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

• Published in: Nature medicine Vol. 17; no. 1; pp. 55 - 63
• Main 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
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.01.2011; Nature Publishing Group
• Subjects: 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
• DOI: 10.1038/nm.2277

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.