Down with Ceramide

Science Signaling  18 Jan 2011:
Vol. 4, Issue 156, pp. ec16
DOI: 10.1126/scisignal.4156ec16

Adiponectin, which is a hormone released from adipocytes, has many beneficial effects, including promotion of insulin sensitivity and cell survival and reduction of inflammation (see Lancaster and Febbraio). Holland et al. showed, in two mouse models of obesity, that treatment with recombinant adiponectin reduced hepatic ceramide content and promoted insulin sensitivity. Adenosine monophosphate–activated protein kinase (AMPK) has been proposed as downstream of adiponectin signaling; however, these effects of adiponectin in the obesity models occurred in mice lacking the kinase Lkb1, which stimulates AMPK. Hepatic ceramide content correlated with the abundance of adiponectin, with mice overexpressing adiponectin showing the lowest hepatic ceramide content and adiponectin-null mice showing the highest amount. Ceramide, which is a proapoptotic molecule and impairs insulin signaling, can be metabolized to sphingosine, which can be further modified to sphingosine 1-phosphate (S1P), an inhibitor of apoptosis and stimulator of cell proliferation. Crossing transgenic adiponectin mice, with varying amounts of adiponectin, with a mouse model of inducible cardiac cell apoptosis or a similar model of inducible beta cell apoptosis showed that adiponectin abundance correlated with cell survival and with animal survival in the cardiac model and pancreatic insulin content and glucose handling in the beta cell model. Examination of the effects of adiponectin in cell culture models of cardiac myocytes or beta cells confirmed the cell-autonomous effects of adiponectin and showed that S1P could mimic the prosurvival effects of adiponectin. Furthermore, the prosurvival effects were blocked by inhibition of sphingosine kinase and were not affected by inhibition of AMPK. The adiponectin receptors exhibit sequence similarity to ceramidases, and mutation of a conserved histidine in this region reduced the ceramidase activity associated with adiponectin stimulation (the cells natively express wild-type receptors providing some basal ceramidase activity). Mouse embryo fibroblasts lacking both isoforms of the receptor have reduced ceramidase activity, increased amounts of ceramide, and decreased amounts of S1P and were refractory to ceramide reduction in response to adiponectin. Thus, adiponectin appears to shift the lipid profile of cells from one associated with apoptosis to one associated with survival by stimulating the intrinsic ceramidase activity of its receptors.

W. L. Holland, R. A. Miller, Z. V. Wang, K. Sun, B. M. Barth, H. H. Bui, K. E. Davis, B. T. Bikman, N. Halberg, J. M. Rutkowski, M. R. Wade, V. M .Tenorio, M.-S. Kuo, J. T. Brozinick. B. B. Zhang, M. J. Birnbaum, S. A. Summers, P. E. Scherer, Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat. Med. 17, 55–63 (2011). [PubMed]

G. I. Lancaster, M. A. Febbraio, Adiponectin sphings into action. Nat. Med. 17, 37–38 (2011). [PubMed]