Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Academic Article uri icon

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.

published proceedings

  • Nat Med

altmetric score

  • 10

author list (cited authors)

  • Holland, W. L., Miller, R. A., Wang, Z. V., Sun, K., Barth, B. M., Bui, H. H., ... Scherer, P. E

citation count

  • 635

complete list of authors

  • Holland, William L||Miller, Russell A||Wang, Zhao V||Sun, Kai||Barth, Brian M||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

publication date

  • December 2010