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

By William L. Holland, Russell A. Miller, Zhao V. Wang, K. Sun, Brian M. Barth, H. Bui, Kathryn E. Davis, Benjamin T. Bikman, Nils Halberg, J. Rutkowski and 8 more. Nature Medicine, 2010

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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.

Subfields: Endocrine and Autonomic Systems, Epidemiology, Physiology

View Paper: https://www.semanticscholar.org/paper/eb57b16a9e538153ab5dea029c53567fb53c84c6

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Citations in the corpus

A ceramide-centric view of insulin resistance. (2012, background): “As demonstrated in Holland et al. (2011a), recent studies revealed that ceramide is indeed an obligate intermediate linking TLR4 to the induction of insulin resistance, both in vitro and in vivo.”
3D structures of membrane proteins from genomic sequencing (2012, neutral): “In the unknown structure AdipoR1, residues with a high total coupling score include putative enzymatic residues S187, H191, D208, H337, and H341 (Holland et al., 2011; Pei et al., 2011) together with the top three high-scoring residues, C195, A235, and Q335, which cluster together (within (cid:1) 4 ”
Why Does Obesity Cause Diabetes? (2022, background): “Since the discovery in mice that adipose tissue produces proinflammatory cytokines that cause insulin resistance (Hotamisligil et al., 1993) and the finding that obesity in people is associated with an accumulation of adipose tissue macrophages (Weisberg et al., 2003), it has been proposed that…”
The multiple-hit pathogenesis of non-alcoholic fatty liver disease (NAFLD). (2016, background): “[82] Holland WL, Miller RA, Wang ZV, et al.”
Extracellular miRNAs: From Biomarkers to Mediators of Physiology and Disease (2019, neutral): “The extent to which alterations in ceramide metabolism might be linked to alterations in exosome formation and release has not been studied, but altered ceramide metabolism is found in metabolic syndrome (Holland et al., 2011; Turpin et al., 2014).”