Poster Presentation ANZOS-Breakthrough Discoveries Joint Annual Scientific Meeting 2018

Targeting skeletal muscle ceramides to alleviate glucose intolerance (#248)

Sarah Turpin-Nolan 1 2 3 , Philipp Hammerschmidt 2 3 , Weiyi Chen 2 3 , Katharina Timper 2 3 , Susanne Brodesser 2 , Jens Bruening 2 3
  1. BDI, Monash University, Clayton, Vic, Australia
  2. CECAD, Cologne, Germany
  3. MPI for Metabolism, Cologne, Germany

Skeletal muscle represents the predominant site of postprandial glucose deposition and accumulates ceramides during lipid oversupply, which contribute to the development of obesity-associated insulin resistance. Ceramides vary in acyl-chain lengths from C12:0-C30:0 which are regulated by the (dihydro)-ceramide synthases 1-6 (CerS). Both CerS5 and 6 generate C16:0 ceramide whilst CerS1 produces C18:0 ceramide. We have previously demonstrated that C16:0 ceramide contribute to diet-induced obesity and glucose intolerance in the liver and brown adipose tissue, however it was not apparent if C16:0 ceramide also promoted insulin resistance in skeletal muscle. Therefore our aim was to determine which CerSs disrupted skeletal muscle glucose homeostasis.

 

Skeletal muscle ceramide profiling of high fat diet (HFD) fed animals revealed increased C18:0, but not C16:0, ceramide. Furthermore, experiments revealed that CerS6 and CerS5/6 deletion in skeletal muscle did not prevent HFD-induced glucose intolerance.

 

Generation of HFD fed CerS1Δ/Δ and CerS1ΔSkM mice selectively reduced C18:0 ceramide without altering skeletal muscle triacylglycerol or diacylglycerol levels. The reduction of skeletal muscle C18:0 ceramide resulted in significant improvements in whole body insulin and glucose tolerance. Hyperinsulinemic-euglycaemic clamps in CerS1ΔSkM mice showed skeletal muscle C18:0 ceramide regulated skeletal muscle glucose uptake, which consequently improved hepatic glucose production.

 

Fgf21 has been demonstrated to exert glucose metabolism-regulatory functions in multiple tissues. HFD fed CerS1ΔSkM mice show increased skeletal muscle expression of Fgf-21 and increased circulating FGF-21 concentrations. Current experiments are assessing if Fgf21 is regulating skeletal muscle glucose uptake in HFD fed CerS1ΔSkM mice.

 

These results demonstrate that targeting C18:0 ceramide in skeletal muscle alleviates HFD-induced insulin resistance and glucose intolerance and demonstrates a tissue-specific function of distinct ceramide species during the development of obesity-associated insulin resistance.