Obesity-induced CerS6-dependent C16:0 ceramide production promotes weight gain and glucose intolerance

Cell Metab. 2014 Oct 7;20(4):678-86. doi: 10.1016/j.cmet.2014.08.002.


Ceramides increase during obesity and promote insulin resistance. Ceramides vary in acyl-chain lengths from C14:0 to C30:0 and are synthesized by six ceramide synthase enzymes (CerS1-6). It remains unresolved whether obesity-associated alterations of specific CerSs and their defined acyl-chain length ceramides contribute to the manifestation of metabolic diseases. Here we reveal that CERS6 mRNA expression and C16:0 ceramides are elevated in adipose tissue of obese humans, and increased CERS6 expression correlates with insulin resistance. Conversely, CerS6-deficient (CerS6(Δ/Δ)) mice exhibit reduced C16:0 ceramides and are protected from high-fat-diet-induced obesity and glucose intolerance. CerS6 deletion increases energy expenditure and improves glucose tolerance, not only in CerS6(Δ/Δ) mice, but also in brown adipose tissue- (CerS6(ΔBAT)) and liver-specific (CerS6(ΔLIVER)) CerS6 knockout mice. CerS6 deficiency increases lipid utilization in BAT and liver. These experiments highlight CerS6 inhibition as a specific approach for the treatment of obesity and type 2 diabetes mellitus, circumventing the side effects of global ceramide synthesis inhibition.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adipose Tissue, Brown / metabolism
  • Animals
  • Body Mass Index
  • Ceramides / metabolism*
  • Diet, High-Fat
  • Female
  • Glucose Intolerance*
  • Humans
  • Lipid Peroxidation
  • Liver / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Transgenic
  • Obesity / metabolism
  • Obesity / pathology
  • PPAR gamma / genetics
  • PPAR gamma / metabolism
  • Sphingosine N-Acyltransferase / deficiency
  • Sphingosine N-Acyltransferase / genetics
  • Sphingosine N-Acyltransferase / metabolism*
  • Weight Gain


  • Ceramides
  • PPAR gamma
  • Sphingosine N-Acyltransferase