Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin

The protein hormone adiponectin is known to have many beneficial systemic effects, including promoting cell survival, anti-inflammation and insulin sensitivity. Phil Scherer and his colleagues have found that these pleiotropic effects are mediated by a ceramidase activity associated with the two kno...

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Vydané v:	Nature medicine Ročník 17; číslo 1; s. 55 - 63
Hlavní autori:	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
Médium:	Journal Article
Jazyk:	English
Vydavateľské údaje:	New York Nature Publishing Group US 01.01.2011 Nature Publishing Group
Predmet:	631/443/319/2723 631/45/776/1178 631/80/82/23 Adenylate Kinase - metabolism Adiponectin - deficiency Adiponectin - genetics Adiponectin - physiology Adiponectin - therapeutic use Animals Apoptosis - physiology Biomedical and Life Sciences Biomedicine Calcium-Calmodulin-Dependent Protein Kinase Kinase - metabolism Cancer Research Cellular biology Ceramidases - drug effects Ceramidases - metabolism Ceramides - metabolism Enzyme Activation Gene Expression Regulation Health aspects Humans Infectious Diseases Insulin Insulin - physiology Kinetics Leptin - deficiency Lipids Metabolic Diseases Metabolism Metabolites Mice Mice, Obese Molecular Medicine Mortality Myocardial Infarction - drug therapy Myocytes, Cardiac - physiology Neurosciences Pancreatic beta cells Physiological aspects Properties Protein hormones Receptors, Adiponectin - physiology Signal transduction Upstream United States
ISSN:	1078-8956, 1546-170X, 1546-170X
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Shrnutí:	The protein hormone adiponectin is known to have many beneficial systemic effects, including promoting cell survival, anti-inflammation and insulin sensitivity. Phil Scherer and his colleagues have found that these pleiotropic effects are mediated by a ceramidase activity associated with the two known isoforms of the adiponectin receptor. 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.
Bibliografia:	ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-1 ObjectType-Feature-2 content type line 23
ISSN:	1078-8956 1546-170X 1546-170X
DOI:	10.1038/nm.2277