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Title: Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin
Authors: Holland, W.L.
Miller, R.A.
Wang, Z.V.
Sun, K.
Barth, B.M.
Bui, H.H.
Davis, K.E.
Bikman, B.T. 
Halberg, N.
Rutkowski, J.M.
Wade, M.R.
Tenorio, V.M.
Kuo, M.-S.
Brozinick, J.T.
Zhang, B.B.
Birnbaum, M.J.
Summers, S.A. 
Scherer, P.E.
Issue Date: Jan-2011
Citation: Holland, W.L., Miller, R.A., Wang, Z.V., Sun, K., Barth, B.M., Bui, H.H., Davis, K.E., Bikman, B.T., Halberg, N., Rutkowski, J.M., Wade, M.R., Tenorio, V.M., Kuo, M.-S., Brozinick, J.T., Zhang, B.B., Birnbaum, M.J., Summers, S.A., Scherer, P.E. (2011-01). Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nature Medicine 17 (1) : 55-63. ScholarBank@NUS Repository.
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. © 2011 Nature America, Inc. All rights reserved.
Source Title: Nature Medicine
ISSN: 10788956
DOI: 10.1038/nm.2277
Appears in Collections:Staff Publications

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