Receptor-mediated activation of ceramidase activity initiates the pleiotropic actions of adiponectin
- William L Holland 1, Russell A Miller , Zhao V Wang , Kai Sun , Brian M Barth , Hai H Bui , Kathryn E Davis , Benjamin T Bikman , Nils Halberg , Joseph M Rutkowski , Mark R Wade , Vincent M Tenorio , Ming-Shang Kuo , Joseph T Brozinick , Bei B Zhang , Morris J Birnbaum , Scott A Summers , Philipp E Scherer
- 1Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
- 0Touchstone Diabetes Center, The University of Texas Southwestern Medical Center, Dallas, Texas, USA.
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View abstract on PubMed
Summary
This summary is machine-generated.Adiponectin enhances insulin sensitivity and cell survival by stimulating ceramidase activity, boosting sphingolipid metabolism. This pathway protects against apoptosis, revealing a unified mechanism for adiponectin's beneficial effects.
Area Of Science
- Endocrinology
- Cell Biology
- Metabolic Signaling
Background
- Adiponectin, an adipocyte-secreted factor, confers insulin sensitivity, anti-inflammatory, and cell-survival benefits.
- The precise molecular mechanism underlying adiponectin's diverse systemic effects remains elusive.
- Sphingolipid metabolism is implicated in various cellular processes, including apoptosis and survival.
Purpose Of The Study
- To elucidate the unifying mechanism by which adiponectin exerts its beneficial systemic effects.
- To investigate the role of adiponectin in regulating sphingolipid metabolism, specifically ceramide and sphingosine-1-phosphate (S1P) levels.
- To determine the impact of adiponectin signaling on apoptosis in pancreatic beta cells and cardiomyocytes.
Main Methods
- Assessed adiponectin's effect on ceramidase activity associated with AdipoR1 and AdipoR2 receptors.
- Utilized models of inducible apoptosis in pancreatic beta cells and cardiomyocytes.
- Examined the consequences of adiponectin and adiponectin receptor deficiency on sphingolipid levels and cell death.
- Investigated the role of AMP-dependent kinase (AMPK) in mediating adiponectin's effects.
Main Results
- Adiponectin potently stimulates ceramidase activity, enhancing ceramide breakdown and sphingosine-1-phosphate (S1P) formation, independent of AMPK.
- Transgenic adiponectin overexpression reduced caspase-8-mediated apoptosis in pancreatic beta cells and cardiomyocytes.
- Genetic ablation of adiponectin increased in vivo apoptosis via a sphingolipid-dependent pathway.
- Loss of both adiponectin receptor isoforms impaired ceramidase activity, elevating ceramide and palmitate-induced cell death.
Conclusions
- Adiponectin's beneficial systemic effects are unified by its ability to stimulate sphingolipid metabolism via ceramidase activity.
- Adiponectin signaling enhances the formation of the anti-apoptotic metabolite sphingosine-1-phosphate (S1P).
- Sphingolipid metabolism is a core upstream signaling component mediating adiponectin's protective and insulin-sensitizing actions.
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