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

Nat Med. 2011 Jan;17(1):55-63. doi: 10.1038/nm.2277. Epub 2010 Dec 26.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenylate Kinase / metabolism
  • Adiponectin / deficiency
  • Adiponectin / genetics
  • Adiponectin / physiology*
  • Adiponectin / therapeutic use
  • Animals
  • Apoptosis / physiology
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase / metabolism
  • Ceramidases / drug effects
  • Ceramidases / metabolism*
  • Ceramides / metabolism
  • Enzyme Activation
  • Gene Expression Regulation
  • Humans
  • Insulin / physiology
  • Kinetics
  • Leptin / deficiency
  • Mice
  • Mice, Obese
  • Myocardial Infarction / drug therapy
  • Myocytes, Cardiac / physiology
  • Receptors, Adiponectin / physiology*


  • Adiponectin
  • Ceramides
  • Insulin
  • Leptin
  • Receptors, Adiponectin
  • Calcium-Calmodulin-Dependent Protein Kinase Kinase
  • Adenylate Kinase
  • Ceramidases

Grant support