Insulin / Q000378:metabolism / Q000494:pharmacology*; D020738:Leptin / Q000378:metabolism / Q000494:pharmacology*; D051379:Mice; D009765:Obesity / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051058:Oncogene Protein v-akt / Q000378:metabolism / Q000502:physiology*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D013851:Thinness / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D014018:Tissue Distribution / Q000187:drug effects
chemical_list: D051397:Aquaglyceroporins; D007328:Insulin; D020738:Leptin; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases; D058570:TOR Serine-Threonine Kinases; C546842:MTOR protein, human