Article

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: 28.05). 01/2011; 17(1):55-63. DOI: 10.1038/nm.2277
Source: PubMed

ABSTRACT 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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    • "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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    • "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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    • "So too has the role of sphingolipids such as ceramides and glucosylceramides as an important class of bioactive lipids, the accumulation of which has been implicated in a multitude of metabolic processes such as atherosclerosis, IR and diabetes [61], and as an important player in NAFLD and its progression to NASH [62]. Adiponectin is a potent stimulator of ceramidase activity and enhances ceramide catabolism [63]. Individuals with higher concentrations of adiponectin also present with lower cardiovascular risk [64] [65]. "
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