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- Title
Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin.
- 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
- 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.
- Publication
Nature medicine, 2011, Vol 17, Issue 1, p55
- ISSN
1546-170X
- Publication type
Journal Article
- DOI
10.1038/nm.2277