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Impaired de novo choline synthesis explains why phosphatidylethanolamine N-methyltransferase-deficient mice are protected from diet-induced obesity Open Access
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Jacobs, René L.
Koonen, Debby P. Y.
Peake, David A.
Proctor, Spencer D.
Kennedy, Brian P.
Dyck, Jason R. B.
Vance, Dennis E.
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Phosphatidylcholine (PC) is synthesized from choline via the CDP-choline pathway. Liver cells can also synthesize PC via the sequential methylation of phosphatidylethanolamine, catalyzed by phosphatidylethanolamine N-methyltransferase (PEMT). The current study investigates whether or not hepatic PC biosynthesis is linked to diet-induced obesity. Pemt+/+ mice fed a high fat diet for 10 weeks increased in body mass by 60% and displayed insulin resistance, whereas Pemt−/− mice did not. Compared with Pemt+/+ mice, Pemt−/− mice had increased energy expenditure and maintained normal peripheral insulin sensitivity; however, they developed hepatomegaly and steatosis. In contrast, mice with impaired biosynthesis of PC via the CDP-choline pathway in liver became obese when fed a high fat diet. We, therefore, hypothesized that insufficient choline, rather than decreased hepatic phosphatidylcholine, was responsible for the lack of weight gain in Pemt−/− mice despite the presence of 1.3 g of choline/kg high fat diet. Supplementation with an additional 2.7 g of choline (but not betaine)/kg of diet normalized energy metabolism, weight gain, and insulin resistance in high fat diet-fed Pemt−/− mice. Furthermore, Pemt+/+ mice that were fed a choline-deficient diet had increased oxygen consumption, had improved glucose tolerance, and gained less weight. Thus, de novo synthesis of choline via PEMT has a previously unappreciated role in regulating whole body energy metabolism.
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- © 2010 by The American Society for Biochemistry and Molecular Biology, Inc.
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Jacobs, R. L., Zhao, Y., Koonen, D. P. Y., Sletten, T., Su, B., Lingrell, S., Cao, G., Peake, D. A., Kuo, M. S., Proctor, S. D., Kennedy, B. P., Dyck, J. R. B., & Vance, D. E. (2010). Impaired de novo choline synthesis explains why phosphatidylethanolamine N-methyltransferase-deficient mice are protected from diet-induced obesity. Journal of Biological Chemistry, 285(29), 22403-22413. http://dx.doi.org/10.1074/jbc.M110.108514
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