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

Overview

MeSH Major

  • Ceramides
  • Glucose Intolerance
  • Sphingosine N-Acyltransferase

abstract

  • 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 date

  • January 2014

Research

keywords

  • Academic Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1016/j.cmet.2014.08.002

PubMed ID

  • 25295788

Additional Document Info

start page

  • 678

end page

  • 86

volume

  • 20

number

  • 4