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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.

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Figure 1: Adiponectin rapidly lowers hepatic ceramide content and improves glucose homeostasis.
Figure 2: Adiponectin promotes cardiomyocyte and HEART-ATTAC survival.
Figure 3: Adiponectin targets the endocrine pancreas and maintains beta cell mass.
Figure 4: Adiponectin alters sensitivity to ceramide-induced apoptosis in INS-1 beta cells.
Figure 5: Adiponectin receptors 1 and 2 confer ceramidase activity in vivo.
Figure 6: Ablating adiponectin receptors 1 and 2 impairs ceramidase activity, S1P generation and cell survival.

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Acknowledgements

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.

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W.L.H. conducted all experiments, except the portions indicated below, and contributed to the writing of the manuscript. R.A.M. conducted in vivo experiments with liver-specific Lkb1−/− mice. Z.V.W. generated all of the ATTAC mouse models used here. K.S. was responsible for the mutagenesis studies of AdipoR1 and AdipoR2. B.M.B. was involved in the studies with INS-1 cells. H.H.B., M.R.W., M.-S.K. and J.T.B. were involved in liquid chromatography–tandem mass spectrometry analysis for determination of sphingolipid content of the samples. K.E.D. assisted in the generation of the Adipor1−/−Adipor2−/− MEFs and high-fat feeding studies using adiponectin transgenic mice. B.T.B. helped in data analysis and RT-PCR of sphingolipid metabolism genes. N.H. performed the experiments with in vivo injections of adiponectin and detection of the protein in beta cells. J.M.R. was involved in designing experiments and protein production. V.M.T. performed ceramidase assays and genotyping. B.B.Z., M.J.B., S.A.S. and P.E.S. were involved in experimental design, data analysis and in the writing of the manuscript.

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Correspondence to Philipp E Scherer.

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Holland, W., Miller, R., Wang, Z. et al. Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat Med 17, 55–63 (2011). https://doi.org/10.1038/nm.2277

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