The Pleiotropic Actions of Adiponectin are Initiated via Receptor-Mediated Activation of Ceramidase Activity

Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
Nature medicine (Impact Factor: 27.36). 01/2011; 17(1):55-63. DOI: 10.1038/nm.2277
Source: PubMed


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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Available from: Kai Sun, Oct 05, 2015
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    • "Moreover, adiponectin deficiency increased ceramide levels and exacerbated insulin resistance. Instead, activation of adiponectin receptors 1 and 2 stimulated sphingosine and sphingosine-1-phosphate synthesis, which improved insulin sensitivity and reduced metabolic inflammation (Holland et al. 2011b). "
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    Handbook of experimental pharmacology 04/2015; DOI:10.1007/164_2015_4
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    • "Therefore, inflammatory signals early after PHx likely promote increases in cellular ceramide, which have been observed after PHx (Alessenko et al, 1999). We expect this effect to be enhanced in Adn-/-mice because of the absence of Adn receptor-dependent ceramidase activity (Holland et al, 2011). Increased ceramide levels have also recently been linked to elevated levels of the tyrosine phosphatase SHP-1 (Gopalan et al, 2013). "
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    • "APN, derived from adipocytes, is a secreted hormone which was considered firstly as an important regulator of energy use and metabolism in endocrinology17. Recently, an increasing number of research papers have been involved in exploring the anti-inflammatory and anti-apoptotic properties of APN1819. Although mounting evidence has confirmed the role of APN in other organ ischemia-reperfusion injury, it is still unclear whether APN is involved in liver IRI. "
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