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.
Selathurai, A., Kowalski, G. M., Burch, M. L., Sepulveda, P. V., Risis, S., Lee-Young, R. S., Lamon, S., Meikle, P. J.
, Genders, A. J., McGee, S. L., Watt, M. J.
, Russell, A. P., Frank, M., Jackowski, S., Febbraio, M. A.
, & Bruce, C. R. (2015). The CDP-ethanolamine pathway regulates skeletal muscle diacylglycerol content and mitochondrial biogenesis without altering insulin sensitivity
. Cell Metabolism
(5), 718 - 730. https://doi.org/10.1016/j.cmet.2015.04.001