Editors' ChoiceDiabetes

Adiponectin Battles Ceramides

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Science Translational Medicine  02 Feb 2011:
Vol. 3, Issue 68, pp. 68ec14
DOI: 10.1126/scitranslmed.3002198

Adiponectin is a hormone that is secreted from fat tissue and exerts a multitude of beneficial effects, including increasing insulin sensitivity, decreasing inflammation, and inhibiting apoptosis. It is also an epidemiological marker for metabolic health in humans; low adiponectin levels are commonly seen in patients with diabetes or with metabolic syndrome. Two adiponectin receptors have been identified: AdipoR1 and AdipoR2. Signaling downstream of these receptors remains poorly defined, although adenosine monophosphate–dependent kinase (AMPK) has been implicated.

Ceramides, which are composed of a sphingosine and a fatty acid, oppose many of the effects of adiponectin. The presence of ceramides correlates with impaired insulin action and insulin resistance in diabetes, lipotoxic heart failure, atherosclerosis, and increased apoptosis, suggesting an important role for ceramides in human health. Now, Holland et al. show that adiponectin receptors have ceramidase activity, which explains the contrasting effects of adiponectin and ceramides.

Inspired by the recently published finding that a yeast homologue of AdipoR, Izh2p, exhibited ceramidase activity, the authors examined the effects of adiponectin treatment on ceramide levels in a variety of genetic and diet-induced models of insulin resistance. Adiponectin treatment resulted in a decrease in ceramide levels in the liver that was accompanied by increased ceramidase activity. In vitro, a doubling of the AdipoR expression resulted in doubled ceramidase activity, which was associated with the presence of the adiponectin receptor protein. In addition, adiponectin administration improved survival in apoptosis models induced by either palmitate or a ceramide analog.

Adiponectin can signal through AMPK activity, yet the authors found that adiponectin’s ability to improve cell survival in apoptosis models occurred independently of AMPK signaling. Sphingosine, the breakdown product of ceramide, exerted adiponectin-like effects and inhibited apoptosis, which suggests that ceramidase activity, not AMPK, is central to AdipoR signaling. Thus, the often opposing effects of ceramides and adiponectin are causally linked through a surprising new twist of adiponectin receptor signaling: the breakdown of ceramides to spingosine-1-phosphate, which is a bioactive lipid with beneficial effects. This study also provides a rationale to treat with adiponectin diseases that have high amounts of ceramides.

W. L. Holland et al., Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin. Nat. Med. 17, 55–63 (2011). [Abstract]

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