title: Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin.
abstract: The adipocyte-derived secretory factor adiponectin promotes insulin sensitivity, decreases inflammation and promotes cell survival. No unifying mechanism has yet explained how adiponectin can exert such a variety of beneficial systemic effects. Here, we show that adiponectin potently stimulates a ceramidase activity associated with its two receptors, AdipoR1 and AdipoR2, and enhances ceramide catabolism and formation of its antiapoptotic metabolite--sphingosine-1-phosphate (S1P)--independently of AMP-dependent kinase (AMPK). Using models of inducible apoptosis in pancreatic beta cells and cardiomyocytes, we show that transgenic overproduction of adiponectin decreases caspase-8-mediated death, whereas genetic ablation of adiponectin enhances apoptosis in vivo through a sphingolipid-mediated pathway. Ceramidase activity is impaired in cells lacking both adiponectin receptor isoforms, leading to elevated ceramide levels and enhanced susceptibility to palmitate-induced cell death. Combined, our observations suggest a unifying mechanism of action for the beneficial systemic effects exerted by adiponectin, with sphingolipid metabolism as its core upstream signaling component.
authors.affiliation: Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
authors.forename: William L
authors.initials: WL
authors.lastname: Holland
authors.forename: Russell A
authors.initials: RA
authors.lastname: Miller
authors.forename: Zhao V
authors.initials: ZV
authors.lastname: Wang
authors.forename: Kai
authors.initials: K
authors.lastname: Sun
authors.forename: Brian M
authors.initials: BM
authors.lastname: Barth
authors.forename: Hai H
authors.initials: HH
authors.lastname: Bui
authors.forename: Kathryn E
authors.initials: KE
authors.lastname: Davis
authors.forename: Benjamin T
authors.initials: BT
authors.lastname: Bikman
authors.forename: Nils
authors.initials: N
authors.lastname: Halberg
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Rutkowski
authors.forename: Mark R
authors.initials: MR
authors.lastname: Wade
authors.forename: Vincent M
authors.initials: VM
authors.lastname: Tenorio
authors.forename: Ming-Shang
authors.initials: MS
authors.lastname: Kuo
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Brozinick
authors.forename: Bei B
authors.initials: BB
authors.lastname: Zhang
authors.forename: Morris J
authors.initials: MJ
authors.lastname: Birnbaum
authors.forename: Scott A
authors.initials: SA
authors.lastname: Summers
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism; D052242:Adiponectin / Q000172:deficiency / Q000235:genetics / Q000502:physiology* / Q000627:therapeutic use; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase / Q000378:metabolism; D055572:Ceramidases / Q000187:drug effects / Q000378:metabolism*; D002518:Ceramides / Q000378:metabolism; D004789:Enzyme Activation; D005786:Gene Expression Regulation; D006801:Humans; D007328:Insulin / Q000502:physiology; D007700:Kinetics; D020738:Leptin / Q000172:deficiency; D051379:Mice; D008820:Mice, Obese; D009203:Myocardial Infarction / Q000188:drug therapy; D032383:Myocytes, Cardiac / Q000502:physiology; D054419:Receptors, Adiponectin / Q000502:physiology*
chemical_list: D052242:Adiponectin; D002518:Ceramides; D007328:Insulin; D020738:Leptin; D054419:Receptors, Adiponectin; D054737:Calcium-Calmodulin-Dependent Protein Kinase Kinase; D000263:Adenylate Kinase; D055572:Ceramidases