@article{2e9a7cf687dc4e44b651decea32843f8,
title = "Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin",
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.",
author = "Holland, {William L.} and Miller, {Russell A.} and Wang, {Zhao V.} and Kai Sun and Barth, {Brian M.} and Bui, {Hai H.} and Davis, {Kathryn E.} and Bikman, {Benjamin T.} and Nils Halberg and Rutkowski, {Joseph M.} and Wade, {Mark R.} and Tenorio, {Vincent M.} and Kuo, {Ming Shang} and Brozinick, {Joseph T.} and Zhang, {Bei B.} and Birnbaum, {Morris J.} and Summers, {Scott A.} and Scherer, {Philipp E.}",
note = "Funding Information: We thank members of the Scherer and Summers laboratories for comments. We would like to thank R. Kitsis for discussions regarding the generation of HEART-ATTAC mice. We thank B. Hammer and the Transgenic Core Facility at UT Southwestern for the generation of the mouse models used in this study and the Metabolic Core Facility at UT Southwestern for help with phenotyping of the mice. Lkb1−/− mice and cells were a kind gift from R. DePinho, Massachusetts General Hospital. INS-1 832/13 cells were generously provided by C. Newgard, Duke University Medical Center. We thank Ariad Pharmaceuticals for providing the dimerization kit and compound AP20187. This work was supported by US National Institutes of Health grants R01-DK55758, R01-CA112023, RC1-DK086629 and P01-DK088761 (P.E.S.); R01-DK56886 and P01-DK49210 (M.J.B.); as well as R21-DK073181 (S.A.S.). W.L.H. was supported by National Research Service Award F32-DK083866 and TL1-DK081181. J.M.R. was supported by F32-DK085935 and T32-HL007360 and K.E.D. was supported by F32-DK081279. N.H. was funded by a grant from University of Copenhagen.",
year = "2011",
month = jan,
doi = "10.1038/nm.2277",
language = "English (US)",
volume = "17",
pages = "55--63",
journal = "Nature medicine",
issn = "1078-8956",
publisher = "Nature Publishing Group",
number = "1",
}