The CDP-Ethanolamine Pathway Regulates Skeletal Muscle Diacylglycerol Content and Mitochondrial Biogenesis without Altering Insulin Sensitivity

Cell Metab. 2015 May 5;21(5):718-30. doi: 10.1016/j.cmet.2015.04.001.


Accumulation of diacylglycerol (DG) in muscle is thought to cause insulin resistance. DG is a precursor for phospholipids, thus phospholipid synthesis could be involved in regulating muscle DG. Little is known about the interaction between phospholipid and DG in muscle; therefore, we examined whether disrupting muscle phospholipid synthesis, specifically phosphatidylethanolamine (PtdEtn), would influence muscle DG content and insulin sensitivity. Muscle PtdEtn synthesis was disrupted by deleting CTP:phosphoethanolamine cytidylyltransferase (ECT), the rate-limiting enzyme in the CDP-ethanolamine pathway, a major route for PtdEtn production. While PtdEtn was reduced in muscle-specific ECT knockout mice, intramyocellular and membrane-associated DG was markedly increased. Importantly, however, this was not associated with insulin resistance. Unexpectedly, mitochondrial biogenesis and muscle oxidative capacity were increased in muscle-specific ECT knockout mice and were accompanied by enhanced exercise performance. These findings highlight the importance of the CDP-ethanolamine pathway in regulating muscle DG content and challenge the DG-induced insulin resistance hypothesis.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cytidine Diphosphate / analogs & derivatives*
  • Cytidine Diphosphate / metabolism
  • Diglycerides / metabolism*
  • Ethanolamines / metabolism*
  • Glucose / metabolism
  • Insulin Resistance*
  • Lipid Metabolism
  • Mice
  • Mice, Knockout
  • Muscle, Skeletal / metabolism*
  • Obesity / genetics
  • Obesity / metabolism
  • Organelle Biogenesis*
  • RNA Nucleotidyltransferases / genetics
  • RNA Nucleotidyltransferases / metabolism


  • 1,2-diacylglycerol
  • Diglycerides
  • Ethanolamines
  • CDP ethanolamine
  • Cytidine Diphosphate
  • RNA Nucleotidyltransferases
  • Ethanolamine-phosphate cytidylyltransferase
  • Glucose