title: Inducible overexpression of adiponectin receptors highlight the roles of adiponectin-induced ceramidase signaling in lipid and glucose homeostasis.
abstract: Adiponectin and the signaling induced by its cognate receptors, AdipoR1 and AdipoR2, have garnered attention for their ability to promote insulin sensitivity and oppose steatosis. Activation of these receptors promotes the deacylation of ceramide, a lipid metabolite that appears to play a causal role in impairing insulin signaling.
  
  
  
  Here, we have developed transgenic mice that overexpress AdipoR1 or AdipoR2 under the inducible control of a tetracycline response element. These represent the first inducible genetic models that acutely manipulate adiponectin receptor signaling in adult mouse tissues, which allows us to directly assess AdipoR signaling on glucose and lipid metabolism.
  
  
  
  Overexpression of either adiponectin receptor isoform in the adipocyte or hepatocyte is sufficient to enhance ceramidase activity, whole body glucose metabolism, and hepatic insulin sensitivity, while opposing hepatic steatosis. Importantly, metabolic improvements fail to occur in an adiponectin knockout background. When challenged with a leptin-deficient genetic model of type 2 diabetes, AdipoR2 expression in adipose or liver is sufficient to reverse hyperglycemia and glucose intolerance.
  
  
  
  These observations reveal that adiponectin is critical for AdipoR-induced ceramidase activation which enhances hepatic glucose and lipid metabolism via rapidly acting "cross-talk" between liver and adipose tissue sphingolipids.
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA. Electronic address: William.Holland@utsouthwestern.edu.
authors.forename: William L
authors.initials: WL
authors.lastname: Holland
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA.
authors.forename: Jonathan Y
authors.initials: JY
authors.lastname: Xia
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA.
authors.forename: Joshua A
authors.initials: JA
authors.lastname: Johnson
authors.affiliation: Center for Metabolic and Degenerative Diseases, Institute of Molecular Medicine, University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
authors.forename: Kai
authors.initials: K
authors.lastname: Sun
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA.
authors.forename: Mackenzie J
authors.initials: MJ
authors.lastname: Pearson
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA.
authors.forename: Ankit X
authors.initials: AX
authors.lastname: Sharma
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA.
authors.forename: Ezekiel
authors.initials: E
authors.lastname: Quittner-Strom
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA.
authors.forename: Trevor S
authors.initials: TS
authors.lastname: Tippetts
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA.
authors.forename: Ruth
authors.initials: R
authors.lastname: Gordillo
authors.affiliation: Touchstone Diabetes Center, Department of Internal Medicine, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA; Department of Cell Biology, The University of Texas Southwestern Medical Center, Dallas, TX 75390-8549, USA.
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
mesh_terms: D017667:Adipocytes / Q000378:metabolism; D052242:Adiponectin / Q000235:genetics; D000273:Adipose Tissue / Q000378:metabolism; D000818:Animals; D055572:Ceramidases / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D005234:Fatty Liver / Q000378:metabolism; D005947:Glucose / Q000378:metabolism / Q000502:physiology; D022781:Hepatocytes / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics; D007328:Insulin / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D020738:Leptin / Q000378:metabolism; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology; D008055:Lipids / Q000502:physiology; D008099:Liver / Q000378:metabolism; D051379:Mice; D008822:Mice, Transgenic; D010880:Piperidines / Q000378:metabolism; D054419:Receptors, Adiponectin / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*
chemical_list: C585113:AdipoRon; D052242:Adiponectin; D007328:Insulin; D020738:Leptin; D008055:Lipids; D010880:Piperidines; D054419:Receptors, Adiponectin; D055572:Ceramidases; D005947:Glucose
keywords: Insulin resistance; NAFLD; Sphingolipid