Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin.

Academic Article

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

  • Holland, William L
  • Miller, Russell A
  • Wang, Zhao V
  • Sun, Kai
  • Barth, Brian
  • Bui, Hai H
  • Davis, Kathryn E
  • Bikman, Benjamin T
  • Halberg, Nils
  • Rutkowski, Joseph M
  • Wade, Mark R
  • Tenorio, Vincent M
  • Kuo, Ming-Shang
  • Brozinick, Joseph T
  • Zhang, Bei B
  • Birnbaum, Morris J
  • Summers, Scott A
  • Scherer, Philipp E
  • Status

    Publication Date

  • January 2011
  • Published In

  • Nature Medicine  Journal
  • Keywords

  • Adenylate Kinase
  • Adiponectin
  • Animals
  • Apoptosis
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase
  • Ceramidases
  • Ceramides
  • Enzyme Activation
  • Gene Expression Regulation
  • Humans
  • Insulin
  • Kinetics
  • Leptin
  • Mice
  • Mice, Obese
  • Myocardial Infarction
  • Myocytes, Cardiac
  • Receptors, Adiponectin
  • Digital Object Identifier (doi)

    Start Page

  • 55
  • End Page

  • 63
  • Volume

  • 17
  • Issue

  • 1