Oral Presentation Australian Diabetes Society and the Australian Diabetes Educators Association Annual Scientific Meeting 2014

Reducing C16:0 ceramide via ablation of CerS6, but not CerS5, protects against HFD-induced obesity and WAT inflammation (#163)

Hayley T Nicholls 1 2 , Sarah M Turpin 1 2 , Diana M Willmes 3 , Susanne Brodesser 2 , Arnaud Mourier 4 , Elaine Xu 1 2 , Jens Brüning 1 2
  1. MPI for Neurological Research, Cologne, Germany
  2. CECAD, Cologne, Germany
  3. Charité - Universitätsmedizin Berlin, Berlin, Germany
  4. Max Planck Institute for the Biology of Aging, Cologne, Germany

Ceramides are bioactive lipids that are thought to contribute to the metabolic syndrome. Ceramides are composed of an acyl CoA attached to a sphingoid backbone; this acylation is catalysed by ceramide synthase (CerS) enzymes. Each of the six mammalian CerSs (CerS1-6) preferentially generates ceramides of specific chain lengths. CerSs and ceramides with different acyl chains show different tissues distributions and functions, however it is currently unknown which ceramide chain lengths, and which CerS enzymes, contribute to metabolic disturbances under conditions of nutrient oversupply.

We show that mice with whole body deletion of CerS6 are protected from high fat diet (HFD)-induced white adipose tissue (WAT) inflammation, glucose intolerance and obesity. This coincides with a reduction of C16:0 ceramides in the WAT, brown adipose tissue and liver. Interestingly, CerS5 deficient mice also show reduced C16:0 ceramide levels in these tissues, yet are not protected from obesity or associated metabolic disturbances.

De novo synthesis ofC16:0 ceramides in macrophages has been shown to contribute to inflammasome activation, and is suggested to be a key component of the signaling networks that connect lipid oversupply to inflammatory pathways and insulin resistance. Since the WAT of CerS6 deficient mice showed reduced inflammatory macrophage infiltration, we hypothesized that ablation of CerS6 in macrophages may improve WAT metabolic inflammation, and correspondingly, insulin sensitivity.  However, neither the specific deletion of CerS6 in hematopoietic, nor myeloid derived cells, improved HFD-induced WAT inflammation or insulin sensitivity. Collectively these results indicate that (1) C16:0 ceramides specifically produced by CerS6, but not CerS5, contribute to HFD-induced obesity and glucose intolerance and (2) that the reduction in WAT inflammation in CerS6 deficient mice, appears to be driven independently from CerS6 deletion in macrophages.